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https://f1000research.com/articles/11-565/v1	24 May 22	{ "type": "Systematic Review", "title": "Assessing the role of vascular risk factors in dementia: Mendelian randomization meta-analysis and comparison with observational estimates", "authors": [ "Liam Lee", "Rosie Walker", "William Whiteley", "Rosie Walker", "William Whiteley" ], "abstract": "Background: Although observational studies demonstrate that higher levels of vascular risk factors are associated with an increased risk of dementia, these associations might be explained by confounding or other biases. Mendelian randomization (MR) uses genetic instruments to test causal relationships in observational data. We sought to determine if genetically predicted modifiable risk factors (type 2 diabetes mellitus, low density lipoprotein cholesterol, high density lipoprotein cholesterol, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, body mass index, and circulating glucose) are associated with dementia by meta-analysing published MR studies. Secondary objectives were to identify heterogeneity in effect estimates across primary MR studies and to compare meta-analysis results with observational studies. Methods: MR studies were identified by systematic search of Web of Science, OVID and Scopus. We selected primary MR studies investigating the modifiable risk factors of interest. Only one study from each cohort per risk factor was included. A quality assessment tool was developed to primarily assess the three assumptions of MR for each MR study. Data were extracted on study characteristics, exposure and outcome, effect estimates per unit increase, and measures of variation. Effect estimates were pooled to generate an overall estimate, I2 and Cochrane Q values using fixed-effect model. Results: We screened 5211 studies and included 12 primary MR studies after applying inclusion and exclusion criteria. Higher genetically predicted body mass index was associated with a higher odds of dementia (OR 1.03 [1.01, 1.05] per 5 kg/m2 increase, one study, p=0.00285). Fewer hypothesized vascular risk factors were supported by estimates from MR studies than estimates from meta-analyses of observational studies.\n\nConclusion: Genetically predicted body mass index was associated with an increase in risk of dementia.", "keywords": [ "Dementia", "Alzheimer's Disease", "Mendelian Randomization", "vascular risk factors", "meta-analysis", "systematic review" ], "content": "Introduction\n\nHigher measured mid-life blood pressure, mid-life and late-life hyperlipidaemia, mid-life obesity and diabetes are associated with the development of dementia in observational cohort studies.1 If this association is causal, risk factors for vascular diseases (e.g. diabetes and hypertension) may be responsible for around 40% of the cases of dementia worldwide.2 However, the effect sizes seen in observational cohort studies are usually larger than those seen in randomized trials of vascular risk intervention to reduce cognitive decline or dementia.3 This may be because cohort studies are limited by residual confounding, reverse causation, differential loss to follow-up, or selection biases.4,5 More data from less biased designs are needed to triangulate the causal effects of vascular risk factors on the development of dementia.\n\nMendelian randomization (MR) uses genetic variants as proxies, or instrumental variables (IVs), to estimate a causal effect of an exposure on an outcome. MR is less susceptible to confounding and reverse causation than observational studies because genetic variants are assumed to be randomly assigned at meiosis.6 As such, MR can be thought of as a “natural” randomized control trial. MR studies are subject to different biases from observational studies. Their validity rests on three key assumptions: (i) the genetic variant has a known association with the risk factor of interest; (ii) the genetic variant is not associated with a known confounder; and (iii) the genetic variant affects the outcome only through the risk factor of interest. As most genetic instrumental variables are only modestly associated with their exposures of interest, MR gives an unbiased but imprecise estimate.7 Meta-analysis of MR studies could mitigate this imprecision. This approach has previously refined estimates of the effect obesity on vascular diseases.8\n\nIn this study, we meta-analysed MR studies of the association of modifiable vascular risk factors with dementia. Secondly, we estimated the heterogeneity between estimates from different MR studies for a given risk factor that used the same outcome cohort. Thirdly, we compared our meta-analysis estimates with estimates obtained from meta-analysis of observational studies.\n\n\nMethods\n\nWe used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline to report this study.9 A protocol has been developed and made available online (Supplementary Material 3).10 Minor amendments in study methodology have been made since its publication. Specifically, 1) the quality assessment questionnaire was shortened from 11 questions to 10 questions; 2) we applied a Bonferroni correction to account for the assessment of multiple risk factors; 3) MR meta-analysis results were compared with observational studies. No ethical approval was required.\n\nWe searched on OVID, Scopus and Web of Science, covering 13 databases: Medline, Embase, AMED, PsycINFO, BIOSIS Citation Index, Web of Science core collection, Current Contents Connect, Data Citation Index, Derwent Innovations Index, KCI-Korean Journal Database, Russian Science Citation Index, SciELO Citation Index, and Zoological Record. The search looked for a combination of dementia, and Mendelian randomization (Supplementary Material 1, Table 1). No risk factors were specified in the search query. We forward searched by screening for all referenced articles in the retrieved articles using Google Scholar. The final search was performed on 22nd October 2021.\n\nWe included published or pre-print studies that used inverse-variance weighted (IVW) two-sample MR with a poly- or oligo-genetic instrument for type 2 diabetes mellitus, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, body mass index (BMI), or plasma glucose. Included studies reported a causal estimate value with an odds ratio (OR), hazard ratio (HR), risk ratio (RR) or β-coefficient by an absolute value of per unit increase, and associated 95% confidence interval (CI) or standard error. When interquartile range was reported, we estimated the standard deviation as interquartile range/1.35.11\n\nWe excluded studies that were duplicates, not written in English, or where no full text was available. We included only one estimate from each cohort per risk factor. Where more than one study had been carried out using a cohort, we included the highest quality study; where the quality of the studies was similar, we included the study with the most recent exposure GWAS. The outcomes were all cause dementia or late-onset Alzheimer’s disease (LOAD). Uncertainties were resolved by discussion with two other reviewers (WNW and RMW).\n\nA quality assessment tool was developed by synthesizing three published guidelines for assessing MR studies12–14 (Table 1). Studies that did not satisfactorily address items 3-5, which describe the three core assumptions of MR, were excluded.\n\n2SMR = 2-sample Mendelian Randomization, has independent outcome and exposure samples. 1SMR = 1-sample Mendelian Randomization.\n\nFor each study, we extracted: GWAS source, ethnicity, number of single nucleotide polymorphisms (SNPs) used as instrumental variables for each risk factor, case/control sample size, effect estimates and units, and measures of variation were extracted for each study. When multiple analysis approaches were used to generate an effect estimate, the value generated using the most SNPs without compromising pleiotropy was used (linkage disequilibrium r2 < 0.2). Effect estimates that included IVs mapping to the APOE locus, which has a known association with dementia were excluded. For studies with missing data, the authors were emailed twice and the study was excluded if no reply was received. The full details are available in Supplementary Material 2, S1 & S2.42\n\nEffect estimates and measures of variation were standardized into common units for each risk factor. The effect estimates were pooled using a fixed effects model to generate an overall estimate for each risk factor of interest. Cochrane Q and I2 statistics were used to assess heterogeneity across studies. Analyses and plots were executed with the Metafor package (version 2.4-0) in R (version 4.0.3).15 A Bonferroni correction was applied to maintain a 5% family-wise error rate, yielding a significance threshold of 0.05 divided by n risk factors assessed (p = 0.05/9).\n\nWe performed sensitivity analysis by meta-analysing using alternative eligible studies, which were excluded in our primary meta-analysis due to outcome cohort overlap or the use of a superseded exposure GWAS. We substituted the studies with IGAP (2013) as the outcome cohort, with another study with the same outcome cohort with either the lowest or highest estimate in attempt to determine any significant change in overall effect estimate. Statistical significance was determined by applying a Bonferroni correction, as described above.\n\nSearch strategy\n\nWe searched on OVID, Scopus and Web of Science for a meta-analyses of cohort studies estimating the association between vascular risk factors with later dementia (Supplementary Material 1, Table 2).\n\nStudy selection\n\nWe selected one representative meta-analysis of observational studies for each risk factor. We considered all articles in English which analysed cohorts, reported OR/HR/RR, and associated 95% confidence interval (CI) or standard error. If multiple meta-analyses were eligible for inclusion per given risk factor, we selected the study with the highest total number of participants.\n\n\nResults\n\nA search of three databases, OVID, Scopus and Web of Science, found 5211 unique articles. After applying inclusion and exclusion criteria to the abstracts, 29 articles were retained (Figure 1). Seventeen articles were not included for meta-analysis after full text review because either the results were not reported per unit increase in risk factor or there was an overlap of between outcome cohorts. Of those seventeen articles, ten studies were reserved for secondary outcome analyses to give a total of 22 articles included in this study (Supplementary Material 2, S1).\n\nArticle relevance was assessed from title and abstract. Subsequently, full text was read for confirmation or further exclusion and additional studies were identified by forward searching from selected articles.\n\nThere were three primary MR studies each for type 2 diabetes16–18 and LDL cholesterol19–21; two studies each for HDL cholesterol,19,22 total cholesterol,19,23 triglycerides,19,21 and systolic blood pressure20,24; and one study each for diastolic blood pressure,25 BMI26 and circulating glucose27 (Figure 1). The MR studies for diastolic blood pressure, BMI, and circulating glucose reported an overall estimate produced through the meta-analysis of two or more outcome cohorts. As such, the estimates from these studies were included in the present study.\n\nQuality assessment was performed on the 12 selected studies (Table 2). All studies addressed the three assumptions of MR. The MR results for each of the six vascular risk factors with more than one MR study were meta-analysed (Figure 2). BMI was significantly associated with dementia as stated in the original study by Li et al. (2021), with higher BMI increasing the odds of developing dementia (1.03 [1.01, 1.05] per 5 kg/m2 increase, p = 0.00285), and met the corrected significance threshold.\n\nYes = Reported, No = Not reported. Each question corresponds to the questions outlined in Table 1.\n\n* Ware et al. (2021) conducted a one sample MR.\n\nUKB = UK Biobank, IGAP = International Genomics of Alzheimer's Project, HRS = Health and Retirement Study, MRC-WTCCC2 = Medical Research Council (MRC)-Wellcome Trust Case Control Consortium, IOP+ = Institute of Psychiatry Plus, ADNI = Alzheimer's Disease Neuroimaging Initiative. Copenhagen Studies = Copenhagen General Population Study and the Copenhagen City Heart Study.\n\nComparison of different MR studies using the same cohort (IGAP) had similar estimates (I2 = 0%) for all risk factors, apart from for LDL-c (I2 = 65.2%) and systolic blood pressure (I2 = 25.2%) (Figure 3). The MR studies included in this analysis all fulfilled the three core assumptions of MR. Sensitivity analysis to replace MR studies using the IGAP (2013) outcome GWAS with another MR study with the most extreme values rendered the meta-analysed effect estimate for all risk factors to remain non-significant (Supplementary Material 1, Figure 1). Diastolic blood pressure, BMI and circulating glucose were excluded from sensitivity analysis because only a single study was reported for each risk factor in this study.\n\nThis figure includes studies that have not been selected in the meta-analysis and is shown to highlight the heterogeneity of results despite using the same outcome cohort. LOAD = Late onset Alzheimer’s disease; IGAP = International Genomics of Alzheimer's Project; CI = Confidence Interval.\n\nFor eight of the risk factors, we compared the effect estimate from MR studies with the effect estimate from the largest available meta-analysis of observational studies (Figure 4).28–33 One risk factor, circulating glucose, did not have an eligible meta-analysis; therefore, the primary study with largest study cohort was included as the comparator.34 The units of estimates from most meta-analyses of observational studies were not explicitly stated, so it was not possible to compare the magnitude of effect with that obtained from the meta-analysis of MR studies. There were significant associations between LDL cholesterol, diastolic blood pressure diabetes and circulating glucose with a higher risk of later dementia in observational studies, but neutral associations from studies using MR.\n\nSample size is the sum of control and case numbers.\n\n\nDiscussion\n\nWe performed a meta-analysis of MR studies assessing the effects of nine modifiable risk factors for vascular diseases on the odds of dementia. With the exception of for BMI, we did not obtain evidence for an association between genetically predicted levels of any vascular risk factor and the odds of developing dementia.\n\nFewer vascular risk factors were associated with dementia based on meta-analysed estimates from MR studies than from meta-analyses of observational studies. This may be because the estimates from cohort studies were limited by residual confounding, or by a selection bias that identified populations with particularly high risk of dementia due to vascular risk factors, or by publication bias towards reporting positive results. The MR studies may have been limited by weak genetic instruments that explained only a small percentage of the variation in the risk factors of interest. For example, in Andrews et al. (2021) and Malik et al. (2021) less than 6% of the variation in blood pressure was explained by all the SNPs identified through GWASs. Moreover, these MR studies are unable to distinguish age-dependent mechanisms. For instance, high systolic blood pressure has been linked with harmful effects during mid-life but protective effects during late-life (>75).35,36 A similar case has been made for cholesterol levels.37 There is additional uncertainty regarding the reliability of GWASs themselves in which genetic instruments were derived from. GWASs may have been underpowered, resulting in unreliable identification of IV SNPs.38 The populations included in the GWASs for exposure and outcome may differ, limiting their comparability. An attempt to mitigate this issue was, however, made by using GWAS studies that focused on populations of European descent. A further consideration is that differences in model formulation between the GWASs from which IVs are identified and observational studies has the potential to limit the comparability of the phenotype under consideration.\n\nAn exploration of the consistency between the findings of MR studies that used different exposure GWASs but the same outcome GWAS (citation) found consistency between the MR estimates for all risk factors, except for LDL cholesterol and systolic blood pressure. This may be because of differences in the SNPs used as IVs for these risk factors. Sometimes differences in the SNPs used as IVs are attributable to a decision to focus on specific pathways: for example, Benn et al. (2017) focused on PCSK9 and HMGCR variants for LDL cholesterol to tackle pathways that are therapeutically relevant based on PCSK9 inhibitors and statins.39 They reported a statistically significant causative effect of LDL-c, unlike other studies that included SNPs from other genomic regions (Figure 3). However, the choice of SNPs may also be simply due to differences in available data. For instance, Østergaard et al. (2015) obtained 24 SNPs to act as IVs for systolic blood pressure from an up-to-date GWAS at that time, while Larsson et al. (2021) obtained 93 IV SNPs from a study published in 2017. Østergaard et al. (2015) concluded that higher systolic blood pressure lowered the odds of dementia, while Larsson et al. (2021) found no significant association (Figure 3). Therefore, recognizing these differences is important when interpreting the estimates from MR studies.\n\nWe identified relatively few eligible studies. Although many potentially relevant primary MR studies were identified, many studies used data from the same source; for example, many studies of Alzheimer’s disease use IGAP (2013).40 Therefore, many otherwise eligible studies had to be excluded to ensure independence of estimates in our meta-analysis (Supplementary Material 2, S2). The limited number of eligible studies led us to pool our two outcomes of interest (Alzheimer’s disease and dementia). Although Alzheimer’s disease constitutes 60-80% of dementia cases, a significant proportion of dementia cases are associated with different diseases with distinct pathophysiology such as vascular dementia.41 Discrepancies in pathophysiology may potentially be reflected in the heterogeneity of estimates as seen in systolic blood pressure where outcomes Alzheimer’s disease and dementia were both present (I2 = 92.6%) (Figure 2).\n\nSecondly, although we meta-analysed studies with unique outcome cohorts, we did not have access to individual participant data. We were therefore unable to control any potential overlap between the cohorts.\n\nThirdly, we found heterogeneity between the MR estimates obtained using the same outcome cohort for two risk factors, systolic blood pressure and LDL cholesterol. This was in spite of key similarities in the study, such as only including population of European ancestry and using the same GWAS to derive the SNPs. The heterogeneity observed is likely to stem from differences in methods, such as discrepancy in rationale for selection of SNPs, p-value cutoff for the use of SNPs as IVs, and discrepancy in covariates when analysing exposure-outcome relationship. The exact effect these differences have on the estimate and its clinical implications remains yet to be characterized. There is a need to assess the effect of such discrepancies and the robustness of MR estimates through sensitivity analyses.\n\n\nConclusion\n\nOut of the nine vascular risk factors assessed in this study, only genetically predicted BMI showed evidence of being causally associated with dementia. Estimates from observational studies for many risk factors were significantly associated with dementia.\n\n\nData availability\n\nOpen Science Framework: Assessing the role of vascular risk factors in dementia: Mendelian randomization meta-analysis and comparison with observational estimates, https://doi.org/10.17605/OSF.IO/UA7Z6.42\n\nThis project contains the following underlying data:\n\n- Supplementary material 1. pdf (search strategy and sensitivity analysis)\n\n- Supplementary material 2. xlsx (raw data and analysis)\n\n\nReporting guidelines\n\nOpen Science Framework: PRISMA checklist for ‘Assessing the role of vascular risk factors in dementia: Mendelian randomization meta-analysis and comparison with observational estimates’, https://doi.org/10.17605/OSF.IO/UA7Z6.42\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).", "appendix": "References\n\nBaumgart M, Snyder HM, Carrillo MC, et al.: Summary of the evidence on modifiable risk factors for cognitive decline and dementia: A population-based perspective. 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Publisher Full Text" }	[ { "id": "157914", "date": "19 Jan 2023", "name": "Daniel A Nation", "expertise": [ "Reviewer Expertise Vascular factors contributing to dementia" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a meta-analysis of mendelian randomization studies and a comparison of this meta-analysis with observational study estimates, to evaluate the potential causal nature of observed associations between 9 vascular risk factors and dementia. The authors conducted a thorough search and identified 12 out of 5211 studies meeting criteria for inclusion in the analysis. Findings indicated higher genetically predicted BMI is associated with slightly higher odds of dementia. Furthermore, fewer vascular risk factors were associated with dementia in mendelian randomization studies than in observational studies. The question of a causal role for modifiable vascular risk factors for dementia is critical to efforts to treat and prevent cognitive impairment, making the topic of this article particularly important. Strengths of the present study include examination of MR which may allow for causal inference, meta-analysis of MR studies in this area which is novel, and comparison with observational studies. The methods appear to be rigorous. Unfortunately, very little can be concluded from the study due to limitations of available data within MR studies themselves and across studies. Although the authors extensively outline these limitations in excellent detail, the limits curtail the ultimate impact of this study. Nevertheless, it was well written and perhaps serves as an initial step forward or a snapshot of field as it currently stands, including the many remaining questions.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required.\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes", "responses": [] }, { "id": "307125", "date": "27 Sep 2024", "name": "Ahmet Turan Isik", "expertise": [ "Reviewer Expertise Cognitive Impairement in older adults", "NPH", "Dysautonomia in DLB" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI have reviewed the manuscript \"Assessing the role of vascular risk factors in dementia: Mendelian randomization meta-analysis and comparison with observational estimates\" with interest. The paper needs to reconsider a few flaws. The background and purpose of the study should be emphasized more clearly. The authors should explain the effects of any potential overlap between the cohorts on the results. It would be better for a statistician to recheck the results because I am not good enough at this topic. No competing interests were disclosed\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? No\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required.\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable", "responses": [ { "c_id": "13263", "date": "07 Feb 2025", "name": "Liam Lee", "role": "Author Response", "response": "Dear Dr Isik, Many thanks for your valuable feedback on our manuscript. We have carefully considered your comments and made the following changes to address them. Comment 1: The background and purpose of the study should be emphasized more clearly. We have revised the background section to provide a clearer explanation of the rationale and purpose of the study. This includes highlighting the limitations of observational studies in inferring causality and the importance of using Mendelian randomization (MR) as a complementary approach. Comment 2: The authors should explain the effects of any potential overlap between the cohorts on the results. We have added a discussion on the effects of cohort overlap in the Limitations section of the manuscript. We acknowledge that cohort overlap could lead to bias, such as inflated precision and potential under- or overestimation of effect sizes. To address this, we emphasized our sensitivity analyses by substituting alternative estimates where possible and found that the overall pooled estimates remained stable. Comment 3: It would be better for a statistician to recheck the results because I am not good enough at this topic. We would like to reassure the reviewer that one of the co-authors, Dr. Walker, is a trained epidemiologist with extensive experience in statistical methods and MR studies. Dr. Walker has validated the statistical analyses and interpretation presented in the manuscript." } ] } ]	1	https://f1000research.com/articles/11-565
https://f1000research.com/articles/13-277/v2	10 May 24	{ "type": "Research Article", "title": "Impact of yoga on the central and peripheral vascular function among desk-based workers: A single-centered trial study", "authors": [ "Poovitha Shruthi P", "Koustubh Kamath", "Vaishali K", "Shivashankar K N", "Suresh Sugumar", "Sneha Ravichandran", "Leena R David", "Peter Hogg", "Guruprasad V", "Banumathe K R", "Shovan Saha", "Rajagopal Kadavigere", "Poovitha Shruthi P", "Koustubh Kamath", "Vaishali K", "Shivashankar K N", "Sneha Ravichandran", "Leena R David", "Peter Hogg", "Guruprasad V", "Banumathe K R", "Shovan Saha" ], "abstract": "Background The aim of this study was to observe and analyze vascular function in ‘prolonged sitting’, followed by a yoga asana routine and pranayama intervention. Participants in this study include those who work from desks in offices. The study required the participants to attend on three separate days at random, and they had to finish a computerized test on each day. On the first day, participants were required to complete a computer test while sitting still for four hours (with the exception of washroom breaks). The next day, they underwent a computerized test along with a pranayama intervention. Finally, on the last day, they underwent a computerized test along with a yoga asana intervention. At the start of the study and after two and four hours, we measured the diameter and velocity of the common carotid artery (CCA) and superficial femoral artery (SFA).\n\nMethods The study was a within-subjects prospective single-center trial conducted in the Department of Radio-Diagnosis and Imaging, Kasturba Medical Hospital, Manipal, India, between September 2022 and January 2023. Participants were asked to do one of the following ‘activities’ over successive weeks: Week 1 – Prolonged sitting; Week 2 – Pranayama intervention; and Week 3 – Yoga asana intervention during prolonged sitting. The baseline and follow-up variables of pulse velocity, endothelial thickness, and shear rate were assessed for normality through a Shapiro-Wilk Test.\n\nResults Our sample included 11 participants with moderate physical activity, five with high physical activity and one with low physical activity. Yoga asana intervention comprised participants sitting continuously for four hours, with a yoga asana intervention being provided every hour, lasting for 10 minutes.\n\nConclusions Yoga asana improves vascular functions in prolonged sitting conditions. This routine can promote the concept of interrupted sitting and ways to reduce it with efficient yoga asana practice without changing the work culture and provide better physical relief.\n\nTrial registration\nClinical Trials Registry – India ( CTRI/2022/09/045628), date of registration: 19/09/2022(CTRI/2022/9/045628)https://ctri.nic.in/Clinicaltrials/main1.php?EncHid=16349.27799,", "keywords": [ "Physical Activity", "Vascular Function", "FMD", "Exercise", "Sedentary lifestyle" ], "content": "Introduction\n\nFor a growing proportion of the world’s population, the impact of the digital working era combined with a tendency to adopt an overall sedentary lifestyle has resulted in people sitting for prolonged periods of time. This can lead to low energy expenditure and lower physical activity (LPA) levels. This has many adverse effects, including early onset of metabolic diseases such as hypertension, type 2 diabetes mellitus, obesity, atherosclerosis, late-life cognitive decline, loss of alertness, and a reduced reaction time.1–8 For an adult, according to the World Health Organization (WHO), the average individual requires at least 150 min of exercise per week.9 However, meeting this demand might not be accessible due to the pressures of modern life. As a result, extended sitting has been one strategy used to assist people in adopting a variety of postural motions, mostly in office-based working contexts.1–8\n\nA root cause of the above disorders has been linked to vascular impairment; therefore, improving vascular blood flow becomes essential in minimizing the potential of developing adverse effects in later life.10 Blood vessels that are particularly affected include the superficial femoral artery (SFA) and common carotid artery (CCA).11 The seated position has a marked and negative impact on SFA blood flow, being confounded by a sedentary lifestyle and working at computers. SFA flow reduction can cause damage and acute distress12; similarly, CCA flow reduction can also have detrimental consequences.\n\nResearch has been published to investigate ways to reduce prolonged sitting and to offer interventions that can improve vascular function whilst minimizing disturbance to the working environment and work productivity.13–16 Additional problems of interventions within the working environment are related to space for physical activity and the cost of any exercise-related equipment. For the workplace, a need exists to identify even more productive, feasible, convenient, cost-limited and practical exercises that increase blood flow without negative impact and at an acceptable cost.\n\nIt is suggested that customized yoga asana, using the pranayama routine, can improve concentration and alertness.17–20 Yoga experts suggest this can improve vascular function and blood flow. However, yoga asana’s impact on CCA and SFA blood flow is unclear. Consequently, our study aimed to observe and analyse CCA and SFA blood flow in ‘prolonged sitting’, followed by a yoga asana routine and pranayama intervention.\n\n\nMethods\n\nThe study was a within-subjects prospective single-centre trial conducted in the Department of Radio-Diagnosis and Imaging, Kasturba Medical Hospital, Manipal, India, between September 2022 to January 2023. After approval from the Institutional Ethics Committee, Kasturba Medical College (KMC) and Kasturba Hospital (KH) (IEC1:108/2022) (approved on 22 July 2022) and Clinical Trial Registry of India (CTRI/2022/9/045628)https://ctri.nic.in/Clinicaltrials/main1.php?EncHid=16349.27799, with prior written informed consent, 17 participants (desk based workers) were recruited for the study. This included nine males (mean age 25, age range 24–28) and eight females, mean age 25 (age range 24–28). Flyers in campus stores and adverts in Manipal University Trading & Property helpline MUTC a facebook based group were used to recruit participants for the study, which was conducted at Kasturba Hospital in Manipal. The participants had no history of cardiovascular or metabolic disorders, the females were not menstruating, none had depression during the study period, and none were taking medication, which might alter vascular function. Self-reported physical activity was assessed using the International Physical Activity Questionnaire (IPAQ).1 The questionnaire assesses time (frequency and duration) spent on vigorous, moderate intensity, walking activities and sitting time in hours for the past seven days. Our sample included 11 participants with moderate physical activity, five with high physical activity and one with low physical activity; the IPAQ data is shown in Table 1. For this investigation, repeated measures ANOVA (parametric) or Friedman’s test (non-parametric) are used as statistical tests performed on JASP statistical software version 0.16.2 (https://jasp-stats.org/previous-versions/).\n\nOver three weeks, participants were requested to do one of the following ‘activities’ over successive weeks: Week 1 – prolonged sitting; Week 2 – pranayama intervention during prolonged sitting; and Week 3 – yoga asana intervention during prolonged sitting. Vascular function was assessed for each of the three conditions including the diameter and blood velocity of the SFA and CCA were measured at the start of the study (0), two, and four hours during sitting using a Doppler ultrasound (Philips, Epiq Elite). Ultrasound machine quality assurance test results fell within manufacturer specifications. Ultrasound was performed by a competent radiologist (see Figure 1).\n\nProlonged sitting comprised of participants sitting continuously for four hours (see Figure 2). Pranayama intervention comprised participants sitting continuously for four hours, with the pranayama intervention being provided every hour, lasting 10 minutes. The yoga asana intervention comprised participants sitting continuously for four hours, with a yoga asana intervention being provided every hour, lasting for 10 minutes.\n\nPranayama practice included Deep breathing, Nadisodhana Pranayama and Bhramari Pranayama.17–19 Yoga asana practices included Tadasana, Ardha Chakrasana, Uttana Mandukasana,20 Skandha Chakra Asana, Kati Chakrasana, Prasarita Padottanasan.\n\n\nResults\n\nThe study comprised 17 participants in the 25–35 age range. Nine males (mean age 25, age range 24–28) and eight females (mean age 25, age range 24–28) made up the participants.25 None of the participants experienced depression throughout the study period, none had a history of cardiovascular or metabolic diseases, and none were taking any medications that would affect vascular function. Additionally, none of the female participants were menstruating. The IPAQ was used to evaluate self-reported physical activity. For the previous seven days, the questionnaire measures the amount of time (frequency and duration) spent on walking activities that are vigorous or moderately intense as well as hours spent sitting down.\n\nFigure 3 illustrates how the results of the CCA reveal that the artery’s width decreases with each set of interventions. In comparison with time, the first and second hours exhibited statistical significance with a p value<0.001, whereas the third and fourth hours do not exhibit statistical significance (p value=0.020). Although the yoga asana intervention shows significance, it does not show statistical significance when compared to pranayama group and prolonged sitting (p value=0.014). Table 2 represents the data of CCA diameter at different time points.\n\n(In figure X axis represents Time, Y axis represents vascular diameter (cm).)\n\nIn addition, the yoga asana intervention did not show statistical significance when compared to the pranayama intervention and prolonged sitting (p value=0.017).\n\nIn the CCA, a reduction in velocity was observed after the pranayama and yoga asana intervention. However, when it comes to prolonged sitting, there was a decrease in velocity at the start of the study and at two hours, followed by an increase in velocity during the final hour as shown in Figure 4. With CCA velocity, neither time nor blood velocity were statistically significant. Table 3 represents the data of CCA velocity at different time points.\n\n(In figure X axis represents Time, Y axis represents velocity (m/s).)\n\nThe diameter of the SFA decreased each hour during prolonged sitting and pranayama intervention. However, during the yoga asana intervention, there was a reduction in diameter at the beginning of the study and at 2 hours, but an increase in diameter was observed in the 4th hour, shown in Figure 5. Neither time nor group showed any significance. Hence the group has not demonstrated any substantial response to any intervention. Tables 4 & 5 represents the data of SFA diameter and velocity at different time points respectively.\n\n(In figure X axis represents Time, Y axis represents diameter in cm.)\n\nIn the CCA, the shear rate increased each hour during prolonged sitting, whereas it decreased in both the pranayama and yoga asana interventions (Figure 6). All interventions showed a reduction in stress in CCA (Figure 7). However, in terms of shear and stress, neither the time nor the group showed any significant difference. Table 6 represents the data of CCA shear and stress at different time points.\n\n(In figure X axis represents Time, Y axis represents velocity (m/s).)\n\n(In figure X axis represents Time, Y axis represents velocity (m/s).)\n\n\nDiscussion\n\nOur study aimed to determine whether yoga asana affects vascular function in desk-based workers. Exercise will maintain and enhance both physical and mental health. By controlling the sympathetic nervous system and hypothalamus pituitary adrenal axis, yoga asana can improve physical and psychological health.21\n\nIn our study, yoga asana intervention improves the vascular function of the carotid and superficial femoral artery diameter. Comparing time, the first and second hours exhibited statistical significance with a p value of <0.001. Compared to the group, the yoga asana intervention showed effectiveness but no statistical significance in the carotid artery. Significance is shown in both the 0th and 2nd hours in the superficial femoral artery, with a p-value of 0.026 and 0.004*, respectively. Although they are not statistically significant. A study by Ross and Thomas (2010) found that both yoga asana and exercise significantly reduced fasting blood glucose levels at three and six months (29.48%, 27.43%; p<0.0001), with yoga asana showing better results in social and occupational functioning compared to the exercise group. The study also found that both yoga asana and exercises improved total serum cholesterol (p<0.0001) and low protein level (p=0.030).19 So, when we compare this to our study it proves that yoga asana shows significant changes.\n\nIn a study by Pearson and Smart (2017), participants underwent aerobic exercise with an intervention duration ranging from four weeks to six months, with the frequency of sessions varying from daily to two days per week, and the time of exercise sessions ranged from 10 to 60 minutes. The study concluded that aerobic exercise training significantly improved endothelial function.21 As compared to our study, the yoga asana intervention showed improvement in both carotid and superficial femoral artery diameter.\n\nA study conducted by Cortez-Cooper examined the effect of different types of intervention on cardiovascular health. The study included three groups: a strength training group, a combination group that received both strength training and aerobic exercise, and a stretching group. The results showed that the strength training and combination groups experienced significant changes in cardiovascular health markers, including carotid artery pulse pressure. The study also found that carotid artery compliance decreased slightly in the strength training and combination groups and increased in the stretching group. However, the study found no carotid-femoral pulse wave velocity changes in the strength training and combination groups. Overall, the combination of strength training and aerobic exercise may be more effective than stretching alone in improving cardiovascular health.22 When compared to our study, the yoga asana intervention gave significant changes.\n\nA study by Thosar et al. (2015) involved 12 men participating in two randomized three-hour sitting trials. The first trial was a sitting trial where the subject was seated in one position without interruption The second trial was a sit-walk trial where the subjects walked on treadmills for five minutes at two mph for 30 minutes, 1.5-hour and 2.5-hour intervals during the sitting period. The study assessed the flow mediated dilation (FMD) of the SFA at baseline, one hour, two hours, and three hours in each trial. The results showed that there was no significant decline in the sitting trial in the FMD at each hour from baseline. The mean shear rate also showed a substantial decrease in the baseline across time. The sit-walk trial, however, showed a significant difference in the FMD and mean shear rate compared to the sit trial, indicating that walking during prolonged sitting may benefit arterial health.23 As compared to our study, both CA and SFA are measured. In our study all interventions – aside from the prolonged sitting – showed a minor decrease in CA velocity over time. When the seated intervention reached the last four hours, it will rise. Compared to time, the first and second hours exhibit statistical significance with a p value of <0.001, whereas the third and fourth hours exhibit significance but do not exhibit statistical significance (p value=0.020). There is no significant difference in SFA. But in our study, yoga asana showed effectiveness in both CA and SFA.\n\nWhen people sit for lengthy periods, their CA shear increases, whereas pranayama and yoga asana interventions showed decreases in CA shear for each hour. In CA shear, both time and group will not show any significance.\n\nLong periods of sitting have been shown to reduce stress in SFA, and yoga asana and pranayama interventions have also been shown to reduce stress over time. Both time and group do not exhibit any significant differences when compared.\n\nThe study by Carter et al. (2018) recruited 15 office workers (10 male). The participants sat for hours with two minutes of light intensity treadmill walking every 30 minutes and four hours sitting with an eight-minute light intensity treadmill walking break every 120 minutes. Middle cerebral artery measures were taken, and it was found that there was no significant difference in cardiorespiratory and hemodynamic measures, but a significant main effect was observed in cerebral blood flow. Post hoc analysis revealed a greater change in middle cerebral artery (MCA) during sitting compared to walking, with a considerable reduction in MCA observed in both the sitting and walking conditions.24 Compared to our study, the diameter significantly decreases in the sitting intervention, but velocity will increase similarly in SFA diameter and velocity decreases during the sitting intervention. Compared to time, the first and second hours exhibit statistical significance with a p value of <0.001, whereas the third and fourth hours demonstrated significance but did not exhibit statistical significance (p value=0.020). The yoga asana intervention showed significance compared to pranayama and prolonged sitting, though it didn’t reach statistical significance (p-value=0.014). In contrast, the yoga asana intervention showed significance but not statistical significance when compared to the group in pranayama intervention and prolonged sitting (p value=0.017). While in CA velocity, neither time nor velocity were significant.\n\nThe yoga asana intervention demonstrated improvement in SFA diameter; however, there was no difference between time and group when compared side by side. Each hour of the intervention resulted in a drop in velocity. The time points at the study’s start (0th hour) and at the 2nd hour demonstrate significance (p-value=0.026). However, while both the 0th and 2nd hours show significance with a p-value of 0.004, they still do not reach statistical significance. The group did not demonstrate any substantial response to any intervention. Hence, it shows that yoga asana will improve vascular function.\n\n\nConclusions\n\nBased on the results, we can observe that yoga asana improved vascular functions in prolonged sitting conditions. Many organizations in India and globally are promoting the practice of yoga asana in the workplace. This routine can promote the concept of interrupted sitting and ways to reduce it with efficient yoga asana practice without changing the work culture and provide better physical relief.", "appendix": "Data availability\n\nHarvard Dataverse: Underlying data for ‘Impact of Yoga on the central and peripheral vascular function among desk-based workers’, https://doi.org/10.7910/DVN/GLGPCZ. 25\n\nHarvard Dataverse: CONSORT checklist for ‘Impact of Yoga on the central and peripheral vascular function among desk-based workers’, https://doi.org/10.7910/DVN/GLGPCZ. 25\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nMesas AE, Guallar-Castillón P, León-Muñoz LM, et al.: Obesity-related eating behaviors are associated with low physical activity and poor diet quality in Spain. J. Nutr. 2012 Jul; 142(7): 1321–1328. PubMed Abstract \| Publisher Full Text\n\nPettit-Mee RJ, Ready ST, Padilla J, et al.: Leg Fidgeting During Prolonged Sitting Improves Postprandial Glycemic Control in People with Obesity. Obesity (Silver Spring). 2021 Jul; 29(7): 1146–1154. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPaz-Krumdiek M, Rodriguez-Vélez SG, Mayta-Tristán P, et al.: Association between sitting time and obesity: A population-based study in Peru. Nutr. Diet. 2020 Apr; 77(2): 189–195. PubMed Abstract \| Publisher Full Text\n\nBiddle SJH, Edwardson CL, Gorely T, et al.: Reducing sedentary time in adults at risk of type 2 diabetes: process evaluation of the STAND (Sedentary Time ANd Diabetes) RCT. BMC Public Health. 2017 Jan; 17(1): 80. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHelmink JHM, Kremers SPJ, van Brussel-Visser FN , et al.: Sitting time and Body Mass Index in diabetics and pre-diabetics willing to participate in a lifestyle intervention. Int. J. Environ. Res. Public Health. 2011 Sep; 8(9): 3747–3758. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nDharmastuti DP, Agni AN, Widyaputri F, et al.: Associations of Physical Activity and Sedentary Behaviour with Vision-Threatening Diabetic Retinopathy in Indonesian Population with Type 2 Diabetes Mellitus: Jogjakarta Eye Diabetic Study in the Community (JOGED.COM). Ophthalmic Epidemiol. 2018 Apr; 25(2): 113–119. PubMed Abstract \| Publisher Full Text\n\nDillon K, Prapavessis H: REducing SEDENTary Behavior Among Mild to Moderate Cognitively Impaired Assisted Living Residents: A Pilot Randomized Controlled Trial (RESEDENT Study). J. Aging Phys. Act. 2020 Jun; 29(1): 27–35. PubMed Abstract \| Publisher Full Text\n\nLabonté-LeMoyne E, Jutras MA, Léger PM, et al.: Does Reducing Sedentarity With Standing Desks Hinder Cognitive Performance? Hum. Factors. 2020 Jun; 62(4): 603–612. PubMed Abstract \| Publisher Full Text\n\nOkely AD, Kontsevaya A, Ng J, et al.: WHO guidelines on physical activity and sedentary behavior. Vol. 3, Sports Medicine and Health Science. Elsevier; 2020; pp. 115–118.\n\nRajendran P, Rengarajan T, Thangavel J, et al.: The vascular endothelium and human diseases. Int. J. Biol. Sci. 2013; 9(10): 1057–1069. Publisher Full Text\n\nSvensson C, Eriksson P, Zachrisson H, et al.: High-Frequency Ultrasound of Multiple Arterial Areas Reveals Increased Intima Media Thickness, Vessel Wall Appearance, and Atherosclerotic Plaques in Systemic Lupus Erythematosus. Front. Med (Lausanne). 2020 Oct 9; 7. Publisher Full Text\n\nWest CR, AlYahya A, Laher I, et al.: Peripheral vascular function in spinal cord injury: a systematic review. Spinal Cord. 2013 Jan 27; 51(1): 10–19. PubMed Abstract \| Publisher Full Text\n\nHildebrand JS, Gapstur SM, Gaudet MM, et al.: Moderate-to-vigorous physical activity and leisure-time sitting in relation to ovarian cancer risk in a large prospective U.S. cohort. Cancer Causes Control. 2015 Nov; 26(11): 1691–1697. PubMed Abstract \| Publisher Full Text\n\nGarten RS, Hogwood AC, Weggen JB, et al.: Aerobic training status does not attenuate prolonged sitting-induced lower limb vascular dysfunction. Appl. Physiol. Nutr. Metab. 2019 Apr; 44(4): 425–433. Publisher Full Text\n\nAguirre-Betolaza AM, Mujika I, Loprinzi P, et al.: Physical activity, sedentary behavior, and sleep quality in adults with primary hypertension and obesity before and after an aerobic exercise program: Exerdiet-hta study. Life. 2020 Aug 17; 10(8): 1–13. Publisher Full Text\n\nRavichandran S, Sukumar S, Chandrasekaran B, et al.: Influence of Sedentary Behaviour Interventions on Vascular Functions and Cognitive Functions in Hypertensive Adults—A Scoping Review on Potential Mechanisms and Recommendations. Int. J. Environ. Res. Public Health. 2022 Nov 16; 19(22): 15120. Publisher Full Text\n\nMuktibodhananda S: Hatha yoga pradipika. Sri Satguru Publications; 2012.\n\nIyengar BKS: Light on the Yoga Sūtras of Patañjali.359.\n\nRoss A, Thomas S: The Health Benefits of Yoga and Exercise: A Review of Comparison Studies. J. Altern. Complement. Med. 2010 Jan; 16(1): 3–12. PubMed Abstract \| Publisher Full Text\n\nHagins M, Moore W, Rundle A: Does practicing hatha Yoga satisfy recommendations for intensity of physical activity which improves and maintains health and cardiovascular fitness? BMC Complement. Altern. Med. 2007 Nov; 7: 40. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPearson MJ, Smart NA: Aerobic Training Intensity for Improved Endothelial Function in Heart Failure Patients: A Systematic Review and Meta-Analysis. Vol. 2017, Cardiology Research and Practice. Hindawi Limited; 2017.\n\nCortez-Cooper MY, Anton MM, Devan AE, et al.: The effects of strength training on central arterial compliance in middle-aged and older adults. Eur. J. Prev. Cardiol. 2008; 15(2): 149–155.\n\nThosar SS, Bielko SL, Mather KJ, et al.: Effect of prolonged sitting and breaks in sitting time on endothelial function. Med. Sci. Sports Exerc. 2015 Apr 25; 47(4): 843–849. PubMed Abstract \| Publisher Full Text\n\nCarter SE, Draijer R, Holder SM, et al.: Regular walking breaks prevent the decline in cerebral blood flow associated with prolonged sitting. J. Appl. Physiol. 2018; 125: 790–798. PubMed Abstract \| Publisher Full Text Reference Source\n\nSukumar S: Impact of yoga on the central and peripheral vascular function among desk-based workers. Harvard Dataverse. 2023; V1. Publisher Full Text" }	[ { "id": "351086", "date": "23 Dec 2024", "name": "Mansoor Rahman", "expertise": [ "Reviewer Expertise Physical Activity", "Cerebral Palsy. Adapted Physical education", "traditional Indian games for Physical activity for individuals with neurodevelopmental disabilities." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIs the work clearly and accurately presented and does it cite the current literature? - There is mismatch in discussion references with duration of this study intervention with the existing evidences chosen to agree the study findings. Are all the source data underlying the results available to ensure full reproducibility? - Intervention procedures and descriptions were not mentioned in detail. Are the conclusions drawn adequately supported by the results? - With single session to conclude requires a strong evidences with theoretical background.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [] } ]	2	https://f1000research.com/articles/13-277
https://f1000research.com/articles/12-118/v1	01 Feb 23	{ "type": "Software Tool Article", "title": "Med-ImageTools: An open-source Python package for robust data processing pipelines and curating medical imaging data", "authors": [ "Sejin Kim", "Michal Kazmierski", "Kevin Qu", "Jacob Peoples", "Minoru Nakano", "Vishwesh Ramanathan", "Joseph Marsilla", "Mattea Welch", "Amber Simpson", "Benjamin Haibe-Kains", "Sejin Kim", "Michal Kazmierski", "Kevin Qu", "Jacob Peoples", "Minoru Nakano", "Vishwesh Ramanathan", "Joseph Marsilla", "Mattea Welch", "Amber Simpson" ], "abstract": "Background: Machine learning and AI promise to revolutionize the way we leverage medical imaging data for improving care but require large datasets to train computational models that can be implemented in clinical practice. However, processing large and complex medical imaging datasets remains an open challenge. Methods: To address this issue, we developed Med-ImageTools, a new Python open-source software package to automate data curation and processing while allowing researchers to share their data processing configurations more easily, lowering the barrier for other researchers to reproduce published works. Use cases: We have demonstrated the efficiency of Med-ImageTools across three different datasets, resulting in significantly reduced processing times. Conclusions: The AutoPipeline feature will improve the accessibility of raw clinical datasets on public archives, such as the Cancer Imaging Archive (TCIA), the largest public repository of cancer imaging, allowing machine learning researchers to process analysis-ready formats without requiring deep domain knowledge.", "keywords": [ "medical imaging", "deep learning", "open source", "data processing", "dicom", "nifti", "nnunet" ], "content": "Introduction\n\nRadiology is a powerful modality of data for clinical work — it gives clinicians the ability to see the inner workings of the human body, that cannot be seen from the outside.1 They can inspect in 2D or 3D, the anatomy surrounding the disease, enabling key information to make life-altering clinical decisions. While regular images taken on cameras or phones are stored in a variety of accessible formats, medical images are encoded in the Digital Imaging and Communications in Medicine (DICOM) standard file format.2\n\nThe DICOM standard was developed in the 1980s due to the increasing need for an interoperable standard for 3D medical images across various manufacturers.2 A key feature of DICOM is the plethora of metadata fields that store information beyond imaging data, such as patient information, clinical variables, and acquisition parameters. As modern medical practice evolved over the years, the DICOM standard has grown to accommodate more metadata fields and encompass new imaging modalities or therapy information.2 This type of data format is unsuitable for imaging analysis as the relevant voxel array must be manually accessed through DICOM hierarchy.2 Furthermore, 3D scans are acquired on a slice-by-slice basis; thus, researchers must stitch together data from multiple files to create one 3D image, adding delays caused by disk reads and consolidation processes.2\n\nSpecialties that rigorously use imaging data are heavily reliant on DICOM, one of which is radiation oncology. Images are used along every step of the clinical workflow: from deriving a precise diagnosis, to designing personalized radiation therapy plans, and delivering each radiation dose with the appropriate alignment and orientation with brief scans. While the defined standard serves as a good guideline, each manufacturer has slightly different implementations. This is especially the case for DICOM-RT (radiotherapy), a subset of modalities for communicating radiotherapy data.2 The DICOM-RT standard includes additional modalities such as RTStruct for contour data, and RTDose for radiotherapy dose maps and dose-volume histograms (DVH).2 While the broad adoption of the DICOM standard to accommodate for various use cases has allowed it to become the defacto standard for encoding, storing, and transferring of medical images, its comprehensive nature has made it difficult for researchers to navigate for the purposes of imaging projects.2\n\n\nCurrent workflows\n\nThe Cancer Imaging Archive (TCIA) (RRID:SCR_008927) is one of the largest public repositories of DICOM images available, with over 140 datasets consisting of more than 60,000 patients.3 The datasets undergo a quality assurance process to ensure the recorded clinical variables are coherent and the DICOM files are not missing any important metadata fields.3 These stringent processes and infrastructure have allowed TCIA to become one of the most comprehensive repositories for biomedical imaging datasets, inviting researchers from different fields to explore new ideas and methods on high quality datasets.3\n\nWhile the underlying data and its annotations are of clinical quality, processing the dataset for subsequent analysis requires a non-trivial amount of effort: manually reorganizing directories and matching radiation therapy structures (RTStruct), referred to as DICOM-RT contours, and radiation therapy plans (RTDose/RTPlan) to its corresponding images.4 This is partly due to the inherently complex nature of clinical datasets, as data is collected on the basis of need and iterative improvements, not structured scientific inquiries. It is also sometimes due to the lack of familiarity from machine learning (ML) and artificial intelligence (AI) researchers in handling the DICOM files for their analytical pipelines. Typical AI imaging datasets have pairwise associations of one image to a single ground-truth label.5 However, one patient in clinical datasets may have multiple RTStruct and RTDose files with one imaging acquisition, one RTStruct and RTDose with multiple images, or worst of all, multiple RTStruct and RTDose files with multiple images.6 In any of these cases, the directories are not always intuitively structured to help researchers understand which files correspond with another.\n\nOnce researchers have successfully curated the dataset into an organized structure for analysis, in order to process the raw dataset into analysis-ready format, they must choose from a variety of processing parameters, ranging from voxel spacing, RTStruct name parsing, and hounsfield unit (HU) window levels, based on the design of their analysis. While these implicit decisions for image processing are often arbitrary, they can greatly impact model training and performance, but are not transparently disclosed in publications.7 This leads to the difficulty of reproducibility of medical deep learning research, adding another deterrence to clinical adoption.\n\nFurthermore, there are a limited number of software packages that researchers can use to quickly parse DICOM-RT files into analysis-ready arrays (Table 1). Chief among those, SlicerRT,8 an extension of 3Dslicer9 (RRID:SCR_005619), an open-source DICOM visualization tool, has been widely used by the medical imaging community. Despite its broad adoption, it is not easily interfaced with Python, the most popular language for machine learning and deep learning.10 RT-Utils is a lightweight, open-source Python package designed to handle RTStruct files with relative ease and simplicity, allowing users to easily export contours into segmentation masks in arrays. However, the functionalities of RT-Utils are limited to the RTStruct modality. PlatiPy is a recent processing library and analysis toolkit for medical imaging, mainly designed for the context of radiation therapy. It features a comprehensive set of image manipulation functions such as registration and atlas-based segmentation methods, allowing researchers the flexibility to process imaging data into any format they need. However, PlatiPy does not solve the inherent complexity of clinical datasets, and researchers must spend hours reorganizing the data into a structured set of samples and labels. The current landscape of open-source medical imaging tools highlights the need for a native Python package that can parse large DICOM/DICOM-RT datasets to an analysis-ready format for ML/AI development in a consistent, reproducible workflow.\n\nRTSTRUCTs: DICOM-RT Contours; RTDOSEs: DICOM-RT Dose; CT: Computed Tomography; MRI: Magnetic Resonance Imaging; NifTI: Neuroimaging Informatics Technology Initiative; Nrrd: Nearly raw raster data; DICOM: Digital Imaging and Communications in Medicine.\n\nTo address the limitations of the current software packages used to process medical images, we developed Med-ImageTools,11 a new Python package designed to help researchers transform complex medical datasets into analysis-ready format with few lines of code. It is also focused on helping researchers develop transparent and reproducible medical image processing pipelines by addressing most of the boilerplate code required for image transformations and processing parallelization. While Med-ImageTools has many modular functions for image, contour, and dose input/output (IO) built on popular frameworks such as SimpleITK, TorchIO and PyDicom, such functionalities are redundant and available in other open-source packages as well. Our main contribution is in the development of AutoPipeline and will mainly discuss its functionalities and implementation.\n\n\nMethods\n\nAutoPipeline is the main feature of Med-ImageTools that allows users to easily process raw DICOM clinical datasets into analysis-ready Nrrd or NifTI files, which are commonly used file formats for 3D volumetric data. It is interfaced using the command line, so the user only needs to submit a single command into the terminal to execute the three core steps in the AutoPipeline process (Figure 1):\n\n1. Crawl: The crawler opens every DICOM file in the dataset, indexing important metadata, such as unique identifiers, modality information, and references to other modalities. This produces a database of every unique image and DICOM-RT modality.\n\n2. Connect: In this step, each patient’s indices of unique files of different modalities are connected to form one coherent sample. There are various heuristics the user may choose to connect samples. The default option is through DICOM metadata, as datasets derived from clinical practice are expected to have corresponding metadata that references unique identifiers of the parent image or RTPlan. Alternative heuristics allow users to deal with anomalies with corrupted or missing metadata.\n\n3. Process: All identified samples are processed according to imaging and transformation parameters defined by the user.\n\nRaw datasets are indexed by the Crawler module and automatically processed by AutoPipeline. DICOM: Digital Imaging and Communications in Medicine; RTSTRUCTs: DICOM-RT Contours; PET: Positron emission tomography. NifTI: Neuroimaging Informatics Technology Initiative; CSV: Comma-separated values.\n\nThe AutoPipeline feature can be directly interfaced once Med-ImageTools is installed. To install Med-ImageTools, the recommended method is via the PyPI package repository in a virtual environment. Running the ‘pip install med-imagetools’ command will install the latest version of Med-ImageTools and its associated dependencies. Now, whenever the user is in the virtual environment where Med-ImageTools is installed, they can directly interact with the AutoPipeline feature in the command line. The simplest way to use it is through ‘autopipeline input_directory output_directory’. This will automatically process the dataset located in ‘input_directory’ and process them at ‘output_directory’ using the default parameters. An extended tutorial of AutoPipeline and all its associated parameters are available here. At the present time, there are no minimum system requirements for Med-ImageTools as it will run regardless of number of processor cores or memory (RAM). However, if the researcher can leverage greater number of cores and RAM, it will allow the AutoPipeline to be parallelized and process the data faster.\n\nAs the crawl and process steps are computationally intensive, all steps in AutoPipeline are automatically parallelized to efficiently leverage all available computational resources. While the output of the AutoPipeline processing can result in terabytes of images, the crawl is limited to a few kilobytes of a metadata database, making it an ideal asset to share with other researchers as a detailed descriptor of a medical imaging dataset. We therefore propose to attach the crawled metadata spreadsheet to large TCIA datasets to allow Med-ImageTools users to process large datasets much faster and more efficiently. These databases are expected to save up to 1000 core-hours of crawling per dataset, accumulating over 2000 core-hours of computation saved per user. By standardizing a commonly repeated imaging processing pipeline into a single unified package, we hope to improve the reproducibility and transparency of future medical imaging research.\n\n\nUse cases\n\nWe showcase the value of the AutoPipeline implemented in Med-ImageTools v1.0.0 for processing three medical imaging datasets, namely Pancreatic-CBCT-SEG from TCIA, liver metastasis private dataset and RADCURE pending public release on TCIA, in order of complexity and sizes. In each use case, we initially describe the process.\n\n40 patients with abdominal CBCT scans and their associated contours of regions of interest and other organs, publicly available on TCIA\n\nThe Pancreatic-CT-CBCT-SEG dataset was processed twice using AutoPipeline: once from scratch, and once using the pre-crawled dataset, available on the tcia-crawls branch of Med-ImageTools. Processing from scratch, the dataset took 10.77 core-hours (10:46), whereas using a pre-crawled database allowed the processing to finish in 9.14 core-hours (9:08) (Figure 2a). The pre-crawled database reduced processing time by 1.63 core-hours, representing an 18% increase in total processing speed or 2 minutes 27 seconds per patient. The time saved from pre-crawled databases is not a substantial quantity for datasets with less than 100 patients. However, when scaled up to larger TCIA datasets such as OPC-Radiomics13 (n=606) and NLST14 (n=26254), it can save researchers 24.7 core-hours and 1072 core-hours, respectively (Figure 2b). While it may vary depending on the research infrastructure utilized, these databases can result in significant savings in billing.\n\n97 patients with abdominal CT scans and their associated contours of liver and gross tumour volumes (GTV), data access described in data availability section below.\n\nThe liver metastasis dataset was processed using the Slicer API to export a CT scan along with segmentations of the liver and GTVs for each patient. In the initial DICOM dataset, each patient had a single RTSTRUCT file along with one or more CT series, one of which was referenced by the RTSTRUCT. The first step of the process was to load the entire DICOM dataset into the Slicer DICOM database via the graphical user interface (GUI), to make the data available inside the Slicer scripting environment. Then, we wrote a script to export an initial set of candidate segmentations for the liver and GTVs for each patient, along with the referenced CT scan. This script leveraged the Slicer API to identify the CT series that was referenced by the patient’s RTSTRUCT and used an ad hoc string filtering function to identify candidate segmentations. Finally, we iteratively refined the set of exported RTSTRUCT contours on a patient-by-patient basis, based on visual checking, and physician feedback. Although this step was time-consuming, there is, at present, no substitute for manual verification to ensure data quality and correctness. On the other hand, the initial database construction and export script using the Slicer API achieved results roughly analogous to the automatic output of AutoPipeline. The export script is approximately 170 lines long and took 7.5 hours to run on the whole dataset-this script is available on our GitHub repository. In contrast, on the same 6-core machine (16GB RAM, Windows 10), AutoPipeline took only 2.3 hours with 1 command line, mainly accelerated by parallelization (Figure 2c).\n\n3,219 patients with head and neck CT scans and their associated contours of organs at risk (OAR) for radiotherapy, pending public release on TCIA.\n\nThe RADCURE dataset is a large dataset of 3,219 head and neck cancer patients and their radiotherapy planning data. The dataset was extracted from two separate treatment planning software systems, meaning the directories and DICOM metadata were structured differently. The directories from each system were restructured using general heuristics, and any abnormal cases were flagged and manually organized. We used SimpleITK and PyDicom to extract the imaging and contour data from the DICOM files, which underwent a similar iterative process as the liver metastatic dataset. The script is over 1000 lines long and takes 30-40 hours to run on the whole dataset using a single core-this script is available on our GitHub repository. AutoPipeline scales dramatically based on the number of cores available, which enables the entire dataset to be processed in 40 minutes using 32 cores, automatically managing the directories from different systems and extracting the contours (Figure 2d).\n\nOne caveat of these comparisons is that the iterative process of filtering appropriate contours, which can add weeks to months of cooperation between the researchers and the physicians, were already conducted in the original processing steps. Various data cleaning steps that require human intervention, such as sorting contour names or selecting specific subseries acquisitions, cannot be fully automated for the foreseeable future. The Med-ImageTools team aims to add features to the package that will assist researchers in these steps, such as adding a flag to visualize all unique contours without requiring code, adding subseries detection to the crawler, and publishing a set of regular expressions (regex) that can be used to automatically choose contours from prominent head and neck datasets on TCIA. Also, these comparisons do not take into account the time it takes for researchers to develop the manual processing scripts. Hence, the actual amount of time saved for the researcher may be greater than the reported times.\n\n\nDiscussion\n\nAlthough ML and AI promise to revolutionize the way we leverage medical imaging data for improving care, they require large datasets to train computational models that can be implemented in clinical practice. However, processing large and complex medical imaging datasets remains an open challenge. To address this issue, we developed Med-ImageTools, a new open-source software package to automate data curation and processing while allowing researchers to share their data processing configurations more easily, lowering the barrier for other researchers to reproduce published works. The AutoPipeline feature will improve the accessibility of raw clinical datasets on public archives, such as TCIA, allowing machine learning researchers to process analysis-ready formats without requiring deep domain knowledge.\n\nWhile our package aims to address challenges encountered across a few medical imaging labs, we acknowledge that there may be infinite other issues that may arise in DICOM datasets. This is one of the key reasons why our package is open-source for community involvement and contribution. Also, as stated previously, there are certain onerous tasks that cannot be automated and must undergo human supervision. These aspects of researcher-clinician collaboration are an inevitable part of medical imaging research and are subject to delay.\n\nNo single solution can completely solve the reproducibility crisis of medical deep learning research, due to a variety of issues ranging from ambiguous data processing techniques to stochasticity of model training. However, community-centered open-source solutions and increased clinical adherence to data standards, such as contour nomenclature,15 can incrementally improve research quality and reproducibility, and make medical deep learning research more accessible for everyone.", "appendix": "Data availability\n\nThe Pancreatic-CT-CBCT-SEG dataset is available on The Cancer Imaging Archive at: https://doi.org/10.7937/TCIA.ESHQ-4D90.\n\nThe pre-crawled Med-ImageTools database of the Pancreatic-CT-CBCT-SEG dataset is available on GitHub at: https://github.com/bhklab/med-imagetools/raw/tcia-crawls/csvs/imgtools_Pancreatic-CT-CBCT-SEG.csv.\n\nThe liver dataset was collected as part of the study titled Radiomics artificial intelligence modelling for prediction of local control for colorectal liver metastases treated with radiotherapy 16 with Institutional Review Board and informed consent. Interested individuals should contact the senior author for access to the dataset, which will be made available following standard institutional rules for IRB and HIPAA.\n\nThe RADCURE dataset is pending public release on TCIA and the article will be updated upon release. Data published on TCIA are subject to TCIA data usage policies and restrictions.\n\n\nReferences\n\nBrant WE, Helms CA: Fundamentals of Diagnostic Radiology.2012.\n\nMildenberger P, Eichelberg M, Martin E: Introduction to the DICOM standard. Eur. Radiol. 2002; 12: 920–927. PubMed Abstract \| Publisher Full Text\n\nClark K, et al.: The Cancer Imaging Archive (TCIA): maintaining and operating a public information repository. J. Digit. Imaging. 2013; 26: 1045–1057. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLaw MYY, Liu B: DICOM-RT and Its Utilization in Radiation Therapy. RadioGraphics. 2009; 29: 655–667. PubMed Abstract \| Publisher Full Text\n\nDeng J, et al.: ImageNet: A large-scale hierarchical image database.In 2009 IEEE Conference on Computer Vision and Pattern Recognition.2009; pp. 248–255. Publisher Full Text\n\nVallières M, Kay-Rivest E, et al.: Data from Head-Neck-PET-CT. The Cancer Imaging Archive. 2017. Publisher Full Text\n\nSabottke CF, Spieler BM: The Effect of Image Resolution on Deep Learning in Radiography. Radiol. Artif. Intell. 2020; 2: e190015.\n\nPinter C, Lasso A, Wang A, et al.: SlicerRT: radiation therapy research toolkit for 3D Slicer. Med. Phys. 2012; 39: 6332–6338. PubMed Abstract \| Publisher Full Text\n\nFedorov A, et al.: 3D Slicer as an image computing platform for the Quantitative Imaging Network. Magn. Reson. Imaging. 2012; 30: 1323–1341. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nYli-Heikkilä M:Data Science Languages. DSNS '19. University of Helsinki;2019.\n\nKazmierski M, Kim S, Ramanathan V, et al.: bhklab/med-imagetools: v4.4.0. Zenodo. 2022. Publisher Full Text\n\nCamp B: Pancreatic-CT-CBCT-SEG - The Cancer Imaging Archive (TCIA) Public Access - Cancer Imaging Archive Wiki.Publisher Full Text\n\nKwan JYY, et al.: Radiomic Biomarkers to Refine Risk Models for Distant Metastasis in HPV-related Oropharyngeal Carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2018; 102: 1107–1116. PubMed Abstract \| Publisher Full Text\n\nClark K: National Lung Screening Trial.Publisher Full Text\n\nMayo CS, et al.: American Association of Physicists in Medicine Task Group 263: Standardizing Nomenclatures in Radiation Oncology. Int. J. Radiat. Oncol. Biol. Phys. 2018; 100: 1057–1066. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHu R, Chen I, et al.: Radiomics artificial intelligence modelling for prediction of local control for colorectal liver metastases treated with radiotherapy. Phys. Imaging Radiat. Oncol. 2022; 24: 36–42. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCranmer K, Kreiss S: decouple software associated to arXiv:1401.0080. [Code] Zenodo. 2014. Publisher Full Text" }	[ { "id": "189015", "date": "17 Oct 2023", "name": "Rachel Sparks", "expertise": [ "Reviewer Expertise Software development", "open source software", "medical image computing" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI think the motivation and justification for why a light weight Python module to support data loading and preprocessing of radiotherapy DICOM formats was very well articulated and clear. And I applaud the authors on making such a useful tool available to the community.\nHowever, I have two major concerns that must be addressed prior to this article being acceptable for indexing.\nFirst there are no details as to the design of Med-Image-Tools this includes important information such as:\n(1) dependencies on other python packages\n(2) what functions or other tools are being leveraged within the tool and how these are arranged.\n(3) the structure of the outputs of this pipeline specifically the csv file corresponding to the 'Dataset Index', the imaging and non-imaging feature outputs. For instance for imaging data how are pre-operative scans and segmentations saved and named (is there a convention is this something the user must write)\n(4) While there is a reference to the tutorial about the processing pipeline I think a high level overview listing the possible options would be appropriate to help the reader understand what this tool can offer.\nMy other concern is related to the use cases. While lines of code is an easy metric to report it is mostly meaningless, some lines of code may be boilerplate or easy to write while others may obviously be different. It is also easy to pad or alter depending on the level of skill of the programmer. I think reporting run time is far more meaningful to your argument and I would stick to these.\nFinally, specifically, for the RADCURE dataset, it is not clear to me why you are comparing run time on a single core versus run time on a 32 core machine. I suspect the reported run time for the comparison could be significantly reduced by using a very simple parallelization which should be achievable tools available in python. I would suggest a fairer comparison for this specific example, it wont detract from the best argument you have which is there you are presenting a nice package so that other developers and researchers do not have to spend time re-writing code. Highlighting where some time savings may be gained is in some ways a secondary advantage.\nFinally, as a minor note the statement that SlicerRT is not easily interfaced with python is not a fully justified statement. One can use the python interface in Slicer to run python scripts and even run from the command prompt by called s'licer.exe --python-code'. However, I think you can modify this to make a true and equally motivated statement which is that SlicerRT requires one to install Slicer/SlicerRT and stay within the slicer ecosystem to process data. Your tool lacks such dependencies so can be a more light weight and does not require running python through another software system.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? No\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? No\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? No\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes", "responses": [ { "c_id": "11384", "date": "07 May 2024", "name": "Benjamin Haibe-Kains", "role": "Author Response", "response": "We thank Dr Sparks for her feedback regarding our manuscript titled ‘Med-ImageTools: An open-source Python package for robust data processing pipelines and curating medical imaging data’. We have added our responses to their comments here in subdivided sections of comments/questions (Q), in bold, our corresponding responses/answers (A), and any relevant sections of the manuscript as an italicized bullet point, with changes emphasized in bold. Q: I think the motivation and justification for why a light weight Python module to support data loading and preprocessing of radiotherapy DICOM formats was very well articulated and clear. And I applaud the authors on making such a useful tool available to the community. A: We thank the reviewer for their recognition of Med-ImageTools’ contribution to the medical imaging community and positively evaluating the authors’ works. Q: However, I have two major concerns that must be addressed prior to this article being acceptable for indexing. First there are no details as to the design of Med-Image-Tools this includes important information such as: (1) dependencies on other python packages A: We thank the reviewer for pointing out the need to communicate the technical dependencies of Med-ImageTools. We have updated our ‘AutoPipeline’ section as follows, to include information on how to find the list of package dependencies. Running the ‘ pip install med-imagetools’ command will install the latest version of Med-ImageTools and its associated dependencies defined by the requirements.txt file. The ‘Current workflows’ section also contains a concise description of what frameworks Med-ImageTools leverages such as follows: While Med-ImageTools has many modular functions for image, contour, and dose input/output (IO) built on popular frameworks such as SimpleITK, TorchIO and PyDicom… Q: (2) what functions or other tools are being leveraged within the tool and how these are arranged. A: We thank the reviewer for calling attention to the need to clarify how other tools/packages function within Med-ImageTools. We have added some information to our ‘AutoPipeline’ section to clarify major operations performed using external tools/packages as follows. For a granular understanding of the integration behind every external tool, we defer the reader to learn about the design choices made throughout the package and its implications by gaining a deeper understanding of the source code available through our GitHub repository. 1. Crawl: The crawler opens every DICOM file in the dataset using Pydicom, indexing important metadata, such as unique identifiers, modality information, and references to other modalities. This produces a database of every unique image and DICOM-RT modality. 3. Process: All identified samples are processed according to imaging and transformation parameters defined by the user. The user can configure parameters such as the pixel spacing in mm(s), which specific modalities to process, the number of cores they want to use for multiprocessing, and define nnU-Net specific flags as well. The images are manipulated using SimpleITK without requiring user intervention. As the crawl and process steps are computationally intensive, all steps in AutoPipeline are automatically parallelized using the joblib backend to efficiently leverage all available computational resources. Q: (3) the structure of the outputs of this pipeline specifically the csv file corresponding to the 'Dataset Index', the imaging and non-imaging feature outputs. For instance for imaging data how are pre-operative scans and segmentations saved and named (is there a convention is this something the user must write) A: We thank the reviewer for this question and for highlighting the lack of clarity of our description of AutoPipeline. The ‘Dataset Index’ is designed to be an autogenerated output of the Crawler and does not require any user interaction to be created; this is simply there to ensure convenient user experience. We have made this and other aspects of the outputs clearer by adding the following sentences to the ‘AutoPipeline’ section. Med-ImageTools also generates files that are not analysis-ready images, such as the autogenerated ‘Dataset Index’ (Figure 1), and stores them in a folder named “.imgtools” at the path of the ‘input_directory’. This is to ensure a convenient user experience and intuitive folder structure by hiding extraneous components. Q: (4) While there is a reference to the tutorial about the processing pipeline I think a high level overview listing the possible options would be appropriate to help the reader understand what this tool can offer. A: We agree with the reviewer that adding this information to our description of AutoPipeline can help readers quickly understand the tool’s strengths before interfacing with the GitHub repository or ReadTheDocs. We have updated the ‘AutoPipeline’ section accordingly. 3. Process: All identified samples are processed according to imaging and transformation parameters defined by the user. The user can configure parameters such as: the pixel spacing in mm(s), which specific modalities to process, the number of cores they want to use for multiprocessing, and define nnU-Net specific flags as well. The images are manipulated using SimpleITK without requiring user intervention. Q: My other concern is related to the use cases. While lines of code is an easy metric to report it is mostly meaningless, some lines of code may be boilerplate or easy to write while others may obviously be different. It is also easy to pad or alter depending on the level of skill of the programmer. I think reporting run time is far more meaningful to your argument and I would stick to these. A: We appreciate the reviewer’s consideration in the metrics reported in Figure 2. However, we believe this metric emphasizes Med-ImageTools’ strength allowing users to process DICOM datasets with a single command line interaction, in contrast to writing dozens of lines of Python/R/MATLAB scripts. One particular reason why we believe a single command line is useful to highlight is to express the ease-of-use for users that may not be comfortable writing their own code for DICOM to NifTI/Nrrd processing, especially if they lack deep domain knowledge. Another, perhaps more, exciting reason is to show the potential of building automated workflows on top of Med-ImageTools. If one were to build an end-to-end automated pipeline starting from clinical DICOM datasets to outputting an inference-ready deep learning model, they could easily develop a reproducible processing step by configuring only the command line interaction of Med-ImageTools, making debugging and custom configurations simpler since the developer would not have to rely on a static script. We have elaborated on Med-ImageTools’ contributions for improved scientific reproducibility in the ‘Discussion’ section as follows. The AutoPipeline feature will improve the accessibility of raw clinical datasets on public archives, such as TCIA, allowing machine learning researchers to process analysis-ready formats without requiring deep domain knowledge. Another exciting potential of Med-ImageTools lies in building automated workflows using AutoPipeline. For a researcher to build an end-to-end automated pipeline starting from clinical DICOM datasets to outputting an inference-ready deep learning model, they could easily develop a reproducible processing step by configuring only the command line interaction of Med-ImageTools, making debugging and custom configurations simpler since the developer would not have to rely on a static script. No single solution can completely solve the reproducibility crisis of medical deep learning research, due to a variety of issues ranging from ambiguous data processing techniques to stochasticity of model training. However, community-centered open-source solutions and increased clinical adherence to data standards, such as contour nomenclature,15 can incrementally improve research quality and reproducibility, and make medical deep learning research more accessible for everyone. Q: Finally, specifically, for the RADCURE dataset, it is not clear to me why you are comparing run time on a single core versus run time on a 32 core machine. I suspect the reported run time for the comparison could be significantly reduced by using a very simple parallelization which should be achievable tools available in python. I would suggest a fairer comparison for this specific example, it wont detract from the best argument you have which is there you are presenting a nice package so that other developers and researchers do not have to spend time re-writing code. Highlighting where some time savings may be gained is in some ways a secondary advantage. A: We thank the reviewer for their comment about Figure 2d. The goal of the comparison was not only to show a reduction in processing time based on parallelization, but to show that our package’s design does not bottleneck any multiprocessing backends and brings meaningful acceleration on large datasets. In other words, we wanted to show that a 32x increase in computational hardware was going to bring at least 32x improvement in performance as observed in Figure 2d. This is in contrast to Figure 2c which does not show similar levels hardware acceleration, but its usefulness in parsing private, unseen data. We have expanded on these ideas in the manuscript as follows: In contrast, on the same 6-core machine (16GB RAM, Windows 10), AutoPipeline took only 2.3 hours with 1 command line, mainly accelerated by parallelization ( Figure 2c). The authors involved in validating Med-ImageTools' effectiveness on this private dataset had no active involvement in the development of the package before its application. This highlights the package’s robustness on unseen data and its potential utility for multi-centre collaborations to ensure consistent processing. One use case might be to enable federated learning platforms to automatically process each node’s datasets without requiring any user intervention. AutoPipeline scales dramatically based on the number of cores available, which enables the entire dataset to be processed in 40 minutes using 32 cores, automatically managing the directories from different systems and extracting the contours ( Figure 2d). These results demonstrate Med-ImageTools' design does not bottleneck any multiprocessing backends and brings meaningful acceleration on very large datasets, such as RADCURE. Q: Finally, as a minor note the statement that SlicerRT is not easily interfaced with python is not a fully justified statement. One can use the python interface in Slicer to run python scripts and even run from the command prompt by called s'licer.exe --python-code'. However, I think you can modify this to make a true and equally motivated statement which is that SlicerRT requires one to install Slicer/SlicerRT and stay within the slicer ecosystem to process data. Your tool lacks such dependencies so can be a more light weight and does not require running python through another software system. A: We thank the reviewer for this point. We have revised the relevant section from ‘Current Workflows’ as follows to better justify our statement. Despite its broad adoption, batch data processing with Slicer requires custom scripting in Python, to be executed in the Slicer ecosystem. Rather than simply installing a package within their Python environment, users must install the Slicer application and add any other dependencies, not provided by Slicer, into the application environment. As a result, machine learning projects relying on Python for data preprocessing will have their code fragmented across multiple environments–the Slicer environment for data processing, and another Python environment for data analysis and machine learning." } ] }, { "id": "189038", "date": "17 Oct 2023", "name": "Johann Faouzi", "expertise": [ "Reviewer Expertise Open source software", "Python programming", "machine learning", "medical applications" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors present their Python package for data processing pipelines and curating medical imaging data in this manuscript. Overall the manuscript is well written and clearly presents the main contributions of this package to the community. Nonetheless, some points on the software side could be improved. Please find my comments below:\n* How does the output format used compare to other formats such as other popular formats such as BIDS (Brain Imaging Data Structure, which is maybe less general since it's intended for brain imaging data)?\n* Figure 2b (and the corresponding text): Raw saved running time, even though useful, is irrelevant without knowing the total running time. Please provide also the saved time as a percentage of the total running time.\n* Figures 2c and 2d: \"1 lines\" => \"1 line\"\n* The authors should consider renaming the \"master\" branch as the \"main\" branch (see https://sfconservancy.org/news/2020/jun/23/gitbranchname/).\n* Is there a reason for Python 3.8 not being tested in the continuous integration (CI) (maybe a limit on the number of jobs)? By the way, Python 3.7 is no longer supported and Python 3.11 has been released for over 9 months (https://devguide.python.org/versions/). The Python versions tested in the CI should probably be updated.\n* Flake8 is installed in the CI but never used. I ran the command locally (flake8 \| wc -l) and obtained 2163 errors or warnings, which is not good. It would be nice to clean the source code a bit.\n* There is no code coverage associated to the tests, which is an important limitation. Please add code coverage to your project. There are \"only\" 16 tests for the moment, so I suspect that a substantial part of the source code is not tested.\n* I don't understand the point of using the \"-s\" option with pytest. I don't find the output (when using this option) to be clear or useful to identify tests that would fail for instance. In particular, I don't think that printing stuff when running the tests in the CI is relevant.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes", "responses": [ { "c_id": "11385", "date": "07 May 2024", "name": "Benjamin Haibe-Kains", "role": "Author Response", "response": "We thank Dr Faouzi for his feedback regarding our manuscript titled ‘Med-ImageTools: An open-source Python package for robust data processing pipelines and curating medical imaging data’. We have added our responses to their comments here in subdivided sections of comments/questions (Q), in bold, our corresponding responses/answers (A), and any relevant sections of the manuscript as an italicized bullet point, with changes emphasized in bold. Q: The authors present their Python package for data processing pipelines and curating medical imaging data in this manuscript. Overall the manuscript is well written and clearly presents the main contributions of this package to the community. Nonetheless, some points on the software side could be improved. Please find my comments below: A: We thank the reviewer for their positive understanding of the authors’ work and constructive feedback, especially on the technical aspects of the package. Q: How does the output format used compare to other formats such as other popular formats such as BIDS (Brain Imaging Data Structure, which is maybe less general since it's intended for brain imaging data)? A: We thank the reviewer for bringing the BIDS standard to the authors’ attention. The BIDS standard is very effective in standardizing brain imaging datasets by adhering to an intuitive structure describing various modalities of brain MRI. Med-ImageTools is mainly geared towards use cases that are broader and less specific than BIDS and its implementation would require fundamental reworkings of the package. However, the benefit of having a BIDS-native output cannot be understated and this feature will be added to the development team’s ongoing development goals. We have revised the relevant section from ‘Current Workflows’ as follows: While Med-ImageTools has many modular functions for image, contour, and dose input/output (IO) built on popular frameworks such as SimpleITK, TorchIO and PyDicom, such functionalities are redundant and available in other open-source packages as well. We have tailored our core features towards broader use cases and development workflows, instead of modality or disease type specific workflows, such as BIDS. Our main contribution is in the development of AutoPipeline and will mainly discuss its functionalities and implementation. Q: Figure 2b (and the corresponding text): Raw saved running time, even though useful, is irrelevant without knowing the total running time. Please provide also the saved time as a percentage of the total running time. A: We appreciate the reviewer’s point about Figure 2b. However, the reported time saved is reported in core-hours, which is a comprehensive unit of total running time. This is because the crawling occurred independently from the end-to-end processing of the datasets to ensure an accurate measure of core-hours saved. Reporting core-hours saved allows the reader to estimate their time/cost savings based on their specific hardware availabilities, either local machine, server-based, or cloud infrastructure, agnOSTIC to the hardware used by the authors. We have emphasIZED this point in our manuscRIPT as fOLLOWS: However, when scaled up to larger TCIA datasets such as OPC-Radiomics 13 (n=606) and NLST 14 (n=26254), it can save researchers 24.7 core-hours and 1072 core-hours, respectively (Figure 2b). The resources saved are reported in core-hours to allow a hardware-agnostic estimation of time and cost savings. While it may vary depending on the research infrastructure utilized, these databases can result in significant savings in billing. Q: Figures 2c and 2d: \"1 lines\" => \"1 line\" Q: The authors should consider renaming the \"master\" branch as the \"main\" branch (see https://sfconservancy.org/news/2020/jun/23/gitbranchname/). Q: Is there a reason for Python 3.8 not being tested in the continuous integration (CI) (maybe a limit on the number of jobs)? By the way, Python 3.7 is no longer supported and Python 3.11 has been released for over 9 months (https://devguide.python.org/versions/). The Python versions tested in the CI should probably be updated. A: We thank the reviewer for their comments. The figures and repository have been updated to address these points. Q: Flake8 is installed in the CI but never used. I ran the command locally (flake8 \| wc -l) and obtained 2163 errors or warnings, which is not good. It would be nice to clean the source code a bit. A: We thank the reviewer for raising the concern about the source code’s sanitation. The authors have reviewed the flake8 output and incorporated it into our codebase. You can find all changes in the following commit: https://github.com/bhklab/med-imagetools/commit/a8c0c3be53b4c9b43da12603b222d261d417a18c. Q: I don't understand the point of using the \"-s\" option with pytest. I don't find the output (when using this option) to be clear or useful to identify tests that would fail for instance. In particular, I don't think that printing stuff when running the tests in the CI is relevant. A: We thank the reviewer’s attention to detail in Med-ImageTools’ CI/CD framework. The -s option is enabled for verbose outputs from Med-ImageTools to be carried through to the standard output of the tests in CI. In the past we have had OS-specific issues that were elucidated through the -s flag, but have removed it for future releases. Q: There is no code coverage associated to the tests, which is an important limitation. Please add code coverage to your project. There are \"only\" 16 tests for the moment, so I suspect that a substantial part of the source code is not tested. A: We thank the reviewer for highlighting the lack of code coverage association of these tests. We agree that this is a clear limitation of the Med-ImageTools’ development pipeline, and have significantly increased the number of unit tests and integrated them into our CI/CD process. Future development efforts will continue to add more tests to our pipeline, including a badge detailing code coverage on our README." } ] } ]	1	https://f1000research.com/articles/12-118
https://f1000research.com/articles/13-1238/v1	16 Oct 24	{ "type": "Research Article", "title": "Do more pregnancies increase the risk of periodontal disease?", "authors": [ "M. Helmi", "Eman AlJoghaiman", "M. Helmi" ], "abstract": "Background Hormonal changes in pregnancy and their induced effect on periodontal health are well documented. The present study is aimed at the potential repercussions of multiple pregnancies on periodontal health.\n\nMaterials and methods Our study utilized data from key sections of the NHANES. All the pertaining and relevant data for the study is collected. Our exposure variable was the number of pregnancies, and the outcome variable was periodontal disease. The number of pregnancies is classified as one, two, three, four, or more. Age, gender, race/ethnicity, education, poverty/income ratio, marital status, and other variables. Multiple logistic regression models were employed to assess the impact of multiple pregnancies on periodontal disease.\n\nResult The crude and multiple logistic regression analyses revealed that none of the variables were significantly associated with the prevalence of periodontitis. In univariate analysis, patients with one or two pregnancies had higher odds of experiencing periodontitis (OR 1.154, 95% CI 0.748-1.779), (OR 1.464, 95% CI 0.864-2.483) respectively. However, these associations did not reach statistical significance.\n\nConclusion Within the limitation of the study, there is no significant relationship between parity and the prevalence of periodontitis, the longitudinal study may be warranted to delve deeper into any potential associations.", "keywords": [ "Parity", "Multiple Pregnancy", "Periodontal Disease", "NHANES" ], "content": "Introduction\n\nPeriodontal diseases are influenced by a variety of factors.1 This prevalent oral condition is initiated by the accumulation of dental biofilm and is further exacerbated by various local and systemic elements.2 Notably, hormonal factors play a significant role in impacting periodontal health.3 Fluctuations in progesterone and estrogen levels during different life stages, including puberty, pregnancy, and menopause, have been identified as contributors to adverse effects on periodontal health.4 The hormonal influence leads to gingival changes that worsen pre-existing dental biofilm-induced gingivitis. Moreover, the absence of estrogen, without the presence of dental biofilm, can result in desquamative changes in the gingiva, representing the other end of the hormonal spectrum.5\n\nDuring the transitional phases between puberty and menopause, the nine-month duration of pregnancy introduces alterations to periodontal health, manifesting as both localized and generalized changes in the gingiva. Localized changes are characterized by the presence of a pregnancy tumor, while generalized changes manifest as an overall enlargement of the gingiva.6 This period is associated with heightened inflammation of the gingival tissues, commonly known as pregnancy gingivitis. Symptoms include redness, tenderness, and swelling of the gingiva, accompanied by spontaneous bleeding or bleeding during routine activities such as tooth brushing or eating.7 Typically commencing in the second month of pregnancy, these changes can peak in severity during the third trimester.8\n\nThe pathogenesis of altered periodontal health during pregnancy involves a combination of factors.4 A key aspect is the rise in levels of hormones such as oestradiol, oestriol, and notably, progesterone. These hormones play a central role in modifying the host immune-inflammatory response to oral bacteria. Specifically, Prevotella intermedia, a Bacteroides species thriving on estrogen and progesterone, experiences a significant increase during pregnancy, serving as a primary bacterial factor.9\n\nFurthermore, these hormones exhibit specific receptors on gingival fibroblasts and epithelial cells, influencing gingival changes. Additionally, they act on endothelial cells, increasing vascular permeability and contributing to the overall alterations observed in the gingiva during pregnancy.10 This intricate interplay underscores the multifaceted nature of periodontal health dynamics in the context of pregnancy.\n\nProgesterone emerges as the key hormone driving these changes, yet estrogen also plays a significant role in inducing vascular changes.11 Simultaneously, deficiencies in host inflammatory cells, particularly in neutrophil chemotaxis, contribute to the adverse aspects of periodontal health. Significantly, vitamin D deficiency is a prevalent concern in the pregnant population, as highlighted in various publications.12 The role of vitamin D in periodontitis is well-documented.\n\nThe susceptibility to oxidative stress increases during pregnancy due to heightened metabolic demands and increased tissue oxygen requirements, a factor strongly implicated in the inflammatory process.13 Additionally, the presence of gestational diabetes may further disrupt host defense mechanisms, altering the delicate balance between health and disease.14 The intricate interplay of these hormonal, nutritional, and metabolic factors underscores the complexity of periodontal health dynamics during pregnancy.\n\nWhile numerous studies have delved into the connection between pregnancy and periodontal disease, there is a scarcity of research exploring the impact of multiple pregnancies on the increased risk of periodontal issues.15,16 Given the tissue changes occurring with each pregnancy and the cumulative effect of repeated exposure in subsequent pregnancies, there is a hypothetical expectation of a deteriorating impact on periodontal health.4 Therefore, understanding the potential repercussions of multiple pregnancies on periodontal health holds significant importance for both expectant mothers and healthcare professionals.\n\nBy acknowledging this potential correlation, healthcare providers can underscore the importance of maintaining good oral hygiene practices and seeking appropriate dental care during pregnancy to mitigate any possible risks. In this context, an effort has been made to investigate the relationship between multiple pregnancies and periodontal health. This exploration aims to enhance our comprehension of potential risks and preventive measures associated with periodontal disease in individuals experiencing multiple pregnancies. Such knowledge can serve as a guide for healthcare professionals, enabling them to offer pertinent advice, facilitate early detection, and provide timely interventions to support optimal periodontal health outcomes in pregnant women.\n\n\nMethods\n\nThe National Health and Nutrition Examination Survey (NHANES) is a comprehensive, cross-sectional survey conducted in the United States, aiming to provide a nationally representative overview of non-institutionalized individuals living in households. Participants in this survey undergo a series of assessments, including the completion of a questionnaire, medical and dental examinations, and various laboratory tests. The protocols for collecting oral health data in the NHANES 2011–2012 and NHANES 2013–2014 cycles were approved by the Centres for Disease Control and Prevention National Centre for Health Statistics Research Ethics Review Board. Written informed consent was secured from all survey participants.\n\nOur study utilized data from key sections of the NHANES, including demographic information, examination results, questionnaire responses, and limited access data. The focus was on individuals aged 18 years and older who underwent a dental examination, with exclusion criteria in place to remove edentulous subjects from our analysis, we ensure a thorough and targeted evaluation of oral health within a diverse and nationally representative sample of the U.S. population.\n\nExposure variable\n\nNumber of pregnancies\n\nOutcome variable\n\nPeriodontal disease\n\nFor this investigation, we used the NHANES complete periodontal examination data to calculate periodontal disease indices using Eke et al. definition of periodontal disease17). According to this definition, periodontal disease was classified as follows: Severe periodontitis: ≥2 interproximal sites with loss of attachment (LOA) ≥6 mm (not on the same tooth) and ≥1 interproximal site with probing depth (PD) ≥5 mm; Moderate periodontitis: ≥2 interproximal sites with LOA ≥4 mm (not on same tooth), or ≥2 interproximal sites with PD ≥5 mm (not on same tooth); Mild periodontitis: ≥2 interproximal sites with LOA ≥3 mm, and ≥2 interproximal sites with PD ≥4 mm (not on same tooth) or one site with PD ≥5 mm and finally, no periodontitis group whose has no evidence of mild, moderate, or severe periodontitis.18\n\nCovariate variable\n\nTo ensure a comprehensive examination and control for any factors that might influence the outcome, our analysis includes a range of covariates. These covariates serve the crucial purpose of minimizing the impact of potential confounders, allowing us to scrutinize the relationship between the exposure and outcome with greater precision. The diverse set of covariates comprises age, gender, race/ethnicity, education, poverty/income ratio, marital status, occupation, smoking habits, alcohol consumption, dental insurance coverage, dental visit frequency, and body mass index (BMI). Age is categorized into six groups: (18-30), (31-40), (41-50), (51-60), and over 60 years. Gender is identified as either female or male. Race and ethnicity are classified as non-Hispanic White, non-Hispanic Black, Mexican American and other Hispanic, and non-Hispanic Asian. Poverty indices are categorized into low, middle, and high. Marital status is delineated as yes or no. Occupation is categorized as working and non-working. Dental visits are categorized as regular and not regular. Dental insurance coverage is classified as yes or no. Smoking status is divided into never, former, and current smokers. Alcohol consumption is classified as alcohol drinker and non-alcohol drinker. The number of pregnancies is classified as one, two, three, four, or more. Lastly, education level is categorized as less than high school, high school, and college graduate or above. By meticulously examining and accounting for these covariates, we aim to obtain results that are closer to the true relationship between the exposure and outcome, free from the confounding effects of other variables.\n\nThe data were obtained by consolidating demographic, health questionnaire, clinical examination, and limited access data from NHANES (2011–2012) with corresponding files from NHANES (2013–2014). To ensure unbiased point estimates and accurate variance estimation, considering the complex sampling design of NHANES, we applied proper sampling weights and utilized a licensed version of SAS survey procedures, following the recommendations of the National Centre for Health Statistics and the Centres for Disease Control and Prevention.\n\nAn analysis of the demographics and disease status of the study population was conducted using the Rao-Scott chi-squared test. Additionally, both simple and multiple logistic regression models were employed to assess the impact of multiple pregnancies on periodontal disease. The multiple regression model included age, sex, race, income, and education level as explanatory variables. The selection of these potential confounders was based on either current literature evidence or their association with insurance and dental care utilization variables observed in bivariate analysis. The significance level was set at p ≤ 0.05, ensuring a rigorous evaluation of the relationships within the study.\n\n\nResults\n\nTable 1 presents the demographic characteristics of the study subjects, including weighted percentages. Among the 2128 subjects, more than one-quarter were aged over 60 years [insert specific age], 42.9% identified as non-Hispanic white, 34.6% had a high household level, and over half had either an associate or college degree. The majority of subjects had some form of health insurance and had visited the dentist within the 12 months preceding the survey.\n\na Weighted row percentages.\n\nThe subjects were categorized based on the severity of periodontitis, dividing them into groups of no, mild, moderate, and severe periodontitis (refer to Tables 2 and 3). The prevalence of periodontitis exhibited a significant difference primarily based on the subjects’ age. Subjects in older age brackets were consistently more likely to have some form of periodontitis compared to their younger counterparts. Additionally, the prevalence of periodontitis on average was higher among pregnant subjects compared to those who were not pregnant.\n\na Weighted row percentages.\n\n* By Rao-Scott chi-square test.\n\na Weighted row percentages.\n\nIn Table 4, approximately 9.4% of subjects with health insurance and 9.2% of subjects without health insurance exhibited some form of periodontitis. Analyzing periodontitis concerning the time elapsed since the last dental visit, we observed that 11% of subjects who had a dental visit within 12 months prior to the survey had periodontitis. For those with a dental visit more than 12 months but less than 24 months prior, 8.5% had periodontitis, and 9.8% of those with their most recent dental visit more than 2 years before the survey had periodontitis.\n\na Weighted row percentages.\n\nBoth crude and multiple logistic regression analyses revealed that none of the variables were significantly associated with the prevalence of periodontitis. In univariate analysis, patients with one and two pregnancies had higher odds of experiencing periodontitis (OR 1.464, 95% CI 0.864-2.483), (OR 1.154, 95% CI 0.748-1.779) respectively. However, these associations did not reach statistical significance (p > 0.05). Patients with dental visits in the 1-2 year range had greater odds (OR 1.129, 95% CI 0.772-1.651) of having periodontitis, but this association was not statistically significant (p > 0.05) (see Table 5).\n\n\nDiscussion\n\nThe primary aim of this study is to investigate the association between multiple pregnancies and the severity of periodontal disease/periodontitis. According to the study results, there was no discernible difference in the prevalence of periodontitis between individuals with single pregnancies and those with multiple pregnancies. However, it was noted that the prevalence of periodontitis was higher in pregnant individuals compared to non-pregnant ones. The study findings also indicated that patients with two pregnancies had higher odds of experiencing periodontitis than those with only one pregnancy, although this difference did not reach statistical significance. Both unadjusted and adjusted odds ratios for the number of pregnancies suggested higher odds of periodontitis during pregnancy.\n\nThe findings of the current study align with earlier reported research.19,20 Previous studies indicated higher gingival index and periodontal probing depth among women with prior pregnancies compared to primigravida. However, after adjusting for factors such as age, socio-economic status, education, and other associated risk factors, no correlation was identified. Nevertheless, some studies have demonstrated a significant association between increased gingival scores and periodontal probing depth in women with multiple pregnancies compared to those with a single pregnancy.21 Additionally, research has shown heightened gingival inflammation and increased periodontal probing depth during pregnancy.22–24\n\nPiscoya et al. conducted a study exploring various factors, including the number of pregnancies and the prevalence of periodontitis. Their findings, organized in a hierarchy, revealed that schooling, family income, smoking, body mass index, and bacterial plaque were associated with the prevalence of periodontitis, but not with multiple pregnancies.20 Another study concluded that, in addition to other factors, pregnant women with two or more previous births [multigravidae] exhibited significantly higher gingival index and periodontal probing depth scores compared to those with one previous birth. However, the increased gingival index and periodontal probing depth in multigravidae might be attributed to untreated gingival or periodontal disease from the first pregnancy persisting during subsequent pregnancies. Furthermore, factors such as low socio-economic status and lower educational levels could contribute to negligence of oral hygiene, leading to an increased prevalence of periodontitis.21\n\nThe variations in study findings may be attributed to several factors. Multiparous women typically tend to be older than prima gravida women, leading to a longer cumulative exposure to etiological agents of disease. Additionally, the absence of treatment during or between pregnancies results in untreated periodontal disease persisting into subsequent pregnancies.21 Multiparous women, especially those with young children, may prioritize other systemic health conditions, diverting attention, time, energy, and finances away from personal dental care. This tendency can result in neglected oral care, increased plaque accumulation, and a higher prevalence of gingival conditions.19\n\nTherefore, the observed higher gingival index and probing depth in multiparous women may be more related to sociodemographic backgrounds than to a true association with parity. It is widely recognized that existing periodontal disease is exacerbated during pregnancy, and pregnancy itself does not directly cause gingival or periodontal disease. Pregnancy-associated physiological changes can superimpose gingival inflammation on pre-existing dental plaque accumulation. If oral health is well-maintained with the absence of gingival inflammation before pregnancy, the condition of pregnancy itself may not induce gingivitis or periodontitis. Notably, existing studies have not taken into account pre-pregnancy gingival inflammation and treatment for the periodontal condition, which could influence the study outcomes.20\n\nHormonal alterations during pregnancy contribute to an increase in specific periodontal pathogens, such as Prevotella intermedia, which utilizes elevated hormone levels as a nutrient. Physiological microvascular changes observed in pregnancy, coupled with exposure to altered dental biofilm, may exacerbate pre-existing gingival conditions. The surge in estrogen levels, particularly progesterone, reaches a 20-fold increase, leading to changes in vascular permeability that cause gingival swelling and elevated crevicular fluid levels.25 The heightened production of prostaglandins, in addition to the vascular burden, may intensify gingival inflammation, result in the loss of keratinization of gingival epithelium, and foster fibroblast proliferation. Furthermore, the altered host response is characterized by decreased chemotaxis and phagocytic capacity of neutrophils, along with the down-regulation of IL-6 production. This exposes the gingival tissue to microbial attack, resulting in increased gingival inflammation.26\n\nGestational diabetes compounds the detrimental effects on host immunity, fostering the proliferation of pathogenic microflora and increasing the risk of periodontal disease.25 Repeated exposure to these events during multiple pregnancies is anticipated to lead to heightened periodontal destruction. However, it has been observed that postpartum, there is a substantial decrease in gingival inflammation, and gingival health is often restored to the pre-pregnancy state.27 Furthermore, the experiences of gingival disease during previous pregnancies may prompt individuals to undergo periodontal treatment, contributing to the restoration of gingival health.28 This could explain the absence of a significant difference in periodontitis among individuals with one pregnancy and those with multiple pregnancies in the present study.\n\nThere are several limitations to our study. Notably, the exacerbation of existing periodontal conditions during pregnancy is a well-known phenomenon. Unfortunately, our study lacked data on the status of gingival inflammation before pregnancy, which could have influenced the study outcomes. Additionally, being a retrospective cross-sectional study, our investigation relied on data from a study not specifically designed to address our hypothesis, potentially introducing clinical variations in the disease process. The utilization of dental care after the first pregnancy was not explored, and if a significant number of individuals underwent periodontal treatment after the initial pregnancy and before subsequent pregnancies, it might impact the outcomes. While a standardized protocol was followed for the diagnosis of periodontal disease, there remains a possibility of misclassification, albeit likely to be non-differential. Periodontal status was assessed only at the baseline survey, and changes over follow-up were not considered. It is conceivable that individuals initially free of periodontal disease might develop the condition later, potentially leading to an underestimation of the association for those groups. To address these limitations, future studies should aim for larger longitudinal prospective designs to validate the findings from this initial study.\n\nWhile the study did not identify a difference in the prevalence of periodontitis between single and multiple pregnancies, the findings hold significance on two fronts. Firstly, the data were obtained from a substantial sample size, highlighting increased gingival and periodontal changes during pregnancy. This underscores the need to educate all women about these findings, aiming to prevent periodontal changes during pregnancy that may impact their regular daily routines. Secondly, as periodontal disease is deemed a risk factor for pregnancy outcomes, its control assumes prime importance. Addressing and managing periodontal health becomes crucial in optimizing pregnancy outcomes.\n\n\nConclusion\n\nIn summary, this study has explored the relationship between parity and the prevalence of periodontitis, revealing no significant association between the prevalence of periodontitis and the number of pregnancies. However, a longitudinal study may be warranted to delve deeper into any potential associations.\n\n\nAuthors’ contributions\n\nBoth Authors contributed equally from the idea to the preparing the draft and both authors reviewed and prepared the final draft of the study.\n\n\nEthics and consent\n\nThe protocols for collecting oral health data in the NHANES 2011–2012 and NHANES 2013–2014 cycles received approval from the Centres for Disease Control and Prevention National Centre for Health Statistics Research Ethics Review Board. All survey participants provided written informed consent before publishing their information.\n\nhttps://www.cdc.gov/nchs/nhanes/irba98.htm", "appendix": "Data availability\n\nFigshare: Do more pregnancies increase the risk of periodontal disease?, https://doi.org/10.6084/m9.figshare.25662546 29\n\nThe project contains the following underlying data:\n\n• Demographical Characteristics (e.g., gender, income, BMI …), Periodontal Disease status, Pregnancy status, and dental visits.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAlJehani YA: Risk factors of periodontal disease: review of the literature. Int. J. Dent. 2014; 2014: 1–9. Publisher Full Text\n\nKinane DF, Stathopoulou PG, Papapanou PN: Periodontal diseases. Nat. Rev. Dis. Primers. 2017; 3: 17038. Publisher Full Text\n\nSteinberg BJ, Hilton IV, Iida H, et al.: Oral health and dental care during pregnancy. Dent. Clin. N. 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PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAhnoux A, Aoussi EL, Anongba DS, et al.: Pregnancy and periodontal health. Study of 133 pregnant women. Odontostomatol. Trop. 2003; 26(102): 37–40. PubMed Abstract\n\nMoore S, Ide M, Wilson RF, et al.: Periodontal health of London women during early pregnancy. Br. Dent. J. 2001; 191(10): 570–573. PubMed Abstract \| Publisher Full Text\n\nEke PI, Page RC, Wei L, et al.: Update of the case definitions for population-based surveillance of periodontitis. J. Periodontol. 2012; 83(12): 1449–1454. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAljoghaiman E, Helmi H: Do more pregnancies increase the risk of periodontal disease?2023.\n\nMachuca G, Khoshfeiz O, Lacalle JR, et al.: The influence of general health and socio-cultural variables on the periodontal condition of pregnant women. J. Periodontol. 1999; 70(7): 779–785. PubMed Abstract \| Publisher Full Text\n\nde Vasconcellos Piscoya MDB , de Alencar Ximenes RA , da Silva GM , et al.: Periodontitis-associated risk factors in pregnant women. Clinics. 2012; 67(1): 27–33. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nTaani D, Habashneh R, Hammad M, et al.: The periodontal status of pregnant women and its relationship with socio-demographic and clinical variables. J. Oral Rehabil. 2003; 30(4): 440–445. PubMed Abstract \| Publisher Full Text\n\nMasoni S, Panattoni E, Rolla P, et al.: Stomatological problems related to pregnancy. A statistical study. Minerva Stomatol. 1991; 40(12): 791–796. PubMed Abstract\n\nRaber-Durlacher J, Van Steenbergen T, Van der Velden U, et al.: Experimental gingivitis during pregnancy and post-partum: clinical, endocrinological, and microbiological aspects. J. Clin. Periodontol. 1994; 21(8): 549–558. PubMed Abstract \| Publisher Full Text\n\nAbraham-Inpijn L, Polsacheva O, Raber-Durlacher J: The significance of endocrine factors and microorganisms in the development of gingivitis in pregnant women. Stomatologiia. 1996; 75(3): 15–18. PubMed Abstract\n\nBendek MJ, Canedo-Marroquín G, Realini O, et al.: Periodontitis and gestational diabetes mellitus: a potential inflammatory vicious cycle. Int. J. Mol. Sci. 2021; 22(21): 11831. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nRaju K, Berens L: Periodontology and pregnancy: An overview of biomedical and epidemiological evidence. Periodontol. 2021; 87(1): 132–142. PubMed Abstract \| Publisher Full Text\n\nGonzalez-Jaranay M, Téllez L, Roa-López A, et al.: Periodontal status during pregnancy and postpartum. PLoS One. 2017; 12(5): e0178234. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nVilla A, Abati S, Pileri P, et al.: Oral health and oral diseases in pregnancy: a multicentre survey of Italian postpartum women. Aust. Dent. J. 2013; 58(2): 224–229. PubMed Abstract \| Publisher Full Text\n\nAljoghaiman E: The Relationship Between Mental Health and Periodontal Disease: Insights from NHANES Data. [Dataset]. figshare. 2024. Publisher Full Text" }	[ { "id": "332865", "date": "04 Nov 2024", "name": "Dr. Talal Shihayb", "expertise": [ "Reviewer Expertise Periodontitis-systemic diseases", "oral epidemiology", "advanced methods", "meta-research in oral health" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors assessed the effects of number of pregnancies on periodontitis. Studying pregnancy outcomes in relation to oral health is crucial. However, I have some comments on the paper:\nIntroduction No comments.\nMethods Can the authors explain why they only selected the 2011-2012 and 2013-2014 cycles of NHANES?\nThe authors excluded edentulous participants from their study. Dealing with edentulous patients is tricky and not straight forward. If the reason for being edentulous was due to periodontal disease, the perhaps edentulous participants may be considered as the most severe form of periodontitis (since the authors are studying prevalent periodontitis and not incident periodontitis). Given that the authors are studying the accumulated exposure of pregnancy on periodontal disease, the results could be different had edentulous participants due to periodontal disease been included in the analysis, I suggest the authors add edentulous as a separate category or at least justify/discuss excluding edentulous participants from the study in the methods/discussion section.\nIf by edentulous participants, the authors meant without any teeth, then any person with 1 tooth is automatically classified as mild periodontitis or no periodontitis and cannot be classified as moderate or severe. However, all included participants should have the chance to be in group of periodontitis, which is unfortunately prevented including participants with just 1 tooth. The authors perhaps may have already included those with at least 2 permanent teeth and if so, should make this clear. If not, then inclusion of participants with at least 2 teeth (if authors are still excluding edentulous participants) in the study or at least discussion of the impact of this aspect on the result is important.\nThe authors defined the exposure as the number of pregnancies. Did the authors include all pregnancies whether completed or not? Providing more details on this aspect would make the paper more clear. Furthermore, the authors used it as a categorical variable instead of a continuous exposure. Unfortunately, this results in loss of information. I suggest the authors add this to the discussion section.\nThe authors have defined the outcome of chronic periodontitis according to CDC/AAP. I suggest replacing the word periodontal disease with chronic periodontitis in the manuscript as the term periodontal disease is an umbrella term that includes multiple conditions.\nI suggest adding more details on how smoking and alcohol were classified or at least cite their webpages if the authors classified them as NHANES originally did.\nThe authors wrote the following under statistical analysis: “To ensure unbiased point estimates and accurate variance estimation, considering the complex sampling design of NHANES, we applied proper sampling weights and utilized a licensed version of SAS survey procedures, following the recommendations of the National Centre for Health Statistics and the Centres for Disease Control and Prevention.” I think using clustering variables to correctly estimate standard errors should be added as both sampling weights and clustering are need to correctly estimate point estimates and standard errors, respectively.\nThe authors have pointed out the covariates that they included in their study and mentioned the following under statistical analysis: “The multiple regression model included age, sex, race, income, and education level as explanatory variables. The selection of these potential confounders was based on either current literature evidence or their association with insurance and dental care utilization variables observed in bivariate analysis. The significance level was set at p ≤ 0.05, ensuring a rigorous evaluation of the relationships within the study.” Determining how the confounding variables were selected is very crucial in order to estimate the causal effect of multiple pregnancies on chronic periodontitis. In this study, the authors rightly determined age, sex, race, income, and education level as confounding variables based on previous knowledge and literature. However, the following on insurance and dental visit was not clear: “their association with insurance and dental care utilization variables observed in bivariate analysis.” Furthermore, assessing associations or confounding variables based on p-values should be avoided (please check [1],[2])\nAs a point related to the one above and based on the criteria the authors went with for determining confounding variables, unfortunately, smoking and diabetes (well-known confounding variables) were left out of the multivariable logistic regression model. Therefore, residual confounding exists in the result. I suggest adding them to the model or at least discuss how the residual confounding of these would impact the odds ratio of number of pregnancies on periodontitis.\nResults The authors did not elaborate on any missing data. Authors should show the frequency and % of missing data for each variables. In addition, authors should describe how they dealt with any missing data in their analysis and discuss its implications on the results.\nThe authors mentioned that they have included the following covariates: “age, gender, race/ethnicity, education, poverty/income ratio, marital status, occupation, smoking habits, alcohol consumption, dental insurance coverage, dental visit frequency, and body mass index (BMI)” Although marital, status and occupation were mentioned in table 4, they along with smoking habits were not mentioned in table 1. Smoking habits was not even mentioned in any table. Authors should add these.\nIn table 5, patients wrote: “Patients with dental visits in the 1-2 year range had greater odds (OR 1.129, 95% CI 0.772-1.651) of having periodontitis, but this association was not statistically significant (p > 0.05) (see Table 5).” The odds ratios of the confounding variables are of no interest to the authors in the study as they are do not correctly estimate their causal effect. This phenomena is well-known as Table 2 fallacy (3). Kindly just report the odds ratios of main variable of interest (number of pregnancies) and remove the other from text or table.\nPlease round the odds of pregnancy on periodontitis to 2 digits as 3 digits adds nothing and just complicates reading the results.\nI suggest removing displaying/discussing the results in text as significant or non-significant and instead focus on the point estimates as well as their precision (please check [1]and[2])\nDiscussion and conclusion The authors wrote in the limitations: “Additionally, being a retrospective cross-sectional study, our investigation relied on data from a study not specifically designed to address our hypothesis, potentially introducing clinical variations in the disease process.” The word retrospective should be removed as this was a cross-sectional study.\nAuthors should further discuss the impact of no-temporality, pregnancy misclassification likelihood and effect, missing data, and leaving out important confounding variables.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "13245", "date": "03 Feb 2025", "name": "Eman AlJoghaiman", "role": "Author Response", "response": "Dear Reviewer, Thank you for your insightful review and valuable suggestions to enhance our manuscript. We have carefully revised the manuscript and highlighted the changes accordingly. We sincerely appreciate your time and thoughtful feedback. Best regards," } ] }, { "id": "343703", "date": "26 Dec 2024", "name": "Nancy Ajwa", "expertise": [ "Reviewer Expertise Public Health", "Periodontology", "Orthodontology", "Dentistry" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe current structure provides a good foundation for the research paper. I have a few minor comments on the paper, which I am splitting in the headings so that authors can easily identify and improve the respective sections. Introduction: -Consider moving some of the detailed descriptions of the hormonal mechanism to later paragraphs for better flow. -Add a brief sentence early in the introduction highlighting why studying multiple pregnancies (versus single pregnancy) is particularly important -Consider mentioning any geographical or population-specific gaps in current knowledge that this study helps address Methods: -Clarify the definition of pregnancy exposure (whether it includes completed pregnancies only or all pregnancies) -Add information about how missing data was handled in the analysis Results: -Round the odds ratios to 2 decimal places instead of 3 for better readability -Include smoking status data in Table 1, as it's an important variable that was mentioned in the methods but not shown in the results Discussion: -Add a brief discussion of the limitations of using pregnancy as a categorical rather than continuous variable -Include a short paragraph acknowledging the potential impact of excluding edentulous participants on the study findings\nThese modifications would improve the manuscript while maintaining its overall scientific merit and indexing. The core findings and conclusions remain sound, and these suggested changes are minor in nature.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13244", "date": "06 Feb 2025", "name": "Eman AlJoghaiman", "role": "Author Response", "response": "Dear Reviewer, Thank you for your insightful review and valuable suggestions to enhance our manuscript. We have carefully revised the manuscript and highlighted the changes accordingly. We sincerely appreciate your time and thoughtful feedback. Best regards," } ] } ]	1	https://f1000research.com/articles/13-1238
https://f1000research.com/articles/13-951/v1	22 Aug 24	{ "type": "Study Protocol", "title": "The effect of surface treatments on the bond strength of polyetheretherketone posts: a systematic review protocol", "authors": [ "Hanen Boukhris", "Aymen Ben Hadj Khalifa", "Hayet Hajjami", "Souha Boudegga Ben Youssef", "Aymen Ben Hadj Khalifa", "Hayet Hajjami", "Souha Boudegga Ben Youssef" ], "abstract": "Abstract*\nBackground Polyetheretherketone (PEEK) is widely used in the biomedical field due to its outstanding biological and mechanical properties. Originally employed as a temporary abutment in implantology, recent research has expanded its indications for more definitive applications, such as frameworks and dental post and core. This shift requires a thorough assessment of PEEK’s adhesion and mechanical characteristics. However, PEEK’s inert properties and intricate chemistry create difficulties in surface treatment, resulting in reduced surface energy and inadequate adhesion. Inducing specific physical and chemical changes aims to overcome these challenges and enhance adhesion for PEEK. Despite its numerous clinical trials, standardized protocols remain lacking. This systematic review aims to assess the impact of surface treatments on the bonding performance of PEEK posts.\n\nMethods A detailed search of the literature will be conducted across several databases including PubMed, Scopus and clinical trial registries. Additional databases such as Cochrane Central, EMBASE, Web of Science and EBSCO will also be included. The search strategy will target controlled randomized studies and non-randomized clinical trials evaluating the impact of surface treatments on PEEK post adhesion strength. The Newcastle-Ottawa Scale (NOS) will be used to assess bias in non-randomized studies, while the Cochrane Risk of Bias (ROB II) tool will be employed for evaluating randomized controlled trials. Data extraction will focus on study design, treatment methods, outcomes and results. This systematic review protocol will adhere to the guidelines for systematic reviews outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).\n\nDiscussion The discussion will explore the implications of findings on clinical practice, highlighting the importance of enhancing PEEK’s bioactivity and surface energy to improve bonding efficacy in dental procedures. Moreover, it will suggest areas for future research to advance dental materials science, aiming to optimize the utilization of PEEK in dental applications\n\nSystematic review registration PROSPERO: CRD42024529783 (Registered on 08/04/2024).", "keywords": [ "Polyetheretherketone (PEEK)", "Posts", "Surface treatments", "Bond strength", "Systematic review" ], "content": "Introduction\n\nEndodontically treated teeth (ETT) with over 50% loss of coronal structure are prone to shear forces during chewing and often necessitate post-and-core placement. Posts are employed to secure the core material, enhancing the stability and retention of the final restoration.1,2\n\nThe growing demand for aesthetic improvements in dental treatments has led to the widespread use of prefabricated fiber posts. These posts offer advantages like uniform stress distribution, biocompatibility, and ease of handling, making them preferable over metal posts for restoring endodontically treated teeth. However, they can cause mechanical stress at the restoration margin and fail to strengthen the tooth structure.\n\nDespite their lower elasticity modulus compared to metal posts, fiber posts still exhibit significantly greater stiffness than dentin. Fiber post and core buildup materials can fail due to several mechanisms, such as cracking of the resin matrix, fracture of the fibers, and detachment at the interface.\n\nA novel material with both low Young’s modulus and satisfactory aesthetics has emerged. Thermoplastic polymer Polyetheretherketone (PEEK) has excellent properties. It has a Young’s modulus (3-4 GPa) lower than that of dentin which helps reduce stress on both restorations and teeth. These qualities make PEEK suitable for various dental applications including post and core systems.3–6\n\nHowever, the achievement of adhesion between PEEK and resin materials is challenging due to its low surface energy and resistant surface modification. Various treatments including chemical and micromechanical methods are recommended to improve the bonding of composite resin to PEEK posts.7–14\n\nThe goal of this systematic review is to assess how effectively PEEK posts perform with various surface treatments. This is crucial for dental professionals as it provides valuable information for developing dependable bonding protocols for PEEK posts and cores.\n\n\nProtocol\n\nThis protocol outlines the process for conducting a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.15,16 The methodology from the F1000 journal will be followed to ensure accuracy and consistency at every step. The review protocol is registered in PROSPERO (CRD42024531175) since April 8, 2024.\n\nPrimary objective: To evaluate the effectiveness of various surface treatments in the improvement of bonding strength for Polyetheretherketone (PEEK) posts.\n\nSecondary objectives:\n\n- To provide evidence-based recommendations for clinicians in the choice of surface treatments for PEEK posts during bonding procedures.\n\n- To identify gaps in the literature and to propose possible suggestions for further research.\n\nThe inclusion criteria are structured according to the PICOS model. This model is designed to specify the key components of the research question.\n\nThe research question for this systematic review is: What is the effect of various surface treatments on retention and bond strength of polyetheretherketone (PEEK) posts used in dental restoration compared to untreated PEEK posts?\n\n• Types of participants: This systematic review will focus on patients requiring dental restoration with polyetheretherketone (PEEK) posts. Eligible participants must be free from medical conditions affecting bone healing, avoid parafunctional habits such as bruxism and have no occlusal problems.\n\n• Intervention types: This systematic review will explore PEEK (Polyetheretherketone) use in dental posts. Patients will receive interventions involving surface treatments like etching with 98% sulfuric acid and sandblasting with 50 μm alumina oxide (Al2O3).\n\n• Types of outcomes: This systematic review will focus on evaluating PEEK posts in dental restorations with different surface treatments before bonding. Key outcomes include retention rate, fracture resistance compared to traditional posts, and marginal adaptation quality. It will also assess bond strength between PEEK posts and dental materials, post-operative sensitivity, restoration longevity and clinical success rate overall.\n\n• Measures of effect: This systematic review will measure effects using quantitative and qualitative assessments. Quantitative measures include statistical analysis of retention rates, fracture resistance, bond strength and restoration longevity.\n\nQualitative measures involve evaluating marginal adaptation quality, post-operative sensitivity and clinical success rates through observational data and patient-reported outcomes. Meta-analytical techniques may be used to synthesize findings across studies for comparison.\n\n• Study types: Included articles will mainly include randomized controlled trials and prospective or retrospective cohort studies. These studies specifically investigate the use of polyetheretherketone (PEEK) posts in dental restorations, focusing on surface treatments. They are chosen for their substantial data and rigorous methodology to meet the research objectives effectively.\n\nExcluded articles will cover case reports, case series, abstracts, discussions, interviews, editorials, and opinion pieces, along with research that does not center on PEEK posts or surface treatments. Additionally, studies lacking adequate data or methodology will be omitted to ensure the review’s reliability and relevance.\n\nA combination of keywords and precise subject headings relevant to the topic will be employed in the refined search strategy, ensuring a comprehensive exploration of pertinent literature. In addition to MEDLINE, databases such as Web of Science, EBSCO, Scopus, Cochrane Central and EMBASE will be meticulously searched to reduce the likelihood of missing relevant studies.\n\nTo achieve comprehensiveness, attempts will be made to locate grey literature and active clinical trials through sources such as dissertations, conference proceedings and clinical trial registries. The expert panel will offer guidance in identifying grey literature sources and evaluating their pertinence to the review.17\n\nFurthermore, reference lists of included studies will be systematically examined as part of the search strategy to identify supplementary articles not retrieved solely through electronic databases.\n\nThis approach aims to reduce publication bias and ensure a thorough review of the available evidence.\n\nFor this systematic review, the study selection process will involve a comprehensive search across all identified databases. Two independent reviewers will screen titles and abstracts to exclude irrelevant studies. Full-text articles of potentially eligible studies will be assessed using predefined inclusion criteria. These criteria will focus on studies that evaluate surface treatments of PEEK in dental post applications.\n\nReviewers will check article reference lists for additional relevant studies. Articles meeting inclusion criteria will proceed to data extraction.\n\nDuring screening, any discrepancies among reviewers will be resolved through discussion. If needed, an additional reviewer (HH) will be consulted to ensure accuracy and consensus.\n\nTo guarantee the reliability of the findings, the methodological quality and risk of bias of the included studies will be evaluated using standardized tools.18\n\nFor randomized controlled trials, the Cochrane Risk of Bias (ROB II) tool will be utilized to assess methodological rigor across key domains: randomization procedures, adherence to intended interventions, completeness of outcome data, outcome measurement and accuracy in reporting results. Each domain will be categorized as having low, high or unclear risk of bias.19\n\nThe quality assessment of non-randomized studies will be conducted using the Newcastle-Ottawa Scale (NOS) which evaluates them based on three main criteria: the selection of study participants, group comparability and outcome ascertainment. Each study will be scored on these criteria with higher scores indicating better methodological quality.20\n\nTwo independent reviewers will conduct the assessments to minimize bias and enhance reliability. Any discrepancies in the assessments will be resolved through discussion or by consulting an additional reviewer (HH) to reach a consensus.\n\nMethodological rigor and assessment of bias will ensure that the review’s conclusions are based on high-quality evidence.\n\nData items: The following details will be extracted from the selected studies: participant demographics, specifics of the interventions, outcome measures, study characteristics (publication year, author, study design …) and results pertaining to bond strength and surface characteristics.\n\nExtraction method: A standardized data extraction form will be created in a Microsoft Excel sheet to systematically capture relevant data from each included study.\n\nData extraction will be conducted by two reviewers working autonomously to ensure consistent and precise handling of the information.\n\nDiscussion will be initiated to resolve any discrepancies, and if needed, input will be sought from a third reviewer (HH).\n\nThis structured approach will guarantee thorough and dependable data extraction for subsequent analysis.\n\nThe extracted data will be rigorously analyzed and synthesized to assess the effectiveness of surface treatments for PEEK in dental post materials. Initial descriptive analysis will summarize study details, participant characteristics, intervention particulars and outcome measures such as bond strength and surface characteristics. Quantitative synthesis, including meta-analysis where feasible, will calculate effect sizes with 95% confidence intervals and assess heterogeneity across studies using statistical tests such as Tau-squared, Cochran’s Q test and I-squared, systematically categorized to understand the range of variability.\n\nSubgroup analyses will explore variations in treatment methods and material types. Sensitivity analyses will test result robustness, and qualitative synthesis will offer a narrative summary where quantitative synthesis is not possible. Findings will be interpreted in the context of clinical relevance, discussing methodological strengths and limitations while proposing directions for future research in optimizing PEEK’s performance in dental applications. Forest plot will be used to depict the results, providing a concise visualization of aggregated study effects.21\n\n\nDiscussion\n\nThe outcomes of this systematic review will be highly relevant for practitioners focused on aesthetic and digital dentistry, especially in the management of damaged teeth. By evaluating the efficacy of surface treatments for polyetheretherketone (PEEK) in dental post materials, this review aims to provide evidence-based guidance on enhancing bond strength and surface characteristics critical for durable dental restorations. The findings are anticipated to inform clinical decision-making, facilitating the selection of optimal surface treatment strategies to improve the longevity and aesthetic outcomes of PEEK-based restorations. Moreover, this review will identify areas where current research is lacking and propose avenues for future investigation, aiming to advance the field of dental materials science and enhance patient care in aesthetic and functional dental rehabilitation.\n\nNo ethical approval is needed for this systematic survey. The authors intend to present the findings at target conferences and publish the research findings in a peer-reviewed journal adopting open science practices.\n\nThis systematic review is currently in the data analysis process. The protocol of this systematic review was submitted to PROSPERO registry on 8th April, 2024 (CRD42024529783).", "appendix": "Data availability\n\nNo data are associated with this article.\n\nFigshare: PRISMA-P checklist for The Effect of Surface Treatments on the Bond Strength of Polyetheretherketone Posts: A Systematic Review protocol, https://doi.org/10.6084/m9.figshare.25771182.v1. 22\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nMezied MS, Alhazmi AK, Alhamad GM, et al.: Endocrowns Versus Post-core Retained Crowns as a Restoration of Root Canal Treated Molars - A Review Article. J. Pharm. Bioallied Sci. 2022 Jul; 14(Suppl 1): S39–S42. PubMed Abstract \| Publisher Full Text\n\nÖzyürek T, et al.: Fracture strength of endodontically treated teeth restored with different fiber post and core systems. Odontology. 2020; 108: 588–595. PubMed Abstract \| Publisher Full Text\n\nArcila L, de Carvalho RN , Bottino M, et al.: Indications, materials and properties of 3D printing in dentistry: a literature overview. ResSocDev. 2020; 9(11). Publisher Full Text\n\nKessler A, Hickel R, Reymus M: 3D printing in dentistry-state of the art. Oper. Dent. 2020; 45(01): 30–40. PubMed Abstract \| Publisher Full Text\n\nAlsadon O, Wood D, Patrick D, et al.: Fatigue behavior and damage modes of high performance poly-ether-ketone-ketone PEKK bilayered crowns. J. Mech. Behav. Biomed. Mater. 2020; 110: 103957. PubMed Abstract \| Publisher Full Text\n\nBae SY, Park JY, Jeong ID, et al.: Three-dimensional analysis of marginal and internal fit of copings fabricated with polyetherketoneketone (PEKK) and zirconia. J. Prosthodont. Res. 2017; 61(02): 106–112. PubMed Abstract \| Publisher Full Text\n\nLee KS, Shin MS, Lee JY, et al.: Shear bond strength of composite resin to high performance polymer PEKK according to surface treatments and bonding materials. J. Adv. Prosthodont. 2017; 9(05): 350–357. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAglar I, Ates SM, Yesil Duymus Z: An in vitro Evaluation of the Effect of Various Adhesives and Surface Treatments on Bond Strength of Resin Cement to Polyetheretherketone: Bond Strength of Resin Cement to PEEK. J. Prosthodont. 2019; 28: e342–e349. Publisher Full Text\n\nMonteiro LC, Pecorari VGA, Gontijo IG, et al.: PEEK and Fiberglass Intra-Radicular Posts: Influence of Resin Cement and Mechanical Cycling on Push-out Bond Strength. Clin. Oral Investig. 2022; 26: 6907–6916. PubMed Abstract \| Publisher Full Text\n\nSong CH, Choi JW, Jeon YC, et al.: Comparison of the microtensile bond strength of a polyetherketoneketone (PEKK) tooth post cemented with various surface treatments and various resin cements. Materials (Basel). 2018; 11: 916. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBenli M, Eker GB, Kahraman Y, et al.: Surface characterization and bonding properties of milled polyetheretherketone dental posts. Odontology. 2020; 108: 596–606. PubMed Abstract \| Publisher Full Text\n\nÇulhaoğlu A, Özkır S, Şahin V, et al.: Effect of various treatment modalities on surface characteristics and shear bond strengths of polyetheretherketone-based core materials. J. Prosthodont. 2020; 29: 136–141. PubMed Abstract \| Publisher Full Text\n\nChaijareenont P, Prakhamsai S, Silthampitag P, et al.: Effects of different sulfuric acid etching concentrations on PEEK surface bonding to resin composite. Dent. Mater. J. 2018; 37: 385–392. PubMed Abstract \| Publisher Full Text\n\nMathew S, Raju IR, Sreedev CP, et al.: Evaluation of push out bond strength of fiber post after treating the intra radicular post space with different post space treatment techniques: a randomized controlled in vitro trial. J. Pharm. Bioallied Sci. 2017; 9: S197–S200. PubMed Abstract \| Publisher Full Text\n\nMoher D, Liberati A, Tetzlaff J, et al.: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009; 6(7): e1000097. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMoher D, Shamseer L, Clarke M, et al.: Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst. Rev. 2015; 4(1): 1. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMigliavaca CB, Stein C, Colpani V, et al.: How are systematic reviews of prevalence conducted? A methodological study. BMC Med. Res. Methodol. 2020 [cited 2020 Dec 12]; 20(1): 96. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nChecklist for Randomized Controlled Trials Critical Appraisal tools for use in JBI Systematic Reviews.[cited 2020 Dec 10].\n\nSterne JAC, Savović J, Page MJ, et al.: RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ (Clinical Research ed.). 2019; l4898. Publisher Full Text\n\nWells GA, Shea B, O’Connell D, et al.: The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute; Accessed January 20, 2024.\n\nBoukhris H, Hajjami H, Ben youssef S.: Clinical Outcomes of Polyetheretherketone (PEEK) Hybrid Prosthesis in All-on-Four Rehabilitation: A Systematic Review Protocol [version 1; peer review: awaiting peer review]. F1000Res. 2024; 13(507). Publisher Full Text\n\nBoukhris H: PRISMA-P checklist for The Effect of Surface Treatments on the Bond Strength of Polyetheretherketone Posts: A Systematic Review protocol. Dataset. figshare. 2024. Publisher Full Text" }	[ { "id": "316835", "date": "18 Sep 2024", "name": "Marwa Emam", "expertise": [ "Reviewer Expertise Fixed prosthodontics", "implant", "occlusion", "ceramics", "dental materials", "esthetics", "digital dentistry." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReview report for the submitted manuscript “The effect of surface treatments on the bond strength of polyetheretherketone posts: a systematic review protocol”\nI would like to thank the authors for submitting their protocol for review. The use of PEEK posts in dental applications is a developing subject, so a systematic assessment of surface treatment procedures is extremely important. PEEK's biocompatibility and mechanical strength make it excellent for dental posts, but the inert surface makes bonding challenging. This review could fill a crucial gap in clinical practice. Overall, the language is clear, but minor editing of English language might be required in the final submitted review. Author might want to explore options for refining their text to improve its flow and readability. This can make their article more engaging and clear. 1. Title: - Approved as is. 2. Abstract: Kindly give a hint on the different surface treatment techniques of PEEK for the reader.\n\n3. Introduction: -I think the introduction is a bit shallow. I would prefer the introduction to begin with PEEK material (history, chemical composition and properties) as it is the main objective of the study. Then going through the different applications quickly and concentrating on the endodontically treated teeth and post indications and PEEK post (ready & custom made) as one of the options available for clinicians. Finally, stating PEEK adhesion properties as a weakness that different surface treatments aim to improve. -Kindly connect short paragraphs into paragraphs of 6-7 lines paragraphs. -Kindly add references to the second & third paragraph. - The authors could elaborate on the therapeutic relevance of PEEK's bond strength as compared to conventional materials like metal, zirconia or fiber posts. 4. Methods: -The protocol is well-structured and follows known principles for systematic reviews (PRISMA). The use of numerous databases (e.g., PubMed, Scopus, Cochrane Central) will ensure a thorough literature review. The intended use of risk-of-bias tools (ROB II and NOS) and data extraction procedures demonstrates a commitment to evidence of excellent quality synthesis. Intervention types: There is no mention of the surface treatments of PEEK aimed for exploration. Only 2 examples were mentioned so kindly give more details regarding treatments to be studied. Outcomes:\nMore precise definitions would be useful in the outcomes section. While bond strength and retention are indicated, it is unclear how they would be tested. Providing additional details on the anticipated outcomes and their clinical significance could enhance the protocol. Evaluation of methodological quality and risk of bias: -The protocol’s description of bias assessment tools (ROB II and NOS) is good, but how will studies with unclear risks of bias be handled in the analysis? Also kindly give more details regarding the “standardized tools” you have mentioned as means of evaluation. Meta analysis: While the authors highlight the possibility of meta-analysis, it would be interesting to describe how they intend to deal with possible heterogeneity among studies (e.g., differences in surface treatments, study designs). 5. Conclusions: Although this protocol presents a well-designed systematic review that is expected to yield useful information about the surface treatments of PEEK posts in dental applications, it would be strengthened by adding the details addressed in the comments above for further enhancement.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes", "responses": [ { "c_id": "13237", "date": "06 Feb 2025", "name": "Hanen Boukhris", "role": "Author Response", "response": "We appreciate the reviewers’ valuable feedback, which has helped improve the clarity, depth, and rigor of our manuscript. Below, we provide detailed responses to each comment and indicate the revisions made accordingly. 1.Introduction Comment: \"The introduction should start with PEEK’s material properties, history, and applications before discussing its role in post-and-core restorations.\" Response: We have reorganized the introduction to first present PEEK’s chemical composition, mechanical properties, and biomedical applications before focusing on its role in post-and-core restorations. The revised introduction now follows a logical progression, improving the contextual framework of the study. Comment: \"Please provide more details on the different surface treatment techniques of PEEK.\" Response: We have expanded the discussion on surface treatments, including plasma treatment, acid etching (98% sulfuric acid), sandblasting (50 μm alumina oxide), laser surface modification, silanization, and air abrasion. These modifications and their rationale are now clearly described. Comment: \"There is limited discussion on the comparative performance of PEEK posts against conventional materials like metal, zirconia, and fiber posts.\" Response: The revised manuscript now includes a comparative analysis highlighting the strengths and limitations of PEEK versus conventional post materials, emphasizing its clinical relevance. Comment: \"How will studies with unclear risk of bias be handled in the analysis?\" Response: We have specified that studies with an unclear risk of bias will undergo sensitivity analysis, and their influence on the final conclusions will be carefully considered. Comment: \"Clarify how heterogeneity among studies will be addressed in the meta-analysis.\" Response: A heterogeneity assessment will be conducted using I² statistics, and subgroup analysis or meta-regression will be applied if significant heterogeneity is detected. Comment: \"Provide more precise definitions of key outcomes.\" Response: We have revised the outcomes section to specify assessment methods for bond strength (e.g., push-out tests), fracture resistance, and marginal adaptation quality. These responses, along with the corresponding revisions, have strengthened our manuscript and improved its clarity. Thank you for your constructive feedback." } ] } ]	1	https://f1000research.com/articles/13-951
https://f1000research.com/articles/13-825/v1	23 Jul 24	{ "type": "Systematic Review", "title": "The use of medicinal marijuana for treating Cerebral Palsy: a literature review", "authors": [ "Daniel McDonough", "James Charles", "Trent Shaw", "James Charles", "Trent Shaw" ], "abstract": "Background Recent studies have established that Medicinal Marijuana (MM) is beneficial in the treatment of spasms, sleep, and pain in adult patients with varying medical diagnoses and symptoms. However, MM has rarely been used for the treatment of Cerebral Palsy (CP) complications in adults. The aim of this systematic literature review was to explore MM interventions globally, with a focus on identifying the best practice with MM for the treatment of complications of CP.\n\nMethods A systematic literature search was performed using keywords and synonyms related to MM treatment and CP complications. Inclusions and exclusions were scoped to scholarly peer reviewed academic literature published 2019 to 2021 located in the Deakin Library collection. A screening process confirmed criteria adherence and identified additional papers in referencing. The papers were appraised and evaluated to ensure selections do not have perceived or actual bias.\n\nResults From 409 publications, 27 papers were selected for review because they investigated the benefits of MM treatment for patients with sleep, pain, and spasm complications. There was no literature found on the use of MM for adults with CP.\n\nDiscussion Recent research has demonstrated that with an informed understanding of MM treatment adult patients with varying medical diagnoses and symptoms can use MM to manage sleep disruption and improve relaxation. Therefore, there are potential benefits for the use of MM in treating spasticity, pain, sleep, quality of life, and social and emotional wellbeing in adult patients with CP. No funding was sort or provided for this review and the results are specific to adults with CP, so they are not to be generalized to other populations.", "keywords": [ "Medicnal Marjuana", "Cerebral Palsy", "Treatment", "Benefits" ], "content": "Introduction\n\nAdults with Cerebral Palsy (CP) are at a higher risk of non-communicable diseases such as cancer, stroke, and chronic obstructive pulmonary disease. This is believed to be related to a lack of medical screening and insufficient services when they transition into adult healthcare service environments (Murphy, 2018). A recent report showed that a patient with CP aged > 18 years is 72% more likely to develop advanced CKD after adjusting from cardiometabolic diseases compared to those without CP (Whitney et al., 2020). It is common for people suffering with CP to have coexisting conditions that are outside of age-based developmental stages such as pain 75%, intellectual disability 50%, hip replacement 33%, incontinence 25%, epilepsy 25%, inability to speak 25%, sleep disorders 20-25%, and behaviour problems 20-25% (Vitrikas et al., 2020). People with CP entering adult life have difficulty swallowing, as many muscles are affected in the oral cavity, making eating solid foods a challenge (Speyer et al., 2019).\n\nSeveral studies have investigated the benefits of Medicinal Marijuana (MM) in the treatment of muscle spasms (Nielsen et al., 2019; Singh & Singh, 2019; Stang et al., 2019), pain (Campbell et al., 2019; Clem et al., 2020; Dzierżanowski, 2019; Wildes et al., 2020), sleep disturbance (Skobic et al., 2020; Sznitman et al., 2020), quality of life (QOL), and social and emotional wellbeing (SEWB) (Capano et al., 2020; Palace & Reingold, 2019). However, MM has rarely been used to treat CP complications in adults. This systematic literature review explored MM interventions globally, with a focus on identifying the best practices with MM for the treatment of complications in adults with CP.\n\nCP effects two–three people per 1,000 live births, and its diagnosis is usually determined between 12 and 24 months of age (Vitrikas et al., 2020). There are many symptoms of CP such as poor posture, balance and movement resulting from brain disfunction and restricted movement known as spasticity, which is caused by compression of the brain and spinal cord, due to reduced blood flow reducing oxygen levels (Stang et al., 2019). Patients with CP have numerous complications and problematic health-related experiences that continue to develop into adulthood such as high muscle tone, spasms, and motor skills, which often contribute to brain injury and developmental problems, seizures, cognitive dysfunction, osteoporosis, pressure ulcers, speech impairment, and hearing impairment (Gulati & Sondhi, 2018; Vitrikas et al., 2020). CP is the most common form of spasticity resulting from a damaged non-progressive central nervous system that can inhibit motor function capacity development leading to low performance, and retardation (Singh & Singh, 2019).\n\nThroughout history, cannabinoids have been used to treat various medical conditions worldwide and have been used medically for thousands of years in various cultures (Crowder, 2019), including to manage spasms (Fairhurst et al., 2020). In the human body, the endocannabinoid system has two key primary cannabinoid receptors, CB1 and CB2, that are linked to the central and peripheral nervous systems (Rosi & Sorbello, 2019). CB1 receptors are found in the nervous system, organs, connective tissue, glands, immune cells, and the brain (Rosi & Sorbello, 2019). CB2 receptors are primarily found in the immune system and can be non-responsive to anti-inflammation in certain parts of the human body during injury (Rosi & Sorbello, 2019). Through the anandamide system, the body produces its own cannabinoids and cannabinoid receptors to produce several psychological effects and activities.\n\nCannabidiol (CBD) and tetrahydrocannabinol (THC) both originate from the cannabis sativa plant and have the potential to modify muscle tone (Fairhurst et al., 2020). THC is an active element and is known to have the most profound effect on pain relief and relaxation (Rosi & Sorbello, 2019). The primary medicinal effects of THC include psychoactive properties, such as stimulation of appetite, muscle relaxation, analgesia, and antiemesis (Fairhurst et al., 2020) However, a higher volume dose of THC can trigger paranoia (Rosi & Sorbello, 2019). CBD also affects antipsychotic activity, muscle relaxants, antioxidants, anticonvulsants, and anxiolytic but does not cause intoxication (Fairhurst et al., 2020; Rosi & Sorbello, 2019) CBD can increase the THC pain relief potential and limit psychoactive effects by working together to increase anti-inflammatory, antioxidant, and antiviral effects (Rosi & Sorbello, 2019). Scientific techniques have been developed to extract oils and provide additional delivery systems for MM, which are grouped into four delivery methods to determine the best possible outcome for each individual (Table 1) (Rosi & Sorbello, 2019).\n\nPain is one of the most common reasons for therapeutic use of MM. Recent studies on patients who use cannabis for pain have mainly used opioids to help control pain management previously (Cooke et al., 2020). MM has also been extensively used to treat sleep disruption and improve relaxation in a variety of patients (Skobic et al., 2020). Even though cannabis is the most commonly used illicit drug in the world today (Zhand & Milin, 2018), in the last twenty years medical cannabis has been used to reduce pain for patients who have conditions such as spasticity and multiple sclerosis (Fairhurst et al., 2020). In 2016, Australia passed legislation allowing registered health professionals the capacity to prescribe MM for their patients (Lintzeris et al., 2020). Currently, MM is prescribed in some Australian states for the treatment of various medical conditions and health issues, such as pain, anxiety, and sleep disorders (Albee & Penilton, 2019).\n\n\nMethod\n\nA systematic literature search methodology was undertaken (Figure 1) to identify interventions related to MM and the various types of MM use and methods amongst populations globally by adopting keywords and synonyms related to the topic (Table 2). A set of inclusions and exclusions (Table 3) were applied so the search scope was limited to relevant scholarly peer-reviewed literature publications from 2019 to 2021 that were available from the Deakin Library collection across five different databases (Table 4).\n\n\n\n• Available in Deakin Library collection across five databases (Table 4)\n\n• Published 2019 to 2021\n\n\n\n• Literature Reviews\n\n• Conference Papers\n\n• Papers not published in English\n\n• Studies on Animals\n\n• Abstracts Only\n\n• Papers on drug “Therapy”,\n\n• Posters Presentations\n\n• Research on Children\n\n\nResults\n\nThe literature search results (Figure 1) initially presented 409 publications as available for review although 71 duplicates were removed. Then a screening process based on a set of conditions (Table 5) identified 25 papers aligned with the review aim. The reference lists of these 25 papers were then scanned using the same literature screening process and 2 more papers were added resulting in a total of 27 papers (Table 6) selected for this literature review. The first and second named authors of this paper both individually completed the entire search and screening process concluding with the same outcome.\n\n\n\n• Publication had at least one keyword from Line 1 (Table 2)\n\n\n\n• Publication had at least one keyword from either Line 2 or Line 3 or Line 4 or Line 5 (Table 2)\n\n\n\n• Keywords (Table 2) must be included in the title or subject line\n\n\n\n1. Albee, T., & Penilton, D. (2019). Consideration of Medical Marijuana Inclusion in Life Care Planning: Implications and Challenges. Journal of Life Care Planning, 17(4), 9-16. https://ezproxy.deakin.edu.au/login?url=https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=141420263&authtype=sso&custid=deakin&site=eds-live&scope=site\n\n2. Babson, K., Sottile, J., Morabito, D., & Babson, K. A. (2017). Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Current Psychiatry Reports, 19(4), 1. https://ezproxy.deakin.edu.au/login?url=https://search.ebscohost.com/login.aspx?direct=true&db=edb&AN=122896491&authtype=sso&custid=deakin&site=eds-live&scope=site\n\n3. Campbell, G., Stockings, E., & Nielsen, S. (2019). Understanding the evidence for medical cannabis and cannabis-based medicines for the treatment of chronic non-cancer pain. European archives of psychiatry and clinical neuroscience, 269(1), 135-144. https://doi.org/10.1007/s00406-018-0960-9\n\n4. Capano, A., Weaver, R., & Burkman, E. J. P. m. (2020). Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: a prospective cohort study. 132(1), 56-61.\n\n5. Clem, S. N., Bigand, T. L., & Wilson, M. (2020). Cannabis Use Motivations among Adults Prescribed Opioids for Pain versus Opioid Addiction [Article]. Pain Management Nursing, 21(1), 43-47. https://doi.org/10.1016/j.pmn.2019.06.009\n\n6. Cooke, A., Chavez, L., & Freisthler, B. (2020). The relationships between chronic pain and changes in health with cannabis consumption patterns [Article]. International Journal of Drug Policy, 76. https://doi.org/10.1016/j.drugpo.2019.102657\n\n7. Crowder, L. (2019). A concise cannabis guide: History, laws and regulations [Chronology]. California Agriculture(03), 103. https://doi.org/10.3733/ca.2019a0022\n\n8. Dzierżanowski, T. (2019). Prospects for the Use of Cannabinoids in Oncology and Palliative Care Practice: A Review of the Evidence. Cancers, 11(2), 129. https://doi.org/10.3390/cancers11020129\n\n9. Fairhurst, C., Kumar, R., Checketts, D., Tayo, B., & Turner, S. (2020). Efficacy and safety of nabiximols cannabinoid medicine for paediatric spasticity in cerebral palsy or traumatic brain injury: a randomized controlled trial. Developmental medicine and child neurology. https://doi.org/10.1111/dmcn.14548\n\n10. Gulati, S., & Sondhi, V. J. T. I. J. o. P. (2018). Cerebral palsy: an overview. 85(11), 1006-1016.\n\n11. Lintzeris, N., Mills, L., Suraev, A., Bravo, M., Arkell, T., Arnold, J. C., Benson, M. J., & McGregor, I. S. J. H. R. J. (2020). Medical cannabis use in the Australian community following introduction of legal access: the 2018–2019 Online Cross-Sectional Cannabis as Medicine Survey (CAMS-18). 17, 1-12.\n\n12. Markovà, J., Essner, U., Akmaz, B., Marinelli, M., Trompke, C., Lentschat, A., & Vila, C. (2019). Sativex ® as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a double-blind, placebo-controlled randomised clinical trial. The International journal of neuroscience, 129(2), 119-128. https://doi.org/10.1080/00207454.2018.1481066\n\n13. Murphy, K. P. (2018). Cerebral palsy, non-communicable diseases, and lifespan care. Developmental Medicine & Child Neurology, 60(8), 733-733. https://doi.org/10.1111/dmcn.13784\n\n14. Nielsen, S., Murnion, B., Campbell, G., Young, H., & Hall, W. (2019). Cannabinoids for the treatment of spasticity. Developmental Medicine & Child Neurology, 61(6), 631. https://ezproxy.deakin.edu.au/login?url=https://search.ebscohost.com/login.aspx?direct=true&db=edb&AN=136200848&authtype=sso&custid=deakin&site=eds-live&scope=site\n\n15. Palace, Z. J., & Reingold, D. A. J. J. o. t. A. M. D. A. (2019). Medical cannabis in the skilled nursing facility: A novel approach to improving symptom management and quality of life. 20(1), 94-98.\n\n16. Pham, M. N., Hudnall, M. T., & Nadler, R. B. (2020). Marijuana, Lower Urinary Tract Symptoms, and Pain in the Urologic Patient [Review Article]. Urology, 139, 8-13. https://doi.org/10.1016/j.urology.2020.01.029\n\n17. Rosi, P., & Sorbello, J. (2019). MEDICAL MARIJUANA AND PAIN MANAGEMENT. Journal of Nurse Life Care Planning, 19(3), 20-24. https://ezproxy.deakin.edu.au/login?url=https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=138528279&authtype=sso&custid=deakin&site=eds-live&scope=site\n\n18. Singh, A., & Singh, M. (2019). Comparison of Modified Ashworth Scale and Modified Tardieu Scale on Assessment of Lower Limb Spasticity in Hemiplegic and Diplegic Cerebral Palsy [Article]. Indian Journal of Public Health Research & Development, 10(11), 2766-2771. https://doi.org/10.5958/0976-5506.2019.04038.5\n\n19. Skobic, I., Apolinar, G. R., Quan, S. F., & Haynes, P. L. (2020). Marijuana versus evidence-based treatments for sleep and relaxation: A cross-sectional study of use and dose modification following involuntary job loss [Article]. Sleep Health: Journal of the National Sleep Foundation. https://doi.org/10.1016/j.sleh.2020.06.008\n\n20. Speyer, R., Cordier, R., Kim, J.-H., Cocks, N., Michou, E., & Wilkes-Gillan, S. (2019). Prevalence of drooling, swallowing, and feeding problems in cerebral palsy across the lifespan: a systematic review and meta-analyses. In (Vol. 61, pp. 1249).\n\n21. Stang, K. M., King, N. E., Gaebler-Spira, D., & Green, M. M. (2019). It all started with a clubfoot: Beliefs surrounding cerebral palsy throughout history [Article]. Journal of Pediatric Rehabilitation Medicine, 12(2), 115-121. https://doi.org/10.3233/PRM-190005\n\n22. Sznitman, S. R., Shochat, T., & Greene, T. (2020). Is time elapsed between cannabis use and sleep start time associated with sleep continuity? An experience sampling method [Article]. Drug and Alcohol Dependence, 208. https://doi.org/10.1016/j.drugalcdep.2020.107846\n\n23. Tawfik, G. M., Hashan, M. R., Abdelaal, A., Tieu, T. M., & Huy, N. T. (2019). A commentary on the medicinal use of marijuana. Tropical Medicine and Health(1). https://doi.org/10.1186/s41182-019-0161-x\n\n24. Vitrikas, K., Dalton, H., & Breish, D. (2020). Cerebral Palsy: An Overview. American family physician, 101(4), 213-220. https://ezproxy.deakin.edu.au/login?url=https://search.ebscohost.com/login.aspx?direct=true&db=mdc&AN=32053326&authtype=sso&custid=deakin&site=eds-live&scope=site\n\n25. Whitney, D. G., Oliverio, A. L., Kamdar, N. S., Viglianti, B. L., Naik, A., & Schmidt, M. (2020). Advanced CKD Among Adults With Cerebral Palsy: Incidence and Risk Factors [Article]. Kidney Medicine. https://doi.org/10.1016/j.xkme.2020.05.012\n\n26. Wildes, M., Bigand, T. L., Layton, M. E., & Wilson, M. (2020). Cannabis Use and Cognition in Adults Prescribed Opioids for Persistent Pain [Article]. Pain Management Nursing, 21(1), 94-99. https://doi.org/10.1016/j.pmn.2019.06.014\n\n27. Zhand, N., & Milin, R. (2018). What do we know about the pharmacotheraputic management of insomnia in cannabis withdrawal: A systematic review [journal article]. American Journal on Addictions, 27(6), 453-464. https://doi.org/10.1111/ajad.12783\n\nVarious appraisal and evaluation tools (Table 7) were utilised to determine the paper’s quality and credibility as well as ensuring the review was without perceived or actual bias. Each paper was then scanned to confirm topic relevance and appropriate coverage of topics (Table 8) towards objectively validating findings. The process revealed there was no literature or study on the use of MM for adults with CP to treat common health-related symptoms and conditions.\n\n\nDiscussion\n\nA follow-up survey conducted 2018-2019 on the self-identified therapeutic reasons for the use of medical cannabis, 2-years after the initial survey following the introduction the legal access of medical cannabis in Australia, demonstrated to close similarity across both surveys that pain, mental health/substance use, sleep or other conditions as the main condition for the use of medical cannabis (Lintzeris et al., 2020). The most recent survey report identified the overwhelming majority of 1388 respondents believed their symptoms improved from the use of MM (Lintzeris et al., 2020). Alarmingly, in the same survey period, 25.8% (284/1103) of the respondents reported they were unaware of the CBD/THC composition of their medical cannabis or that compositions between batches varied 23.9% (264/1103) (Lintzeris et al., 2020). Unfortunately, the potential concern raised for the ill-formed user of medical cannabis is also apparent in other studies that suggest more research is needed on the appropriate composition, dosage, and timing of MM when treating and managing specific medical conditions and symptoms (Babson et al., 2017; Skobic et al., 2020; Sznitman et al., 2020).\n\nInternationally, there are many reasons why individuals pursue the use medical cannabis including but not limited to pain, anxiety, spasticity, and sleep disorders (Albee & Penilton, 2019). There is some evidence that MM has beneficial effects for adults in relieving spasticity symptoms, pain management, and sleep apnoea (Tawfik et al., 2019). A review of evidence for the effectiveness of cannabinoids in Oncology and palliative care practice acknowledged the limited and contradictory results on the effects of MM treatment for symptoms, including pain, sleep, and spasticity, though determined with consideration of finding the appropriate dosage then the benefits overweighed the possible risk for palliative care patients, especially in the earlier phases of progressive disease (Dzierżanowski, 2019). The following sections presents more results in relation to MM treatments for sleep, pain, spasticity, QOL, and SEWB.\n\nIn recent years, research has shown an understanding on the effects of MM and cannabinoids derivatives that have been used for treating sleep disorders (Babson et al., 2017). It is known that MM with cannabidiol has different effects based on dose; for example, a lower dose has been shown to be stimulating and is related to sleep disorders, and a higher dose can have the effect of sedation (Babson et al., 2017). People with sleep disorders found that cannabidiol at medium to high doses can improve sleep (Babson et al., 2017). Recent clinical trials have suggested that the THC/CBD ratio (Sativex) at the right dose can improve sleep in people with chronic pain. A study comparing the self-reported use of marijuana to evidence-based treatments for sleep/relaxation concluded that differences in THC/CBD composition and timing of dosage changes results (Skobic et al., 2020). For instance, it was found that 160mg/day of CBD increased sleep time and reduced sleep disturbance, while a high dose (15mg) of THC at night could result in memory impairment, increased sleepiness, and mood changes in the day after (Skobic et al., 2020).\n\nA study on the use of cannabis at a particular time to improve sleep presented the notion that the cannabis industry are making various unfounded claims on potential benefits of MM treatment for sleep leading to suggesting cannabis users be more informed and seek evidenced-based alternatives to improve sleep, such as, pharmacological and behavioral treatments (Sznitman et al., 2020). However, the study sample was of 802 frequent cannabis users and it is not made clear whether or not the participants used cannabis for a sleep disorder nor that the cannabis used was medicinal or recreational (Sznitman et al., 2020). A literature review on the pharmacotheraputic management of insomnia in cannabis withdrawal determined there is inconclusive evidence for treatment options due to the preliminary stages of the work (Zhand & Milin, 2018). There has been limited research on MM to improve sleep, with studies having limitations of small sample sizes. Therefore, caution must be exercised when interpreting presented results. There have also been limitations with follow-up, highlighting the importance of examining the long-term effects of MM as a treatment for improving sleep (Babson et al., 2017).\n\nResearch by Cooke et al. (2020) was one of the first studies to evaluate the daily use of cannabis in comparison with the change in health status associated with pain severity (Cooke et al., 2020). They examined cannabis consumption patterns associated with chronic pain and the control of different types of pain as well as investigating the demographics of each patient, impact of cannabis use, and overall health of patients (Cooke et al., 2020). The research was a cross sectional study design, which has limitations of conclusions about causation i.e. “cannabis might depress general health for people who have high pain” (Cooke et al., 2020). The sample size (n=295) included medical cannabis patients, and the evaluation was designed for patients with both low and high pain levels. They measured daily cannabis consumption and the difference between low and high pain levels with the significance of MM (Cooke et al., 2020). The relationship between cannabis use and the treatment of chronic pain can be dependent on route of administration and dose response effects. Given the complex nature of chronic pain, a myriad of causes and combinations of cannabis use have been identified. Therefore, it is difficult to determine the frequency of cannabis use among patients and how it affects the health of patients with chronic pain. Further research is needed to determine the frequency of cannabis use in patients with chronic pain (Cooke et al., 2020).\n\nA review of 48 studies conducted by Pham et al. (2020) aimed to describe the role of MM and cannabinoids in lower urinary tract symptoms (LUTS) and dysfunction related to chronic pain, determined in clinical trials and preclinical studies (Pham et al., 2020). The review revealed mixed results and limited evidence though there was enough evidence to suggest MM could target the endocannabinoid system to treat LUTS and other bladder conditions (Pham et al., 2020). Unfortunately, the increased availability of legalised MM and cannabinoid derivatives will continue to outpace clinical investigations into the benefits of MM treatment for pain and as such will require physician-patient conversations to be held with a better understanding of how MM interacts with the human body (Pham et al., 2020).\n\nWildes et al. (2020) also concluded at the end of their study that more research is needed to better understand the effects of MM on the human body, in particular cognition and mood (Wildes et al., 2020). They attempted to unpack the complex interplay of variables of persistent pain and how CBD and THC could affect change leading to the determination more investigations are required in relation to THC/CBD composition and dosage (Wildes et al., 2020). A different study on the use MM for the treatment of persistent pain identified study participants were motivated to use MM to manage a variety of health-related symptoms such as pain, sleep, anxiety, and withdrawal instead of opioids (Clem et al., 2020). Even though the study had limitations restricting generalizable findings the study investigated the motivation of participants to use MM to treat pain and as such were able to recommend a better understanding of alternative therapies that could help reduce the overall use of opioids given the well-documented side effect complications and likely opioid dependency (Clem et al., 2020).\n\nThe study conducted by Fairhurst et al. (2020) was the only study that used MM as a treatment for CP. It was a prospective randomized placebo-controlled trial, which focused on 72 adolescents (8 to 18 years old) who suffered from spasticity and traumatic central nervous system (CNS) injury and investigated the efficacy, safety, and tolerance of MM (Fairhurst et al., 2020). The study investigated the benefits of sleep improvement with MM and although the results were not statistically significant, sleep scores showed some relevant numerical improvements (Fairhurst et al., 2020). It should be noted that the measures investigated in this study were designed and developed for adults (>30 years), and several adverse reactions were experienced by young people after receiving MM. These adverse reactions may have been related to doses designed for adults, regardless of the reason why the adverse reactions affected the progression of the trial (Fairhurst et al., 2020). A review of studies that included adults and paediatric participants in examining the effectiveness of cannabinoids in treating spasticity determined more favourable outcomes for adults than paediatric patients (Nielsen et al., 2019). The paediatric studies produced low quality evidence whereas the adult studies of randomized controlled clinical trials demonstrated cannabinoids have more efficacy in reducing muscle spasticity (Nielsen et al., 2019).\n\nA study of 191 participants on the use of MM to treat spasticity with adult (18y+) multiple sclerosis patients did prove the trialled THC:CBD spray demonstrated a more efficacious alternative to readjusting underlying antispasticity drugs (Markovà et al., 2019). Markovà et al. (2019) conducted a randomized control trial to investigate a 12-week treatment program for using Sativex® as an add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in a two-phase trial. Optimization of the underlying antispasticity medications was permitted in both groups across all study periods (Markovà et al., 2019). The study criteria included adult (18y+) multiple sclerosis patients that had encountered spasticity for at least 12 months and had co-existing symptoms of chronic pain, spasm, low mobility, sleep disturbance, depression, anxiety, and fatigue (Markovà et al., 2019). The criteria excluded who had taken THC, CBD spray in the past, or currently using cannabis or cannabinoid-based drugs of any form within 30 days prior to the study period and any family history of psychiatric disorders (Markovà et al., 2019).\n\nAn 8-week prospective, single-arm cohort study of 97 chronic pain patients for the potential role of cannabinoids as an alternative for opioids concluded a significant effect on reducing opioid intake, reducing pain, and improving QOL (Capano et al., 2020). The study enrolled 30-65 year old patients suffering from moderate to severe chronic pain for at least 3 years and had been stable on opioids for 1 year. Then they excluded participants if they had any history of substance disorder; any psychotic disorder; an abnormal drug screen in the previous 12-months; a history of non-fatal overdose; any epileptic activity in the previous 12-months; an incapacitating system disorder (cardiac, renal, or hepatic), or any known allergy to cannabis-based products (Capano et al., 2020). Analysis of results were evaluated with four indices - Pain Disability Index (PDI-4); Pittsburgh Sleep Quality Index (PSQI), Pain Intensity and Interference (PEG); and Patient Health Questionnaire (PHQ-4). The study found 53% of the participants who added CBD hemp extract reduced or eliminated opioids and 94% of all CBD users reported QOL improvements (Capano et al., 2020).\n\nAn evaluation of a MM symptom management program implemented in an American skilled nursing facility for the safe use of MM for chronic conditions, especially chronic pain, neuropathy, and Parkinson’s disease influenced the recommendation that clinicians should consider the historical experiences and contemporary findings in the potential benefits of MM as an alternative therapy (Palace & Reingold, 2019). Prior to the program implementation, an evaluation of meta-analysis from various trials, studies, and reviews found mixed results and relevant findings that aligned with the geriatric medical practice of focusing on simplifying medication regimes, avoiding polypharmacy, and eliminating medications with potentially harmful side effect profiles (Palace & Reingold, 2019). The innovative program ignored traditional options for symptom management guided by Food and Drug Administration (FDA) approved medications and created an approved program so residents were able to legally obtain and use MM for symptom management in the facility (Palace & Reingold, 2019). The program evaluation found most residents using MM to treat pain reported sustained improvement in chronic pain severity leading to opioid dosage reduction and an improved sense of SEWB (Palace & Reingold, 2019).\n\nThis systematic literature review only examined publications that specifically investigated MM in adults in relation to sleep, pain, and spasm. The limitation of the focus of this study is that the results may not be generalizable to other populations.\n\n\nConclusion\n\nThere is no literature on the use of MM in adults with CP. This literature review found the evidenced-based potential benefits for the use of MM to treat spasticity, pain, and sleep symptoms and for improving QOL, and SEWB. However, from the findings of this review, further studies are needed on the appropriate composition, dosage and timing of MM when used as a treatment therapy. Furthermore, the review findings have established a need to study the use of MM treatment for adults with CP in relation to treating spasticity, pain, and sleep symptoms as well as improving QOL, and SEWB.", "appendix": "Data availability\n\nNo data are associated with this article.\n\nAll extended data for this article can be found here:\n\nFigshare: The Use of Medicinal Marijuana for Treating Cerebral Palsy: A Literature Review, https://doi.org/10.6084/m9.figshare.25928494.v2 (Shaw et al., 2024).\n\nThis project contains the following underlying data:\n\n• The Use of Medicinal Marijuana for Treating Cerebral Palsy: A Systematic Review.\n\n○ This is a systematic literature review to explore MM interventions globally with a focus on MM treatment of symptoms and conditions associated with adult CP patients, including spasticity, pain, sleep, QOL, and SEWB.\n\n• Review The Use of MM for CP 24 #30 Flow Diagram.\n\n○ This is a flow diagram of the research methodology.\n\n• Review The Use of MM for CP 24 #30 abstract checklist.\n\n○ A checklist of abstract items within the literature review.\n\n• Review The Use of MM for CP 24 #30 checklist.\n\n○ A checklist of sections and items within the literature review.\n\nDetail of license\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgements\n\nI would like to acknowledge the traditional owners of all the many Aboriginal and Torres Strait Islander Nations that make up the great continent of Australia. As a Kaurna man I would like to acknowledge my Kaurna community, our Elders, representatives, and ancestors.\n\n\nReferences\n\nAlbee T, Penilton D: Consideration of Medical Marijuana Inclusion in Life Care Planning: Implications and Challenges. J. Life Care Plan. 2019; 17(4): 9–16. Reference Source\n\nAromataris EMZ: Joanna Briggs Institute Reviewer’s Manual.2017. https://reviewersmanual.joannabriggs.org/\n\nBabson K, Sottile J, Morabito D, et al.: Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Curr. Psychiatry Rep. 2017; 19(4): 1. Publisher Full Text Reference Source\n\nCampbell G, Stockings E, Nielsen S: Understanding the evidence for medical cannabis and cannabis-based medicines for the treatment of chronic non-cancer pain. Eur. Arch. Psychiatry Clin. Neurosci. 2019; 269(1): 135–144. PubMed Abstract \| Publisher Full Text\n\nCapano A, Weaver R, Burkman E: Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: a prospective cohort study. Postgrad. Med. 2020; 132(1): 56–61. PubMed Abstract \| Publisher Full Text\n\nCASP: CASP checklists. Critical Appraisal Skills Programme (CASP): Making sense of evidence.2014.\n\nClem SN, Bigand TL, Wilson M: Cannabis Use Motivations among Adults Prescribed Opioids for Pain versus Opioid Addiction. Pain Manag. Nurs. 2020; 21(1): 43–47. PubMed Abstract \| Publisher Full Text\n\nCooke A, Chavez L, Freisthler B: The relationships between chronic pain and changes in health with cannabis consumption patterns. Int. J. Drug Policy. 2020; 76: 102657. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCrowder L: A concise cannabis guide: History, laws and regulations. Calif. Agric. 2019; 73: 103. Publisher Full Text\n\nDzierżanowski T: Prospects for the Use of Cannabinoids in Oncology and Palliative Care Practice: A Review of the Evidence. Cancers. 2019; 11(2): 129. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nFairhurst C, Kumar R, Checketts D, et al.: Efficacy and safety of nabiximols cannabinoid medicine for paediatric spasticity in cerebral palsy or traumatic brain injury: a randomized controlled trial. Dev. Med. Child Neurol. 2020; 62: 1031–1039. Publisher Full Text\n\nGulati S, Sondhi V: Cerebral palsy: an overview. Indian J. Pediatr. 2018; 85(11): 1006–1016. Publisher Full Text\n\nLintzeris N, Mills L, Suraev A, et al.: Medical cannabis use in the Australian community following introduction of legal access: the 2018–2019 Online Cross-Sectional Cannabis as Medicine Survey (CAMS-18). Harm Reduct. J. 2020; 17: 1–12. Publisher Full Text\n\nMarkovà J, Essner U, Akmaz B, et al.: Sativex ® as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a double-blind, placebo-controlled randomised clinical trial. Int. J. Neurosci. 2019; 129(2): 119–128. PubMed Abstract \| Publisher Full Text\n\nMurphy KP: Cerebral palsy, non-communicable diseases, and lifespan care. Dev. Med. Child Neurol. 2018; 60(8): 733–733. PubMed Abstract \| Publisher Full Text\n\nNHMRC: How to use the evidence: assessment and application of scientific evidence. Canberra: Australian Government; 2000.\n\nNielsen S, Murnion B, Campbell G, et al.: Cannabinoids for the treatment of spasticity. Dev. Med. Child Neurol. 2019; 61(6): 631–638. Publisher Full Text Reference Source\n\nPalace ZJ, Reingold DA: Medical cannabis in the skilled nursing facility: A novel approach to improving symptom management and quality of life. J. Am. Med. Dir. Assoc. 2019; 20(1): 94–98. PubMed Abstract \| Publisher Full Text\n\nPham MN, Hudnall MT, Nadler RB: Marijuana, Lower Urinary Tract Symptoms, and Pain in the Urologic Patient. Urology. 2020; 139: 8–13. PubMed Abstract \| Publisher Full Text\n\nRosi P, Sorbello J: MEDICAL MARIJUANA AND PAIN MANAGEMENT. J. Nurse Life Care Plan. 2019; 19(3): 20–24. Reference Source\n\nSCImago: Scimago Journal & Country Rank.2007. Reference Source\n\nShaw T, Charles J, McDonough D: The Use of Medicinal Marijuana for Treating Cerebral Palsy: A Systematic Review. figshare. Journal contribution. 2024. Publisher Full Text\n\nSingh A, Singh M: Comparison of Modified Ashworth Scale and Modified Tardieu Scale on Assessment of Lower Limb Spasticity in Hemiplegic and Diplegic Cerebral Palsy. Indian J. Public Health Res. Dev. 2019; 10(11): 2766–2771. Publisher Full Text\n\nSkobic I, Apolinar GR, Quan SF, et al.: Marijuana versus evidence-based treatments for sleep and relaxation: A cross-sectional study of use and dose modification following involuntary job loss. Sleep Health. 2020; 7: 113–117. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSpeyer R, Cordier R, Kim J-H, et al.: Prevalence of drooling, swallowing, and feeding problems in cerebral palsy across the lifespan: a systematic review and meta-analyses. Dev. Med. Child Neurol. 2019; 61: 1249.\n\nStang KM, King NE, Gaebler-Spira D, et al.: It all started with a clubfoot: Beliefs surrounding cerebral palsy throughout history. J. Pediatr. Rehabil. Med. 2019; 12(2): 115–121. PubMed Abstract \| Publisher Full Text\n\nSznitman SR, Shochat T, Greene T: Is time elapsed between cannabis use and sleep start time associated with sleep continuity? An experience sampling method. Drug Alcohol Depend. 2020; 208: 107846. PubMed Abstract \| Publisher Full Text\n\nTawfik GM, Hashan MR, Abdelaal A, et al.: A commentary on the medicinal use of marijuana. Tropical Medicine and Health. 2019; 47: 35. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nVitrikas K, Dalton H, Breish D: Cerebral Palsy: An Overview. Am. Fam. Physician. 2020; 101(4): 213–220. Reference Source\n\nWhitney DG, Oliverio AL, Kamdar NS, et al.: Advanced CKD Among Adults With Cerebral Palsy: Incidence and Risk Factors. Kidney Medicine. 2020; 2: 569–577.e1. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWildes M, Bigand TL, Layton ME, et al.: Cannabis Use and Cognition in Adults Prescribed Opioids for Persistent Pain. Pain Manag. Nurs. 2020; 21(1): 94–99. PubMed Abstract \| Publisher Full Text\n\nZhand N, Milin R: What do we know about the pharmacotheraputic management of insomnia in cannabis withdrawal: A systematic review. Am. J. Addict. 2018; 27(6): 453–464. PubMed Abstract \| Publisher Full Text" }	[ { "id": "330978", "date": "28 Oct 2024", "name": "Natalia Szejko", "expertise": [ "Reviewer Expertise Cannabis based medicine", "neurology", "psychiatry" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for providing me the opportunity to review this interesting paper that concerns an interesting topic of CP and use of cannabis based medicine.\nOverall the paper is interesting and relevant to the field. However, I have some small suggestions that could be considered before the paper will be indexed. It is not clear to me why there is a separate paragraph entitled introduction, which is followed by the one entitled background. In my understanding they are essentially the same? Please provide more information, maybe consider merging both? I also think that there should be more emphasis on the treatment of spasticity with CBM in the introduction. Pain is important of course, but this is crucial in CP also. Also, a brief mention of previous studies about CBM and CP should be discussed at least mentioning the areas where it was used, are these basic science studies or clinical? Are there any RCTs or meta analyses? As the authors clearly describe in the methodology, this is a systematic review, which should be stated in the title. Please add. Although I really like the Tables and Figures that the authors prepared, I suggest to put also a descriptive part in the results – are the studies included RCTs, case reports, retrospective studies? What are the main results? If CBM is effective to treat pain, which CBM specifically? At which dose? Any side effects? The same goes for other symptoms, please describe in more detail. This is now part of the discussion, but I would suggest to move it to results section instead. I would also not say that one treats quality of life, but would rather name it as improvement of quality of life. Could the authors also clarify the abbreviation SEWB? Could the authors also clarify why only studies in adults were included? Are there no such studies in children?\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes", "responses": [ { "c_id": "13241", "date": "06 Feb 2025", "name": "Daniel McDonough", "role": "Author Response", "response": "Thank you for taking the time to review our paper we have found your suggestion and comments informative and helpful please see our responses below. Reviewer - It is not clear to me why there is a separate paragraph entitled introduction, which is followed by the one entitled background. In my understanding they are essentially the same? Comment - Thank you for your suggestion, we have now combined background and Introduction together see new introduction. Reviewer - Please provide more information, maybe consider merging both? Comment - We have now merged both as suggested. Reviewer - I also think that there should be more emphasis on the treatment of spasticity with CBM in the introduction. Comment - We have added treatment of spasticity in the relation CBM see introduction paragraph two. Reviewer - Pain is important of course, but this is crucial in CP also. Also, a brief mention of previous studies about CBM and CP should be discussed at least mentioning the areas where it was used, are these basic science studies or clinical? Comment - Sorry if this wasn’t clear but our search did not find any papers in relation to MM for a treatment for adults with CP, although there was paper that claimed to focus on the treatment for CP for MM for adults on a closer analysis it focused on the treatment of adolescents see page 14 Reviewer - Are there any RCTs or meta-analyses? Comment - Our search strategy only found one paper that was a RCT i.e. Fairhurst et. al 2020 and there were several meta-analyses i.e. Zhand, N., & Milin, R. (2018). Dzierżanowski, T. (2019). Babson, K., Sottile, J., Morabito, D., & Babson, K. A. (2017). Now we have attempted to highlight this in the paper, see results section. Reviewer - As the authors clearly describe in the methodology, this is a systematic review, which should be stated in the title. Please add. Comment - The use of systematic in the body of the paper referred to systematic nature of our search for repeatability. On reflection we don’t believe we should have used the term “systematic literature review”. Therefore, we have decided to remove all references to systematic literature review, from this paper. Reviewer - Although I really like the Tables and Figures that the authors prepared, I suggest to put also a descriptive part in the results are the studies included RCTs, case reports, retrospective studies? Comment - We have added to the results section, see paragraph in main results section on the types of studies examined i.e. randomized control trials, cross sectional studies, prospective cohort studies, placebo-controlled randomized clinical trials, cohort studies, and retrospective studies, meta-analysis and longitudinal observational studies. Reviewer - What are the main results? Comment - Thank you for your comment we have added context to the results section see page 14 Reviewer - If CBM is effective to treat pain, which CBM specifically? Comment - Thank you for your comment we have added context to the results section see page 14 Reviewer - At which dose? Comment - Thank you for your comment we have added context to the results section see page 14 Reviewer - Any side effects? Comment - Side effects is described in the discussion section but have also added to the main results section as suggested Reviewer - The same goes for other symptoms, please describe in more detail. This is now part of the discussion, but I would suggest to move it to results section instead. Comment - We have attempted to describe in more detail the symptoms and have added it to the results section as suggested. Reviewer - I would also not say that one treats quality of life, but would rather name it as improvement of quality of life? Comment - Thanks for pointing this out, we have now modified the language to use terms like “improving quality of life”. Reviewer - Could the authors also clarify the abbreviation SEWB? Comment - Thanks for pointing this out, we have written this in full i.e. Social and emotional wellbeing, prior to using the acronym. Reviewer - Could the authors also clarify why only studies in adults were included? Are there no such studies in children? Comment - We conducted this literature review to provide evidence for the use of MM with adults, as we proposed to conduct a case study, investigating medicinal marijuana for the treatment of an adults with Cerebral Palsy. Additional comment Thank you for your suggestion, just to clarify the first author Daniel McDonough conducted this literature review as part of his thesis for his Master of Public Health. We are clinicians and clinical researchers, and the first author conducted to inform a case study which was also a part of his Master of Public Health. The first author has completed his Master of Public Health, and we found the literature very informative and helpful to be able to conduct our case study. We also believe other clinical researchers proposing to conduct research to treat symptoms with CP may also find it helpful. We have now submitted the findings of our case study for publication. Title: A case study investigating medicinal marijuana for the treatment of an adult with Cerebral Palsy." } ] }, { "id": "330974", "date": "14 Nov 2024", "name": "Mê-Linh Lê", "expertise": [ "Reviewer Expertise Information professional with 10+ years of knowledge synthesis work" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAs an information professional, I have limited my comments below to those relating to the methodology and citations of the paper.\n\nMethods While the title of this article says it is a literature review, throughout the text the terms used is systematic review (SR), and several practices (e.g., use of a PRISMA flow chart, PRISMA checklist) suggest the authors attempted some aspects of a SR. However, the methods as outlined here are not those of a systematic review and should not be written as such.\n\nIn brief, some of the issues are:\n1. An extremely limited time frame of 2 years and the authors included only material available in their specific library collection. This is not how SRs are completed as they must locate ALL evidence on a specific topic.\n2. Lack of use of any subject terms specific to individual databases, such as MESH or CINAHL search terms\n3. Lack of any reproducible search strategy for any database (although really all databases search strategies should be provided). Listing only the keywords is not sufficient. A quick search in MEDLINE using more advanced search terms quickly found several papers that would have been relevant to this article.\n4. The authors write “The first and second named authors of this paper both individually completed the entire search and screening process concluding with the same outcome.”. This is not how systematic reviews are completed. There is one search done, and then at least two authors need to conduct screening individually, and then come together at the end to resolve conflicts.\n5. The inclusion or exclusion criteria listed are not appropriate in that they do not focus on the studies themselves. They are just focused on study type, but not what the study is about. Also what is listed in the text for inclusion (e.g., must have a keyword) is not what is talked about in Table 3.\n6. The screening process was not conducted according to SR suggested processes. The authors indicate that they used the presence of a keyword in specific lines or parts of a paper to decide whether to include or not include. Again, this doesn’t align with their stated inclusion criteria and is not correct SR screening methodology.\n7. The authors note that their study is unique in that is focused on an adult population. This is not strictly true, but the authors still could have included content or summaries now what the research on medical marijuana on children with cerebral palsy suggests\n8. While I did not conduct an examination of every reference cited, there were several written in the text that are not accurate. For example, the authors write “Even though cannabis is the most commonly used illicit drug in the world today (Zhand & Milin, 2018), […]. However, that article does not actually report that finding. Zhang & Milin instead link out to a different study. I would also argue that both of these articles are outdated (2018 and 2015 respectively), especially in light of recent legislative changes to cannabis in places like the US, Canada, and Australia. The authors should look for more updated references for their content.\n9. There are numerical errors in the PRISMA flow chart. I also note that there are grammatical and spelling errors throughout the text.\n— Ultimately, I think this article needs to be more clearly reclassified as a literature review. All instances of the word ‘systematic’ should be removed so as not to give casual readers a false sense of what they are looking at, and so as not to confuse indexing procedures. I would also urge the authors to both broaden their years (2-3 years is not even sufficient for a literature review) and where they are searching. The fact that they found no literature on the topic strongly suggests that they need to adjust their search parameters. I applaud the authors for attempting to use a more transparent and comprehensive process for their search but as it was conducted it is not sufficient or exhaustive enough for either a systematic review or a comprehensive literature review.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? No\n\nIs the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required.\n\nAre the conclusions drawn adequately supported by the results presented in the review? No\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable", "responses": [ { "c_id": "13242", "date": "06 Feb 2025", "name": "Daniel McDonough", "role": "Author Response", "response": "Thank you for taking the time to review our paper we have found your suggestion and comments informative and helpful please see our responses below. Reviewer Methods: While the title of this article says it is a literature review, throughout the text the terms used is systematic review (SR), and several practices (e.g., use of a PRISMA flow chart, PRISMA checklist) suggest the authors attempted some aspects of a SR. However, the methods as outlined here are not those of a systematic review and should not be written as such. Comment The use of the term “systematic” in the body of the paper referred to systematic nature of our search for repeatability and the use of a PRISMA flowchart and checklist. On reflection we don’t believe we should have used the term “systematic literature review”. Therefore, we have decided to remove all references to systematic literature review, from this paper. Reviewer In brief, some of the issues are: 1. An extremely limited time frame of 2 years and the authors included only material available in their specific library collection. This is not how SRs are completed as they must locate ALL evidence on a specific topic. Comment We chose to only have two years as we wanted to look at the most recent and up to date literature on the topic. Also, we agree not how a SR is completed, it was never our attention to do an SR and we have now removed any mention systematic review throughout the paper. Reviewer 2. Lack of use of any subject terms specific to individual databases, such as MESH or CINAHL search terms Comment Thank you for your comment, we understand limitations of not using individual data bases. Just to clarify the first author Daniel McDonough was enrolled at Deakin University and conducted this literature review as part of his thesis for his Master of Public Health. We only used Deakin University library database, for convenience and accessibility. Reviewer 3. Lack of any reproducible search strategy for any database (although really all databases search strategies should be provided). Listing only the keywords is not sufficient. A quick search in MEDLINE using more advanced search terms quickly found several papers that would have been relevant to this article. Comment We agree and understand the limitations of our search strategy conducted. However, this literature review was never intended to be an all-encompassing systematic literature review. It was conducted for a specific reason i.e. Investigate the use of MM for treatment of pain, sleep, spasms, SEWB for adults with CP. The result of this study was used to inform a proposed research project investigating the use of MM for the complications of CP, which has now been completed. Reviewer 4. The authors write “The first and second named authors of this paper both individually completed the entire search and screening process concluding with the same outcome.”. This is not how systematic reviews are completed. There is one search done, and then at least two authors need to conduct screening individually, and then come together at the end to resolve conflicts. Comment Thanks for picking this up we have changed to “The first and second authors of this paper both individually completed the entire search and screening process. If there were any conflicts for inclusion the third author was invited to resolve any conflicts. However, both the first and second author agreed with all inclusions, so the third author was not required to participate”. See literature search results. Reviewer 5. The inclusion or exclusion criteria listed are not appropriate in that they do not focus on the studies themselves. They are just focused on study type, but not what the study is about. Also what is listed in the text for inclusion (e.g., must have a keyword) is not what is talked about in Table 3. Comment Apologies this was not clear, we used the study type exclusion inclusion with keywords as a convenient way to student to include and exclude papers we have now modified the table to more consistent and accurate. Reviewer 6. The screening process was not conducted according to SR suggested processes. The authors indicate that they used the presence of a keyword in specific lines or parts of a paper to decide whether to include or not include. Again, this doesn’t align with their stated inclusion criteria and is not correct SR screening methodology. Comment Thank you for your comment we have tried to clarify the inclusion and exclusion and removed any mention of SR. Reviewer 7. The authors note that their study is unique in that is focused on an adult population. This is not strictly true, but the authors still could have included content or summaries now what the research on medical marijuana on children with cerebral palsy suggests Comment Understand your point however, we are clinicians and clinical researchers, we conducted this literature review to provide evidence for the use of MM with adults, as we proposed to conduct a research study, investigating medicinal marijuana for the treatment of adults with Cerebral Palsy. Therefore, we were not interested in studies investigating children. Reviewer 8. While I did not conduct an examination of every reference cited, there were several written in the text that are not accurate. For example, the authors write “Even though cannabis is the most commonly used illicit drug in the world today (Zhand & Milin, 2018), […]. However, that article does not actually report that finding. Zhang & Milin instead link out to a different study. I would also argue that both of these articles are outdated (2018 and 2015 respectively), especially in light of recent legislative changes to cannabis in places like the US, Canada, and Australia. The authors should look for more updated references for their content. Comment Thanks for picking this up, this information is not relevant for the focus of this paper, we have now removed this. Reviewer 9. There are numerical errors in the PRISMA flow chart. I also note that there are grammatical and spelling errors throughout the text. Comment Thankyou for bringing this to our attention we have now attempted to make corrections. Sorry we can’t see the numerical in PRISMA flowchart can you clarify for us to make appropriate changes. Reviewer Ultimately, I think this article needs to be more clearly reclassified as a literature review. All instances of the word ‘systematic’ should be removed so as not to give casual readers a false sense of what they are looking at, and so as not to confuse indexing procedures. I would also urge the authors to both broaden their years (2-3 years is not even sufficient for a literature review) and where they are searching. The fact that they found no literature on the topic strongly suggests that they need to adjust their search parameters. I applaud the authors for attempting to use a more transparent and comprehensive process for their search but as it was conducted it is not sufficient or exhaustive enough for either a systematic review or a comprehensive literature review. Comment Thank you for your suggestion, just to clarify the first author Daniel McDonough conducted this literature review as part of his thesis for his Master of Public Health. We are clinicians and clinical researchers, and the first author conducted to inform a research project which was also a part of his Master of Public Health. The first author has now completed his Master of Public Health, and we found the literature very informative and helpful to be able to conduct our research. We have now submitted the findings of our research for publication. Title: A case study investigating medicinal marijuana for the treatment of an adult with Cerebral Palsy. Therefore, we appreciate your suggestion, but we feel this literature could be really helpful for other clinical researchers and unfortunately, we are not in the position to expand our search." } ] } ]	1	https://f1000research.com/articles/13-825
https://f1000research.com/articles/13-1367/v1	15 Nov 24	{ "type": "Clinical Practice Article", "title": "“Unmasking the Uncommon”: A case series of multi-drug resistant Elizabethkingia meningoseptica causing late-onset sepsis and meningitis in preterm neonates", "authors": [ "Prajnha U.P.", "Anisha Maria Fernandes", "Suchitra Shenoy M.", "Sinchana Bhat", "Prajnha U.P.", "Suchitra Shenoy M.", "Sinchana Bhat" ], "abstract": "Elizabethkingia meningoseptica is an uncommon nosocomial pathogen that causes meningitis, pneumonia, and sepsis in neonates and in immunocompromised individuals. It exhibits resistance to many commonly employed first-line antibiotics used to treat gram-negative pathogens. Herein, we present three cases of late-onset sepsis with multi-drug resistant (MDR) Elizabethkingia meningoseptica in high-risk neonates. Case 1 was a one-day-old preterm low-birth-weight infant who presented with respiratory distress syndrome and septic shock. The patient was intubated and administered empirical broad-spectrum antibiotics and antifungal agents. Blood culture grew Candida krusei,\nhence Amphotericin B was initiated. Repeat blood culture on day 27 showed gram-negative bacilli, identified as Elizabethkingia meningoseptica by MALDI-TOF . Antibiotic susceptibility testing (AST) revealed resistance to Piperacillin/Tazobactam, but sensitivity to Vancomycin, Levofloxacin, and Minocycline. IV Vancomycin was administered, which resulted in clinical improvement and negative blood culture results. Case 2 was an eleven-day-old preterm, low-birth-weight baby who presented with fever. Initial investigations revealed normal complete blood counts (CBC) parameters and elevated CRP levels. Blood and CSF cultures isolated Elizabethkingia meningoseptica with a similar AST pattern. Intravenous Ciprofloxacin was initiated with clinical improvement and negative follow-up blood cultures. Case 3 was a one-day-old preterm baby, appropriate-to-gestational age, presenting with respiratory distress syndrome. The infant was intubated and started on inotropic support and intravenous antibiotics. Blood cultures on day 4 showed Elizabethkingia meningoseptica and Vancomycin was started. Follow-up cultures on days 6 and 14 grew Acinetobacter baumannii. A combination of Levofloxacin and Colistin was added, and blood cultures were negative after seven days, with clinical improvement.\nElizabethkingia meningoseptica is a significant cause of hospital-acquired infections, especially in Neonatal Intensive Care Unit (NICU), leading to outbreaks. Clinicians must have a high degree of suspicion of E. meningoseptica for gram-negative bacilli causing sepsis and meningitis in high-risk patients. Recent technological advances have enabled accurate speciation to guide therapy and reduce morbidity and mortality rates.", "keywords": [ "Elizabethkingia meningoseptica", "late-onset", "sepsis", "meningitis", "Multi-drug resistance" ], "content": "Introduction\n\nElizabethkingia meningoseptica is an uncommon cause of infection that mostly affects immunocompromised individuals.1 In neonates, premature birth weight and very low birth weight are major risk factors. E. meningoseptica infections present as early onset sepsis and meningitis with a high mortality rate. Reports of late-onset sepsis and meningitis are rare.2 E. meningoseptica is found in both natural and hospital environments, and is isolated from contaminated water supplies, equipment surfaces and tubing, infant formulas, and IV solutions.3,4 Its ability to form biofilms allows it to persist in hospital environments, with outbreaks being reported, especially in Neonatal Intensive Care Units (NICU).5 Its intrinsic resistance and recent reports of multi-drug resistant strains (MDR) are a cause for growing concern.1 In the absence of established guidelines for antibiotic susceptibility testing (AST) and lack of evidence-based treatment regimens, treatment failures are common with negative patient outcomes.1\n\nWe present three cases of late-onset sepsis in high-risk neonates born at a district government hospital and admitted to the NICU simultaneously. All had a similar MDR AST profile but were successfully treated.\n\n\nCase report\n\nA 1-day-old preterm baby (32 weeks + 1 day) with low birth weight (1.42 kg), born via emergency LSCS, presented with respiratory distress syndrome and septic shock. The neonate was transferred to the NICU, intubated, started on inotropic support, and administered intravenous antibiotics (cefotaxime and gentamicin) and antifungals (fluconazole). On examination, the patient’s temperature was 36.5°C, pulse rate was 180/min, respiratory rate was 50/min, bilateral crepitations, and blood pressure was 40/24 mmHg. Results of cardiovascular and abdominal examinations were normal. On central nervous system examination, the child appeared dull.\n\nThe complete blood count (CBC) was within normal limits. Blood collected for culture in a pediatric BD BACTECTM (peds plus/F) bottle showed no growth. Serial counts showed a worsening trend, with increased CRP levels (23 mg/dL). On day 4, blood culture showed growth of Candida krusei with sensitivity to Voriconazole, Caspofungin and Amphotericin B. Voriconazole was initiated. Follow-up blood cultures sent on days 8 and 19 of admission showed persistence of Candida krusei. Hence, the treatment was changed to Amphotericin B.\n\nA follow-up blood culture on day 27 of admission flagged as positive within 24 h. Gram staining showed gram-negative bacilli, and culture yielded aerobic, 1 to 2 mm smooth, circular, greyish white non-hemolytic colonies on blood agar, and non-lactose fermenting semitranslucent colonies on MacConkey agar. The isolate was identified as Elizabethkingia meningoseptica by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) (BiomerieuxTM) and antibiotic susceptibility testing (AST) performed using VITEK 2 Compact (BiomerieuxTM). Vancomycin susceptibility was tested by using an E-strip. The isolate was sensitive to Vancomycin, Levofloxacin, Minocycline, and resistant to Piperacillin/Tazobactam. Antibiotics were changed IV Vancomycin 22 mg IV BD for 6 days. The child showed clinical signs of improvement and negative blood culture results.\n\nAn 11-day-old preterm (34 weeks + 2 days), low birth weight (1.86 kg) male baby delivered by normal vaginal delivery presented with fever. On admission, the child had a temperature of 100 °F. Neurosonogram results were normal. CBC, liver, and kidney function parameters were within normal limits; however, the CRP level was elevated (116 mg/dL). Blood cultures were collected in pediatric BACTEC bottles. The neonate was administered Piperacillin and Amikacin empirically.\n\nThe blood culture bottle flagged positive at 24 hours and showed short gram-negative bacilli. The organism was identified as Elizabethkingia meningoseptica with a sensitivity pattern identical to that of the first case. On day 8 of admission, as there was no clinical improvement and the CRP level was still elevated (131 mg/dL), lumbar puncture was performed. CSF cytology showed neutrophilic pleocytosis with increased protein (442 mg/dl) and decreased glucose (2 mg/dl) levels. CSF culture yielded E. meningoseptica with the same sensitivity pattern. The antibiotic was changed to intravenous Ciprofloxacin (20 mg TID). A follow-up blood culture on day 12 of admission showed no growth, and the markers of sepsis were negative. The patient showed clinical improvement.\n\nA 1-day-old preterm baby (28 weeks + 2 day), appropriate for gestational age (970 g), born via emergency LSCS, presented with respiratory distress syndrome. The neonate was transferred to the NICU, intubated, and started on inotropic support and intravenous antibiotics (cefotaxime and amikacin).\n\nOn examination, the patient’s temperature was 36.5°C, pulse rate was 146/min, respiratory rate was 64/min, with bilateral crepitations. Results of cardiovascular and abdominal examinations were normal. On central nervous system examination, the child appeared dull. CBC was within the normal limits. Blood cultures showed no growth. Serial counts showed a worsening trend.\n\nBlood culture collected on day 8 yielded Elizabethkingia meningoseptica within 36 h with the same AST pattern as the previous cases. Inj. Vancomycin (15 mg BD) was administered for 6 days. Follow-up blood cultures yielded pan-drug-resistant Acinetobacter baumannii. Inj Meropenem 20 mg BD, and IV Colistin 1.5 lakh IU/day in two divided doses was administered for 14 days, after which blood culture showed no growth, and the child showed clinical signs of improvement.\n\n\nDiscussion\n\nElizabethkingia meningoseptica is an emerging nosocomial pathogen widespread in natural environments. It can persist under harsh conditions in healthcare facilities and has been isolated from hospital water supplies and critical care equipment such as mechanical ventilators and indwelling catheters, resulting in outbreaks.3,4 In neonates, E. meningoseptica infection typically manifests as either early onset sepsis or meningitis. Predisposing factors in neonates include prematurity, very low birth weight, central venous catheters, immunosuppression, and prolonged and prior exposure to higher antibiotic concentrations.1,3 Neurological complications are common in 30.4% of survivors who develop hydrocephalus and 6.5% experience varying degrees of hearing loss.2,3\n\nRecent reports show a notable increase in E. meningoseptica infections, possibly due to advanced automated methods.3 E. meningoseptica is resistant to a wide range of antimicrobials including β-lactams, macrolides, tetracyclines, polymyxins, chloramphenicol, and aminoglycosides. Uniquely, it is susceptible to antibiotics used to treat gram-positive infections such as Vancomycin, Clindamycin and Rifampicin. Thus, most empirical treatments for gram-negative infections are ineffective. The potential for multi-drug resistance and the absence of established guidelines for antibiotic susceptibility testing make management even more challenging. Based on the available data, a combination of vancomycin and ciprofloxacin, linezolid, or rifampicin has demonstrated high cure rates in the treatment of E. meningoseptica meningitis and bacteremia.1,3\n\nAttempts must be made to trace the source of the infection and to take stringent steps to prevent the transmission of this infection. Infection prevention recommendations include consistently using alcohol-based hand rubs following hand washing and using sterile water to change diapers. It is also important to periodically repair, clean, super chlorinate, and replace sink taps. Continuous training is essential to reinforce proper hand hygiene practices and contact precautions for hospital personnel.6\n\nThere are a few reports of E. meningoseptica causing late-onset sepsis and meningitis.1,2 Interestingly, all of our patients had late-onset sepsis and meningitis. Cases 1 and 3 presented with bacteremia, whereas case 2 showed meningitis. Prematurity was a common risk factor for all neonates. Additionally, cases 1 and 3 had other predisposing factors such as the use of central venous catheters and prolonged and prior exposure to higher antibiotic concentrations. Timely identification of cultures allows for prompt and tailored therapy with good patient outcomes. Long-term follow-up is required to assess the potential neurological complications. Neonates were admitted to the NICU during the same period. We hypothesized that our cases were nosocomial infections; however, environmental screening failed to identify the source of infection.\n\nThe presence of gram-negative bacilli causing bacteremia or meningitis in neonates with risk factors must alert clinicians to E. meningoseptica. Prompt and appropriate antibiotic therapy is key to curbing long-term morbidity and mortality.\n\n\nEthics and consent\n\nThis study was approved by the Institutional Ethics Committee (Kasturba Medical College, Mangalore), Reg No. ECR/541/Inst/KA/2014/RR-20, DHR Reg. No. EC/NEW/INST/2020/742. Approval was given on 20.12.2023 with protocol number IEC KMC MLR-12/2023/513.\n\nWritten informed consent for publication of clinical details and/or clinical images was obtained from the parents of the patients.", "appendix": "Data availability statement\n\nNo data are associated with this article.\n\n\nReferences\n\nPatro P, Das P, Padhi P: Intrinsically resistant bacteria as looming disaster: a rare case report of Elizabethkingia meningoseptica meningitis in a neonate. J. Lab. Physicians. 2021 Feb 22; 13(01): 070–073. Publisher Full Text\n\nHashmi AW, Ahmad M, Israr MM, et al.: Multi-Drug-Resistant Elizabethkingia meningoseptica: A Rare Cause of Late-Onset Sepsis in a Preterm Neonate. Cureus. 2023 Jan 29; 15(1). Publisher Full Text\n\nSingh S, Sahu C, Patel SS, et al.: Clinical profile, susceptibility patterns, speciation and follow up of infections by Elizabethkingia species: study on a rare nosocomial pathogen from an intensive care unit of north India. New Microbes New Infect. 2020 Nov 1; 38: 100798. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nUmair A, Nasir N: Clinical features and outcomes of critically ill patients with Elizabethkingia meningoseptica: an emerging pathogen. Acute Crit. Care. 2021 Jul 26; 36(3): 256–261. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLi Y, Liu T, Shi C, et al.: Epidemiological, clinical, and laboratory features of patients infected with Elizabethkingia meningoseptica at a tertiary hospital in Hefei City, China. Front. Public Health. 2022 Sep 20; 10: 964046. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAlmatari K, Alhabsi R, Al-Rashdi M, et al.: Elizabethkingia Meningoseptica Infection in Neonates: Two Case Reports from the Eastern Region of Oman. Oman Med. J. 2022 Sep; 37(5): e416. PubMed Abstract \| Publisher Full Text \| Free Full Text" }	[ { "id": "341910", "date": "25 Nov 2024", "name": "Godwin Justus Wilson", "expertise": [ "Reviewer Expertise Antimicrobial resistance", "Antimicrobial Stewardship", "Clinical Informatics" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article provides an insight into Elizabethkingia meningoseptica infections, particularly in neonates, emphasizing their rare occurrence but severe implications, especially in immunocompromised or premature infants. The case studies presented offer valuable real-world examples of late-onset sepsis and meningitis caused by this pathogen, highlighting its multi-drug-resistant (MDR) nature and the challenges clinicians face due to the lack of standardized treatment guidelines.\nOverall, the article provides valuable clinical insights and emphasizes the need for prompt detection, tailored treatment, and robust infection control to improve outcomes for neonates affected by this challenging pathogen.\n\nIs the background of the cases’ history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the conclusion balanced and justified on the basis of the findings? Yes", "responses": [] }, { "id": "357608", "date": "22 Jan 2025", "name": "Mark Fahmy", "expertise": [ "Reviewer Expertise Published a case series of Elizabethkingia BSI in adults." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have written an interesting summary of three cases of Elizabethkingia meningioseptica BSI in pre-term infants.\n\nMajor comments: In the discussion section \"wide range of antimicrobials including β-lactams...\" - would argue that some strains retain susceptibility to piperacillin - tazobactam (accepting none in this series were susceptible, which itself is interesting and worth discussing/evaluating in the context of existing literature). However, other published literature has reported susceptibility and clinical success with piperacillin-tazobactam (e.g. Burnard D et al. 2020 (Ref 1) Comba IY, et al. 2022 (Ref 2)\nIn the discussion section \" Uniquely, it is susceptible to antibiotics used to treat gram-positive infections such as Vancomycin, Clindamycin and Rifampicin...\" I think that the role of vancomycin and rifampicin for treatment of Elizabethkingia BSI is more uncertain than this discussion suggests, and while it might be reasonable to consider use in severe infections/as part of a multi-drug regimen in complex infections, there is a dearth of evidence suggesting the strong conclusion made by the authors \" a combination of vancomycin and ciprofloxacin, linezolid, or rifampicin has demonstrated high cure rates in the treatment of E. meningoseptica meningitis and bacteremia\"\nFurther discussion about the ambiguities and gaps in the literature regarding these therapies for Elizabethkingia would allow for more nuanced recommendations.\n\nIn particular, it can be noted that 1) In adult patients, there have been documented rates of failure with vancomycin therapy as details here: Jean SS, et al., 2017 (Ref 3)\n2) There is a high prevalence of VanW gene in Elizabethkingia isolates in Australia (and this has been demonstrated elsewhere as well). This gene has also been found to confer a VanB type phenotype in other organisms. Stewart AG, et al., 2023 (Ref 4)\n3) There is overall limited data for the use of rifampicin in gram negative infections. Drapeau CM, et al., 2010 (Ref 5)\nMinor comments: In case 1 (and subsequent cases) susceptibility testing is described as use of VITEK-2 + E-test for susceptibility testing. \"antibiotic susceptibility testing (AST) performed using VITEK 2 Compact (BiomerieuxTM). Vancomycin susceptibility was tested by using an E-strip.\" There could be better description of the interpretive criteria used to determine susceptibility. In particular, what breakpoints were used- I assume CLSI non-enterobacterales breakpoints for more traditional agents (e.g. piperacillin, levofloxacin) but there would not be calibrated breakpoints for vancomycin- reporting what the MIC result would be more accurate. Minocycline sensitivity can be inferred from doxycycline or tetracycline susceptibility- was this done or was a minocycline disc/etest performed?\n\nI think the comments about control of environmental sources is very interesting. \" It is also important to periodically repair, clean, super chlorinate, and replace sink taps\" and \"We hypothesized that our cases were nosocomial infections; however, environmental screening failed to identify the source of infection.\" I agree that a nosocomial infection is likely if all three cases were acquired around the same time - it may be worth mentioning that more clearly in the case histories to emphasize this point.\nHowever some additional information may be interesting and make the discussion more applicable to a wider audience- 1) Was sequencing considered or done on the isolates from the patients to see if there was close relationship and potentially establish common epidemiological link?\n2) How was environmental sampling done- e.g. what was sampled, what methods were used to try and isolate Elizabethkingia sp. There are a variety of published methods for environmental sampling/isolation, none of them specific for Elizabethkingia > our laboratory uses these guidelines for sampling and isolation (https://www.health.vic.gov.au/infectious-diseases/victorian-guideline-on-environmental-sampling-for-cpe)\nOtherwise the authors have prepared an interesting summary of three cases of this rare but important pathogen, including a good description of a variety of risk factors and clinical outcomes.\n\nIs the background of the cases’ history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the conclusion balanced and justified on the basis of the findings? Partly", "responses": [ { "c_id": "13215", "date": "06 Feb 2025", "name": "Anisha Maria Fernandes", "role": "Author Response", "response": "The authors thank Dr. Fahmy for his in-depth review and suggestions. We have tried to address all the comments including expanding the discussions on suseptibility testing and interpretative criteria used, global patterns of susceptibility and therapeutic recommendations, as well as environmental screening methods used. Regarding susceptibility testing for Minocycline, the MIC testing was done by the VITEK 2 Compact (Biomerieux TM)." } ] } ]	1	https://f1000research.com/articles/13-1367
https://f1000research.com/articles/12-199/v1	20 Feb 23	{ "type": "Research Article", "title": "Social distancing between personal belongings during the COVID-19 pandemic", "authors": [ "Wen Guo", "Ayumi Ikeda", "Kaito Takashima", "Yoshitaka Masuda", "Kohei Ueda", "Atsunori Ariga", "Kyoshiro Sasaki", "Yuki Yamada", "Wen Guo", "Ayumi Ikeda", "Kaito Takashima", "Yoshitaka Masuda", "Kohei Ueda", "Atsunori Ariga", "Kyoshiro Sasaki" ], "abstract": "Background: The COVID-19 pandemic has led to instructions and suggestions from governments and experts to maintain social (physical) distance between people to prevent aerosol transmission of the virus, which is now becoming the norm. Thus, we examined whether the pandemic extended the distance between personal belongings.\nMethods: We recruited 68 university students and instructed them to place their belongings on a long table following another participant (i.e., confederate). We measured the physical distance between the two belongings (i.e., the participant’s and the confederate’s). We collected data between June 10, 2022 and January 23, 2023. Pre-pandemic data was from Ariga (2016). Analysis was completed with one-tailed t-tests.\nResults: Compared with the pre-pandemic results, via one-tailed t-test, the distance between the two belongings during the pandemic was significantly longer. Our results supported the hypothesis that the psychological framework for processing people’s belongings has dramatically changed during this pandemic.\nConclusion: This change may have been driven by social distancing practices or an increase in perceived vulnerability to disease. Our results provide new implications for future public spatial design, in other words, not only the distance between people, but also the distance between their belongings.", "keywords": [ "personal space", "COVID-19", "social distancing", "perceived vulnerability to disease (PVD)" ], "content": "Introduction\n\nSocial psychology and proxemics have addressed personal space as the spatial range within which we feel uncomfortable when it is encroached by others (Sommer, 1959; Hall, 1966). The center of this range is the self, but it is not restricted to the physical body, and there is more evidence that the concept of self is expanding in space and time. For example, the body representation of the self can be greatly modulated based on the perceived position of sound produced by one’s actions (Tajadura-Jiménez et al., 2012), and the ‘cutaneous rabbit’ can be felt not only on one’s body but also on the object that one is grasping (Miyazaki et al., 2010). The line of sight away from the eye can still be perceived as exerting force on the object (Guterstam et al., 2019). Furthermore, the extension of body representations to objects has been observed in neuroscience (Iriki et al., 1996).\n\nOne observed phenomenon is in some school situations where there are desk-mates; after an argument, desk-mates will avoid putting their stationery close to the other’s belongings. It is possible that people develop a tendency to recognize personal belonging as a representation of the self at an early age (Pedersen, 1973). Moreover, our previous study has shown that a sense of ownership of the body is conferred to objects (Sasaki, Watanabe, and Yamada, 2018). According to James (1890), the self is the sum of all that he can call his, including all possessions, which gives him the same emotions. Briefly, we regard our possessions as part of ourselves. Is this sense of ownership of objects related to personal space? Ariga (2016) reported that participants placed their own objects at a greater distance from the objects of those who were unfavorable. These findings suggest that individuals’ personal space extended to the space surrounding their belongings (i.e., extended personal space).\n\nThe COVID-19 pandemic has persisted for more than three years. Governments and experts have provided instructions and suggestions to maintain a certain social (physical) distance between people to prevent droplet and aerosol infection of the virus (Yonemitsu et al., 2020; Yang et al., 2021), and this is now becoming the norm (Yamada et al., 2021). Along with the research development, we know that aerosol is one of the transmission routes (Anderson et al., 2020). Coronaviruses can be released into the surrounding air and exist for an extended period for long-distance transportation (Jiang et al., 2021), which means that exposed people and objects may carry the coronavirus present in aerosols. Regardless of the purpose or function of a place, the dense gathering of many people must be avoided. Is it possible to receive such health guidance consistently and imperceptibly influence people’s social cognitive behavior? Recent studies have reported that interpersonal distance (IPD) increased during the COVID-19 pandemic (Tootell et al., 2021), and enlarged IPD preferences were predicted to persist beyond the pandemic (Welsch et al., 2021). The results of an experiment in Arabia revealed that in the post-epidemic era, 76% of the participants were already subjectively reluctant to share close physical distance or socially polite touch with others (Khan et al., 2021). Responding to precautions, the external manifestation is that we have actively increased our physical distance, but in reality, personal space has also expanded accordingly.\n\nHow has the COVID-19 pandemic and countermeasures against it changed human-human and human-object interactions? Considering the findings of Ariga (2016), one’s personal space extends to his/her belongings, leaving them with an ‘extended personal space’. The present study aimed to examine if the ‘extended personal space’ increased as well as the personal space that has been affected under the pandemic of COVID-19.\n\nWe initially tried to confirm that extended personal space would be larger during the COVID-19 pandemic than during peacetime (i.e., before the pandemic). Maintaining a social (physical) distance from each other is valid for preventing viral infection by droplets and aerosols. Such avoidance of a close distance from other people over a long period modulates personal space (Tootell et al., 2021; Welsch et al., 2021). Thus, if it is true that space surrounding one’s belongings is based on the interpersonal relationship of their owner (Ariga, 2016), we predicted that extended personal space would be larger at the present time than at peacetime (i.e., comparing extended personal space in the present time with that in Ariga’s study).\n\n\nMethods\n\nThe present study was pre-registered on the Open Science Framework (OSF) prior to conducting the experiment (Yamada et al., 2023).\n\nEthical approval for this study was obtained from the Graduate School of Human-Environment Studies, Kyushu University (approval number:2021-030). Written informed consent was obtained from all participants twice, before the experiment and after the debriefing. This was because, due to the structure of the experiment, it was impossible to give the participants all the information about what this experiment was about before the experiment. Specifically, that the person participating with the participant was a confederate, that the confederate was intentionally being friendly or unfriendly, and that the distance between the confederate’s belonging and that of the participants was the variable we wanted to measure were explained to the participants after the experiment. If this was told to the participants before the experiment, they would know the purpose of the experiment, and the experimental manipulation would be invalidated because of the demanded characteristics.\n\nThe students who participated in the experiment were recruited from the university. We recruited the students via some social networking services (SNS) such as Twitter and LINE. In addition, they contacted us to participate in the experiment by scanning the QR code on our recruitment poster, or were directly recruited face-to-face by the experimenters on campus. The inclusion criteria were native Japanese or international students who could speak Japanese proficiently. They were paid 1000 yen to agree to participate. As in Ariga (2016), data were collected from equal numbers of male and female participants in each group. One of the three potential confederates (three of the authors) participated in the experiment in pairs with an external participant.\n\nPower analysis was performed using GPower software (Faul et al., 2007). We planned to perform a one-tailed t-test on the main hypothesis. There were no related studies; thus, it was difficult to estimate the effect size. In this case, adopting an unbiased effect size (i.e., medium effect size) for power analysis is widely accepted (e.g., Chen and Kao, 2012; Juristo and Moreno, 2003). Considering this and the point when the sample size of Ariga (2016) was N = 40, we performed a power analysis (Cohen’s d = 0.5, α = .05, 1-β = .80, allocation ratio N2/N1 = 1.7), and consequently, the calculated sample sizes were N = 40 per group 1 and N = 68 per group 2. Therefore, we set N = 108 as the required sample size, and hence collected data from 68 participants. The pre-registered exclusion criterion was participants who did not place their own belongings on the table; their data were excluded, and additional participants were recruited until the available participants reached 68. Finally, we collected data from 70 participants; of these, two participants were excluded since they did not bring any belongings. Data from the remaining 68 (male = 34, female = 34, M = 20.9, SD = 2.2) participants were included in the analysis. All the participants provided written informed consent after a debriefing at the end of the experiment.\n\nTo examine our main hypothesis, we compared extended personal space before the COVID-19 pandemic (i.e., the peacetime) using Ariga’s (2016) data with that during the pandemic (the present data). There was one between-participants factor in this hypothesis. In addition, to exploratorily investigate whether the data have the same tendency as Ariga (2016), the experiment employed friendly confederate and unfriendly confederate conditions, which was a between-participants factor.\n\nThe experimental setup is shown in Figure 1. A participant entered the waiting room, where the confederate was already present, and sat next to the confederate’s chair. In the friendly condition, the confederate started to talk about the weather with the participant and then tried to continue chatting freely. However, in the unfriendly condition, the confederate ignored the participant’s conversation and sighed every 15 seconds. Then, in both conditions, the experimenter instructed the participant and the confederate to place their belongings on the table and leave the waiting room to the experimental room. The confederate put his belongings in first and then left the room. The experimenter measured the shortest distance between the two belongings and took pictures. Distance was used as the dependent variable: If both belongings were in contact, the distance was coded as 0. In the experimental room, the participants completed a fake task and a rating task of favorability for the other participant (i.e., confederate). After the experiment was completed, we asked the participants two questions: ‘Do you realize our manipulation of favorability for the confederate?’ and ‘Why did you put the belongings there?’\n\nNote. Left panel: A typical positioning of the belongings is depicted. In the experiment, the confederate and participant placed their personal belongings on the table sequentially (first, the confederate placed their backpack on the right side of the table every time). The experimenter measured the minimum distance between the two belongings (accurate to millimeters). Right panel: schematic representation of the experimental room. Two chairs were set up next to the room door: first, the confederate would sit on chair B and then, the participant was asked to sit on chair A, after entering the room. The table (W 60 cm × H 150 cm) for placing their belongings was facing the chairs.\n\nWe planned to perform the following pre-registered analyses.\n\nConfirmatory analysis: First, as our study aims to explore the changes in expanded personal space from peacetime to the pandemic, we compared our results with those of the original study (Ariga, 2016), using their data. A one-tailed t-test was conducted to confirm whether the mean distance between the nearest edges of belongings (Figure 1, left) would be significantly longer in the present experiment (i.e., the pandemic condition) than in the original (i.e., the peacetime condition). In this and subsequent analyses, the alpha level was set to α = .05 as the inference criterion.\n\nExploratory analysis: For a manipulation check, we conducted a one-tailed t-test of the favorability scores for the confederates to confirm whether these scores would be significantly higher in the friendly condition than in the unfriendly condition. Additionally, to test whether there was a difference in the effect of interpersonal relationships on extended personal space between peacetime and the pandemic, a two-way between-participants analysis of variance (ANOVA) with confederate (friendly vs. unfriendly) and experimental timing (peacetime vs. pandemic) as between-participants factors on the mean distance between belongings was conducted. For ANOVA, a significant interaction between these factors would support the hypothesis that there is a difference in the effect of interpersonal relationships on extended personal space between peacetime and the pandemic. Furthermore, the significant main effect of the confederate would indicate that we could have replicated the phenomenon of the original study (Ariga, 2016).\n\nR 4.1.0 (R Core Team, 2021) was used for all analyses in this study, and the analysis code is available at OSF (Guo et al., 2023). Effect size (Cohen's d) was calculated by effectsize package (Ben-Shachar, Lüdecke, and Makowski, 2020) version 0.6.0.1. For ANOVA, we used the anovakun function (Iseki, 2022) version 4.8.7.\n\n\nResults\n\nA total of 68 participants, 34 in the unfriendly condition (male = 17, female = 17, M = 20.83, SD = 2.22) and 34 in the friendly condition (male = 17, female = 17, M = 20.97, SD = 2.23), participated in the present study (Guo et al., 2023).\n\nAs pre-registered, we calculated the mean distance between the nearest edges of belongings (Figure 2). Welch’s unpaired t-test showed that the mean distance was significantly longer in the pandemic condition (M = 43.6, SD = 25.0) than in the peacetime condition (Ariga, 2016; M = 20.6, SD = 15.6) (t(105.63) = 5.88, p < .001, d = 1.10). The results suggest that people place their belongings further away from others in the COVID-19 era, supporting our hypothesis.\n\nNote. Red circles show mean values.\n\nNext, to check whether our manipulation was successful, we calculated the mean favorability for each condition (friendly and unfriendly) (Figure 3). Welch’s unpaired t-test showed that the friendly condition (M = 8.21, SD = 1.43) had a significantly higher mean favorability than the unfriendly condition (M = 5.15, SD = 1.52) (t(65.76) = 8.54, p < .001, d = 2.07). These results suggest that the experimental manipulation was effective.\n\nNote. Red circles show mean values.\n\nIn addition, we conducted an exploratory two-way between-participants ANOVA with the confederate (friendly vs. unfriendly) and experimental timing (peacetime vs. pandemic) as between-participants factors on the distance between belongings (Figure 4). The results showed a significant main effect of the experimental timing (F(1, 104) = 27.39, p < .001, ηG2 = 0.21). However, neither a significant main effect of the confederate (F(1, 104) = 1.66, p = .20, ηG2 = 0.02) nor an interaction (F(1, 104) = 0.85, p = .36, ηG2 = 0.01) were found. These results suggest that people place more distance between their belongings and others' in the COVID-19 era, regardless of whether the other participant (i.e., confederate) was friendly.\n\nNote. Red circles show mean values.\n\n\nDiscussion\n\nThis study aimed to investigate whether the distance between personal belongings changed during the COVID-19 pandemic. We directly replicated the experiment on the phenomenon in which distance was governed by the interpersonal relationship between owners, called extended personal space (Ariga, 2016), and explored the effect of COVID-19 on this phenomenon. Compared with the results for peacetime from Ariga (2016), the gross distance between personal belongings during the pandemic was significantly longer. The results suggest that our pre-registered hypothesis was supported; extended personal space increased during the COVID-19 pandemic. The large effect size of the difference implies that the psychological framework for processing people’s own belongings changed dramatically during this pandemic.\n\nIn this study, the procedure was directly repeated from the original experiment; the participants were Japanese university students, as in Ariga (2016), which ensured that the significant increase in distance was not due to inherent differences in personal space based on ethnicity (Hall, 1966) or age (Fry and Willis, 1971). The two experiments differed in period (peacetime vs. pandemic). Participants in this study were university students who were under the COVID-19 pandemic during their university years; they were required to maintain social distance and avoid unnecessary outings. Maintaining social distancing means reducing or minimizing human interactions (Wilder-Smith and Freedman, 2020). Several studies have confirmed the increase in personal space during the COVID-19 pandemic and suggested the practice of social distancing attributed to the increase (Fini, Tummolini, and Borghi, 2021; Fazio et al., 2021). Moreover, our study found that the distance between objects increased during the pandemic. Considering Ariga (2016), personal belongings have the same personal space-like properties as the owner, belongings also maintain their social distance when they are placed. This distance could manifest in the elongated distance of personal belongings.\n\nOne possibility is that the participants recognized the confederate and their belonging as carriers of an infectious disease. In Japan, perceived vulnerability to disease (PVD) has increased during the COVID-19 pandemic compared to pre-pandemic era (Yonemitsu et al., 2020), and the perceived risk of COVID-19 infection is associated with increased personal space (Holt et al., 2022). Since personal belongings also can be the source of infection through aerosols, the perceived risk of infection may extend to them. This suggests that participants without sufficient prior information could place their belongings at a distance from the confederate’s belonging to avoid contamination as they were unsure whether the stranger and their belonging were infected with viruses.\n\nAnother possibility is that participants tried to be compliant. In the US, a 1% increase in new cases (deaths) in the last seven days is associated with a 3% (11%) increase in social distancing intensity (Besley and Dray, 2022). In Japan, the number of cases and deaths is reported daily in the news which could maintain a high level of compliance (i.e., willingness to distance themselves socially). In fact, all valid participants in this study voluntarily wore face masks, which is a routine infection control measure. We speculated that participants may have maintained a distance between belongings to ensure compliance. This compliance-based explanation can coexist independently with the above explanation of infection avoidance.\n\nIntriguingly, the results of the exploratory analysis did not show the main effect of confederate conditions during the COVID-19 pandemic, which is inconsistent with Ariga (2016). A ceiling effect based on the large effect of the pandemic may have been involved in our study. Thus, this unfriendly manipulation did not have a salient impact on the placement location of the participants’ belongings. In other words, the width of the desk (150 cm) was long enough in the pre-pandemic period (Ariga, 2016), but may have been too short to study the effect of the confederate during the pandemic period (see Figure 1). The replicability of the original phenomenon in the confederate itself needs to be confirmed by more replication studies.\n\nAlthough there is a large difference between the present study and Ariga (2016) in terms of the COVID-19 pandemic, other potential differences could have existed as hidden moderators, which might have impacted the results. For example, Rissho University, where the Ariga (2016) experiment was conducted, is in Tokyo, while Kyushu University, where we conducted the present study, is in the deep mountainous countryside. Many of the students at Rissho University, the sample from which the peacetime data was generated, use fully crowded trains to commute to campus every day, possibly affecting one’s personal space.\n\nIn addition, about a decade has passed since Ariga’s (2016) data collection and the present study. Therefore, we should consider that changes, unrelated to the pandemic, might have occurred in the long term. For example, in the 2010s, smartphones became widespread in Japan, and hence, social media and social networking services (SNS) have greatly developed (Ministry of Internal Affairs and Communications, 2017). Although this is just a speculation, the distance for social interaction may have changed over time, as such communication without the effect of physical distance from the other person becomes mainstream. This issue can be addressed in the future by examining the relationship between personal spaces and SNS use.\n\nTo dissociate the factor of the pandemic from other potential factors, conducting the study using the same procedure again after the pandemic would be effective. If future research compares the data of Ariga (2016), the present research, and future research, such as a single case design (i.e., ABA design), they can extract the impact of the COVID-19 pandemic to our personal space more clearly than our study. Alternatively, examining the association between the impact and individual differences in disgust proneness (Haidt, McCauley, and Rozin, 1994; Curtis, De Barra, and Aunger, 2011) or compliance (Zajenkowski et al., 2020) might be helpful. This pandemic has inspired researchers worldwide, and too many papers were published (Pai, 2020). However, it is essential to reverify scientific knowledge, including our study, in the post-COVID-19 era. This should lead to strong knowledge in preparation for the next pandemic.\n\n\nConclusion\n\nIn summary, this study examined expanded personal space during the COVID-19 pandemic. Personal space is modulated by several factors including gender, personality traits (Khmiliar et al., 2020), mental status (Park et al., 2009; Schoretsanitis et al., 2016; Kennedy et al., 2009), and social function (e.g., social cognition; Holt et al., 2015). The distance of personal space serves as a mechanism to avoid disease when the body is threatened by a virus (Park, 2015). Thus, specific conditions in which the threat of infection is extremely high, such as the COVID-19 pandemic, could motivate people to place belongings at increasing distances from others. Although the present study could not clarify the mechanism of this phenomenon and has several limitations discussed above, the results show that people significantly increased, with a large effect size, the distance between personal belongings during the COVID-19 pandemic. Without regard to personal favorability, the distance between personal belongings now is already twice as great as that in peacetime. Our results provide new insights into future spatial design of public spaces. Not only the social distance between people's seats but also personal belongings need their ‘own space’ in open places. For example, but not limited to, lockers (or shelving) in gyms and large public baths should be increased in space to ensure the psychological safety and comfort of users.", "appendix": "Data availability\n\nOpen Science Framework: The influence of the COVID-19 pandemic on personal space extends to belonging (https://doi.org/10.17605/OSF.IO/SR3X8) (Guo et al., 2023).\n\nThis project contains the following underlying data:\n\n• Analysis code. (Analysis for t-tests and ANOVA of data).\n\n• Raw data.csv (Measurements of distance between each participant and confederate’s belongings for friendly and unfriendly settings for current study and Agriga 2016 data).\n\n• Picture of the distance between the two belongings.zip. (Pictures of belongings in friendly and unfriendly settings.)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAnderson EL, Turnham P, Griffin JR, et al.: Consideration of the aerosol transmission for COVID-19 and public health. Risk Anal. 2020; 40(5): 902–907. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAriga A: Expansive personal space: Distance between personal belongings reflects the interpersonal distance of their owners. Japanese J. Psychol. 2016; 87: 186–190. PubMed Abstract \| Publisher Full Text\n\nBen-Shachar MS, Lüdecke D, Makowski D: effectsize: Estimation of Effect Size Indices and Standardized Parameters. J. Open Source Softw. 2020; 5(56): 2815. Publisher Full Text\n\nBesley T, Dray S: Pandemic responsiveness: Evidence from social distancing and lockdown policy during COVID-19. PLoS One. 2022; 17(5): e0267611. 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PeerJ. 2021; 9: e11559. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nYonemitsu F, Ikeda A, Yoshimura N, et al.: Warning ‘Don't spread’ versus ‘Don't be a spreader’ to prevent the COVID-19 pandemic. R. Soc. Open Sci. 2020; 7(9): 200793. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nZajenkowski M, Jonason PK, Leniarska M, et al.: Who complies with the restrictions to reduce the spread of COVID-19? Personality and perceptions of the COVID-19 situation. Personal. Individ. Differ. 2020; 166: 110199. PubMed Abstract \| Publisher Full Text \| Free Full Text" }	[ { "id": "186686", "date": "24 Jul 2023", "name": "Leon O. H Kroczek", "expertise": [ "Reviewer Expertise experimental psychology", "social interaction research" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary: In the present, pre-registered study, participants were asked to place their belongings on a table together with the belongings of a confederate while the physical distance between personal belongings is measured as an outcome variable. These data are then compared to pre-pandemic data of the same paradigm from Ariga (2016). The authors find an increase in physical distance in the current compared to the original study and interpret these findings in the light of changes of social distances induced by the Covid-19 pandemic. The authors also investigate a within-subject manipulation, i.e. the influence of confederate friendliness on distance between belongings but do not find a significant effect and thus cannot replicate the results of Ariga (2016).\nReview: I think the present study uses an interesting and unobtrusive way to study interpersonal distance. I also applaud the authors for pre-registering their study. However, one major limitation of this study is that the main comparison is with respect to an unmatched group of participants almost 10 years ago, at a different university. The effects could be driven by changes in social distancing introduced by the Covid-19 pandemic, but there are also several other effects that could influence the data. The authors report that the sample had the same sex ratio as the original study, but what about other factors like mood, (social) anxiety, age, other person-related characteristics? Also trivial points, like whether the same kind of belongings were used between studies (jackets or handbags) might have influenced the results (e.g. jackets might fall from the table when placed too close to the border). Some of this is already discussed in the limitations but needs to be highlighted when making claims about Covid-19 related changes of behavior.\nIn my view, it would be much more convincing if the authors could show that distance is influenced by a subjective variable related to perceived vulnerability to Covid-19 (e.g. individual fear of an infection, belief about importance of social distancing as a policy against spread of infection, fear for family members,…, but also belief about whether belonging can be the source of infections) or an objective variable like cases reported in the news, number of active restrictions due to the pandemic, availability of vaccines. It seems also to be the case that standard deviations were bigger in the present study, suggesting a stronger influence of individual characteristics. Anyway, this point needs to be made more clearly throughout the manuscript and should even be reported in the abstract. Side note: Looking in the pre-registration the effect of the within-subject factor “alcohol disinfection” could be also informative about that.\nAs a related point, it would be great to get more information on the state of the pandemic at the test center during the test period. How many new infections were reported during this time? What were the active policies against spread of infections, was the topic very present in the media? I ask this because in Germany, in the second half of 2022 the pandemic was less of a topic than in the years before and there were (almost) no impacts of Covid-19 related restriction in everyday life. I wonder whether similar claims could be made about Japan during this time?\nIn addition, it would strengthen the argument of the authors to describe how the actual distance between persons was related to the distance between belongings. Was the distance in belonging correlated to actual distancing? Please also include more details on the paradigm here: How big was the distance between chairs in the experimental setting? Was it closer or further than a minimum recommended distance? Could this influence the placing of belongings?\nThe authors suggest that a ceiling effect precluded them from finding an effect of friendliness as in Ariga 2016. Looking at the distributions most of the distances were below 60 cm with the table being 150 cm wide (but please state where exactly on the table the belongings of the confederate where located), and original effect being around 10 cm. These data seem to suggest that the effect would have been observable if present. Another interpretation might therefore be that the belongings may not reflect personal space after all (contrary to Ariga, 2016). This should be discussed.\nMinor:\nI suggest to change the wording “peacetime” to “pre-pandemic” throughout\n\nI had difficulties understanding the first paragraph, maybe consider rephrasing it. Also there is more recent evidence on the relation of peripersonal space and interpersonal distance (e.g. see works of Yann Coello)\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? No", "responses": [ { "c_id": "12200", "date": "27 Aug 2024", "name": "Kaito Takashima", "role": "Author Response", "response": "Replies to the comments by Dr. Leon O. H Kroczek (University of Regensburg, Regensburg, Germany): Reviewer Comment: “I think the present study uses an interesting and unobtrusive way to study interpersonal distance. I also applaud the authors for pre-registering their study. However, one major limitation of this study is that the main comparison is with respect to an unmatched group of participants almost 10 years ago, at a different university. The effects could be driven by changes in social distancing introduced by the Covid-19 pandemic, but there are also several other effects that could influence the data. The authors report that the sample had the same sex ratio as the original study, but what about other factors like mood, (social) anxiety, age, other person-related characteristics? Also trivial points, like whether the same kind of belongings were used between studies (jackets or handbags) might have influenced the results (e.g. jackets might fall from the table when placed too close to the border). Some of this is already discussed in the limitations but needs to be highlighted when making claims about Covid-19 related changes of behavior.” Author Reply: Thank you for your comments. Unfortunately, the current evidence cannot assess the possibility that differences in data collection year, person-related characteristics, and university might influence the distance between inter-belongings. In addition, although the participants’ belongings were limited to bags in the previous study (Ariga, 2016), in the present study, we did not restrict participants to carry only bags. We agree with your comment that it is important to highlight this information when making claims about COVID-19-related changes in behavior. Thus, in the conclusion part, we added, “…the results show that people significantly increased, with a large effect size, the distance between personal belongings during the COVID-19 pandemic. It is important to note, however, that the results of the present experiment do not fully demonstrate that COVID-19 was the only factor that affected the expanded personal space between belongings.” As we stated in the Discussion section, our hypothesis was that the distance between objects to which the interpersonal relationship expands increased during the COVID-19 period, but we considered COVID-19 as just one possible reason for this. To avoid misunderstanding among readers and other researchers, we adjusted the tone of the descriptions related to the plausible explanations of our results in the Discussion section of the revised manuscript:\" ... extended personal space increased during the period of COVID-19 pandemic, but we consider COVID-19 as one of the reasons for this change. \" Reviewer Comment: “In my view, it would be much more convincing if the authors could show that distance is influenced by a subjective variable related to perceived vulnerability to Covid-19 (e.g. individual fear of an infection, belief about importance of social distancing as a policy against spread of infection, fear for family members,…, but also belief about whether belonging can be the source of infections) or an objective variable like cases reported in the news, number of active restrictions due to the pandemic, availability of vaccines. It seems also to be the case that standard deviations were bigger in the present study, suggesting a stronger influence of individual characteristics. Anyway, this point needs to be made more clearly throughout the manuscript and should even be reported in the abstract. Side note: Looking in the pre-registration the effect of the within-subject factor “alcohol disinfection” could be also informative about that.” Author Reply: Several studies related to personal distance during COVID-19, such as Fini et al. (2021), have shown that interpersonal distance is influenced by the perception of Realistic Threat, as measured through the COVID-19 threat. Moreover, previous research suggests that the public's practice of social distancing is not solely driven by the perception of infection but also by the social meaning of collective health (Fazio et al., 2021). We have added the following to the third paragraph of the introduction: “... which means that exposed people and objects may carry the coronavirus present in aerosols. Doremalen et al. (2020) compared the survivability of SARS-CoV-2 (leading to COVID-19) and SARS-CoV-1 on different surfaces. They found that the survival time of SARS-CoV-2 on various material surfaces ranged from a few hours to a few days, suggesting that the surface of an item can be a potential pathway for virus transmission. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) have also mentioned that the virus can be transmitted through direct contact with contaminated surfaces.” We greatly appreciate your suggestion to include these previous research findings in the manuscript and the abstract. This will help clarify to readers that the increased distance between belongings during COVID-19 may be influenced by the perceived threat that objects can also be a source of infection. Regarding the “alcohol disinfection” condition, it belonged to another experiment in our lab. For this experiment, we can only provide the results, which indicate that expanded personal space does not change depending on hand disinfection. Reviewer Comment: “As a related point, it would be great to get more information on the state of the pandemic at the test center during the test period. How many new infections were reported during this time? What were the active policies against spread of infections, was the topic very present in the media? I ask this because in Germany, in the second half of 2022 the pandemic was less of a topic than in the years before and there were (almost) no impacts of Covid-19 related restriction in everyday life. I wonder whether similar claims could be made about Japan during this time?” Author Reply: We utilized Google Trends to track the frequency of the keyword \"コロナ\" (Japanese term for COVID-19) in Google searches. The data revealed that media coverage of COVID-19 in Japan fluctuated significantly, with the peak occurring at the onset of the pandemic in early 2020. Our experiment took place from June 2022 to January 2023, during which time the final wave of COVID-19 peaked, and media coverage remained high. However, by January 2023, media coverage started to decrease. Additionally, COVID-19-related information was widely disseminated not only through news and entertainment media but also in public places such as restaurants and shopping malls, where social distancing and health and safety measures were prominently displayed. According to Japanese news reports [Please refer to the below links for Image 1 and Image 2], the number of new COVID-19 infections across Japan exceeded 40,000 per day starting in June 2022, reaching over 100,000 per day by July 2022. This marked the highest number of cases since the initial outbreak of COVID-19 in Japan in 2020. Image 1 Reference link: https://f1000research.s3.amazonaws.com/linked/669428.Image_1.pdf Image 2 Reference link: https://f1000research.s3.amazonaws.com/linked/669429.Image_2.pdf Reviewer Comment: “In addition, it would strengthen the argument of the authors to describe how the actual distance between persons was related to the distance between belongings. Was the distance in belonging correlated to actual distancing?” Author Reply: While we believe that our current findings reflect the physical distance between the confederate and the participant, we did not measure this distance during the actual experiment. Instead, we fixed their physical distance to eliminate any potential influence that physical distance might have had on the placement of objects, as it could have affected the results. Reviewer Comment: “Please also include more details on the paradigm here: How big was the distance between chairs in the experimental setting? Was it closer or further than a minimum recommended distance? Could this influence the placing of belongings?” Author Reply: The distance between the two chairs was approximately 30-40 cm, significantly less than the recommended social distancing measure of 2 meters due to the constraints of the experiment room's size and layout. The small distance between chairs may have created a sense of social anxiety and constriction at the beginning, making participants place belongings farther away to alleviate seated proximity in subsequent place sessions. No studies have been done to illustrate the effect of physical proximity on the unraveling of the distance between items. We added this part of the influence of chair distance on the distance of placing objects in the limitation part. \"... as they were unsure whether the stranger and their belongings were infected with viruses. Moreover, some previous studies declared that the confined spaces may enhance the feeling of personal space invasion, thereby increasing psychological stress and anxiety (Aiello et al ., 1977; Evans, & Wener, 2007). In the present study, for strict replication and fair comparison, the chair distance was set to be the same as in the original experiment conducted in the pre-pandemic period, but the small distance between chairs may have created a sense of social anxiety and constriction at the beginning, making participants place belongings farther away to alleviate seated proximity in subsequent place sessions. No studies that have been done to illustrate the effect of physical proximity on the unraveling of the distance between items. \"... and sat next to the confederate’s chair. The distance between two chairs was roughly 30-40 cm.\" in the Procedure section. Reviewer Comment: “The authors suggest that a ceiling effect precluded them from finding an effect of friendliness as in Ariga 2016. Looking at the distributions most of the distances were below 60 cm with the table being 150 cm wide (but please state where exactly on the table the belongings of the confederate where located), and original effect being around 10 cm. These data seem to suggest that the effect would have been observable if present. Another interpretation might therefore be that the belongings may not reflect personal space after all (contrary to Ariga, 2016). This should be discussed.” Author Reply: Thank you for your insightful comment. Our manuscript lacked a crucial piece of information: the size of the confederate's belongings, which is approximately 36 cm wide. We have now included this detail in our manuscript. Although the confederate experimenters tried to place their belongings as far as possible to the left corner of the desks, the space left for the participants was estimated to be around 100-110 cm. Additionally, the maximum distance between the belongings would be approximately 60 cm, assuming the participant's belongings were about 40 cm wide. Attempting to increase the distance by 10 cm from the unfriendly confederate's belongings to the average brings it close to the maximum possible distance. Participants might have avoided placing their belongings in the corners due to concerns about them falling. We believe that if the desks had been longer, participants could have placed their belongings further from the unfriendly confederate's belongings without the risk of them falling. Based on this context, we interpreted the results as being influenced by a ceiling effect. Your comment helped us identify and address this missing information. Reviewer Comment: Minor: “I suggest to change the wording “peacetime” to “pre-pandemic” throughout.” Author Reply: We changed it to “pre-pandemic”. Reviewer Comment: “I had difficulties understanding the first paragraph, maybe consider rephrasing it. Also there is more recent evidence on the relation of peripersonal space and interpersonal distance (e.g. see works of Yann Coello)” Author Reply: Thank you for your comments. We have rewritten the first paragraph and added new studies to help clarify our logic for you and the readers. “Social psychology and proxemics have long addressed personal space as the spatial range surrounding the individual (Sommer, 1959; Hall, 1966). The space around them represents a mediation zone between the body and the environment, contributing to the organization of social life. For example, when this space is encroached by others, we may feel uncomfortable or may prepare our bodies for defensive responses (Hall, 1966; Coello and Cartaud, 2021). However, the center of personal space is oneself, but it is not restricted to the physical body; much evidence proposed that the concept of self is expanding in space and timeline. For example, the ‘cutaneous rabbit’ can be felt not only on one’s body but also on an object that one is grasping (Miyazaki et al., 2010). The line of sight away from the eye can still be perceived as exerting force on the object (Guterstam et al., 2019). Furthermore, the extension of body representations to objects has been observed in neuroscience (Iriki et al., 1996). As a result, personal space boundaries also expand with the extension of body perception.”" } ] }, { "id": "259293", "date": "14 May 2024", "name": "Tomoko Isomura", "expertise": [ "Reviewer Expertise experimental psychology", "embodied cognition", "social cognition" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary: This pre-registered study aimed to examine the effect of the COVID-19 pandemic on human behavior, specifically how long people prefer to keep their personal belongings distanced from others. The authors set up a scenario in which participants placed their personal belongings on a desk after a confederate had done the same, without being aware of the study's purpose. They measured the physical distance between the belongings of the participant and the confederate. The obtained data were compared with those from a previous study (Ariga, 2016), conducted before the pandemic using identical procedures. The results showed that the distance between belongings in the present study was greater than reported in the previous study. The authors concluded that the pandemic has increased the personal space people maintain, which further extends the distance they keep from others' belongings. Additionally, although the authors manipulated the confederate’s friendliness—a factor that the previous study demonstrated had an effect—this manipulation did not induce any differences in the present study.\n\nI found this study interesting, particularly in that the methods they employed were well-designed to capture human’s implicit attitude for the boundaries of self and others. The manuscript is generally well written, and it is valuable that the authors pre-registered this study. However, I have some concerns about this manuscript in its current form, as follows.\nFirstly, I question whether the terms \"extended\" or \"extension of\" personal space accurately represent the phenomenon described. I acknowledge that our representation of the bodily self can be modulated when manipulating objects or interacting with others, potentially resulting in an \"extension,\" enlargement, or prolongation—or even the opposite—of one's peri-personal or personal space. However, the mental attitude of keeping one's belongings separate from others', especially when the objects are placed away from the body (e.g., on a desk when temporarily leaving), does not seem to me to constitute an \"extension\" of personal space, although I agree that it reflects some processing of self-other boundaries. It would be advantageous if the authors could include additional literature to support this concept, beyond Ariga (2016). On a related but more minor point, the authors state in the second paragraph of the Introduction that Sasaki et al., 2018 demonstrated that a sense of body ownership is conferred to objects. However, I believe that this study is more appropriately interpreted as showing that the sense of \"object ownership\" is driven by body-related processing, and the authors' interpretation may be somewhat misleading.\nSecondly, and more importantly, I found it highly challenging to assert that the effect observed by the authors is truly driven by the COVID-19 pandemic, given the limited measures they collected. While I acknowledge the inherent challenges in proving such causation, I suggest that the authors provide more information and/or conduct additional analyses to make the study more persuasive. Firstly, the authors should clearly state the size of the table and the position of the chair, ensuring they are indeed identical to those used in Ariga (2016). The authors should include this information in the main text, not just within a figure. I assume that the relative position of the chairs to the table would affect the participant’s behavior, as people tend to place objects directly in front of where they are seated. Thus, it is essential that these parameters were controlled between the studies. I also suggest the authors provide more information about the confederates, including their sexes and ages, because Ariga (2016) demonstrated that the relationship between the confederates' and participants' sexes had a clear effect on the results. Furthermore, I speculate that the size or number of the participants' belongings could affect the distance measures. It seems that Ariga (2016) considered only the participant’s bag, but what was the case in this study? If the authors have pictures of the placement of the belongings, they might be able to conduct additional analyses that could potentially rule out the influence of the size/number of the participant’s belongings on the findings. Ideally, it would have been valuable if the authors had collected some subjective scales related to the pandemic, such as how afraid the participants were of or how cautious they were about the infection. This could be a subject to consider for future studies.\nMinor points:\nIn the third paragraph of the Introduction, the authors reference Tootell et al., 2021, as a study that reported an increase in interpersonal distance during the pandemic. However, I believe that this study was conducted before the pandemic. Could it be that the authors intended to cite Holt et al., 2022 instead? The authors should clearly specify the timing of data collection within the Methods section of the main text. Upon reviewing the raw data provided by the authors, I noticed that it includes 70 data. If I understood correctly, there should only be 68 data since 2 participants did not bring any belongings. Please check this. This study did not find any effect of the confederate's friendliness on the participants' behavior. The authors claims that this result is inconsistent with findings from Ariga (2006), potentially due to a ceiling effect. However, since the ANOVA revealed only a main effect of experimental timing and the interaction was not significant, it may be misleading to definitively state that the findings are inconsistent regarding the effect of the confederate's friendliness.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "12201", "date": "27 Aug 2024", "name": "Kaito Takashima", "role": "Author Response", "response": "Replies to the comments by Dr.Tomoko Isomura (Graduate School of Informatics, Nagoya University, Nagoya, Japan): Reviewer Comments: “This pre-registered study aimed to examine the effect of the COVID-19 pandemic on human behavior, specifically how long people prefer to keep their personal belongings distanced from others. The authors set up a scenario in which participants placed their personal belongings on a desk after a confederate had done the same, without being aware of the study's purpose. They measured the physical distance between the belongings of the participant and the confederate. The obtained data were compared with those from a previous study (Ariga, 2016), conducted before the pandemic using identical procedures. The results showed that the distance between belongings in the present study was greater than reported in the previous study. The authors concluded that the pandemic has increased the personal space people maintain, which further extends the distance they keep from others' belongings. Additionally, although the authors manipulated the confederate’s friendliness—a factor that the previous study demonstrated had an effect—this manipulation did not induce any differences in the present study. I found this study interesting, particularly in that the methods they employed were well-designed to capture human’s implicit attitude for the boundaries of self and others. The manuscript is generally well written, and it is valuable that the authors pre-registered this study. However, I have some concerns about this manuscript in its current form, as follows.” “Firstly, I question whether the terms \"extended\" or \"extension of\" personal space accurately represent the phenomenon described. I acknowledge that our representation of the bodily self can be modulated when manipulating objects or interacting with others, potentially resulting in an \"extension,\" enlargement, or prolongation—or even the opposite—of one's peri-personal or personal space. However, the mental attitude of keeping one's belongings separate from others', especially when the objects are placed away from the body (e.g., on a desk when temporarily leaving), does not seem to me to constitute an \"extension\" of personal space, although I agree that it reflects some processing of self-other boundaries. It would be advantageous if the authors could include additional literature to support this concept, beyond Ariga (2016). On a related but more minor point, the authors state in the second paragraph of the Introduction that Sasaki et al., 2018 demonstrated that a sense of body ownership is conferred to objects. However, I believe that this study is more appropriately interpreted as showing that the sense of \"object ownership\" is driven by body-related processing, and the authors' interpretation may be somewhat misleading.” Author Reply: Thank you very much for your insightful comments. Before starting this study, we extensively debated the differences between the sense of ownership and personal space and territory, ultimately concluding that this phenomenon is related to personal space. Here, we outline our rationale: The most significant evidence that the extended space is part of personal space is its variability depending on the level of familiarity with others. The size of personal space is not fixed; it varies depending on the level of familiarity with others. Ariga (2016) reported that this feature is also reflected in owned objects. Our focus on this feature is why we use the term \"personal space.\" While it is true that the \"extension of personal space\" shares similar characteristics with personal space in terms of variability based on familiarity with others, we agree with your point that the \"extension of personal space\" discussed in our study is not entirely the same as \"personal space.\" As you pointed out, concepts such as the sense of ownership and territory are likely relevant to this phenomenon. To prevent readers from misunderstanding the same confusion as you, we have clarified the concept of “extension of personal space” in the original article: The end of the second paragraph in the introduction: “…extended to the space surrounding their belongings (i.e., extended personal space). The placement of such personal belongings can be considered the most significant evidence of an extension of personal space, as it shares the same characteristics with personal space (Russell & Ward, 1982; Becker, 1973), that the variability depending on the level of familiarity with others.” Additional references: Russell, J. A., & Ward, L. M. (1982). Environmental psychology. Annual Review of Psychology, 33, 651–688. https://doi.org/10.1146/annurev.ps.33.020182.003251 Becker, F. D. (1973). Study of spatial markers. Journal of Personality and Social Psychology, 26, 439–445. As for the second point you mentioned about the citation of Sasaki et al (2018), after checking, we agree that this citation is not optimal and potentially misleading here. The argument for this statement is also mentioned later in the paragraph, so we have deleted this sentence. Reviewer Comments: “Secondly, and more importantly, I found it highly challenging to assert that the effect observed by the authors is truly driven by the COVID-19 pandemic, given the limited measures they collected. While I acknowledge the inherent challenges in proving such causation, I suggest that the authors provide more information and/or conduct additional analyses to make the study more persuasive. Firstly, the authors should clearly state the size of the table and the position of the chair, ensuring they are indeed identical to those used in Ariga (2016). The authors should include this information in the main text, not just within a figure. I assume that the relative position of the chairs to the table would affect the participant’s behavior, as people tend to place objects directly in front of where they are seated. Thus, it is essential that these parameters were controlled between the studies. I also suggest the authors provide more information about the confederates, including their sexes and ages, because Ariga (2016) demonstrated that the relationship between the confederates' and participants' sexes had a clear effect on the results.” Author Reply: Thank you very much for pointing out the inadequacies in our description. For the purpose of controlling the possible influence of the experimental setting on the results, in the present experiment, we used a table of exactly the same size as Ariga (2016), and the positions of the chairs and table were exactly the same as in Ariga's (2016) study. Indeed, including these contents in the main text can help readers better eliminate concerns about the impact of experimental settings on the results, so we clearly stated the contents of this part in the main text. That said, we should consider other factors, than COVID-19, like mood, anxiety, or other person-related characteristics. Moreover, in our experiment, the confederates were three graduate male students who took turns according to their schedules. Their average age was 23.6 years old (the confederate in the original experiment was a 21-year-old male). We also added information about the gender and age of the confederates in the original text. Reviewer Comments: “Furthermore, I speculate that the size or number of the participants' belongings could affect the distance measures. It seems that Ariga (2016) considered only the participant’s bag, but what was the case in this study? If the authors have pictures of the placement of the belongings, they might be able to conduct additional analyses that could potentially rule out the influence of the size/number of the participant’s belongings on the findings.” Author Reply: Although we asked participants to come with their bags, we did not force them. Participants came with their bags, jackets, notebooks, and so on. Because we did not record the type of belongings as well as the size of them, it is difficult to analyze the effects of them. Instead, to control the effect of the size of the items on the results, we standardized the measurements by only measuring the minimum distance between two objects and did not include the size of the objects themselves. We believe that with this approach we can minimize the effect of object size on the results and make full use of the sample size. Reviewer Comments: “Ideally, it would have been valuable if the authors had collected some subjective scales related to the pandemic, such as how afraid the participants were of or how cautious they were about the infection. This could be a subject to consider for future studies.” Author Reply: Unfortunately, we did not measure subjective scales related to the pandemic. We added this point in the Discussion section for future research. Instead, the trend of the pandemic was added in the main text, following the other reviewer. Reviewer Comments: Minor points: “In the third paragraph of the Introduction, the authors reference Tootell et al., 2021, as a study that reported an increase in interpersonal distance during the pandemic. However, I believe that this study was conducted before the pandemic. Could it be that the authors intended to cite Holt et al., 2022 instead?” Author Reply: Thank you very much for pointing out our misunderstanding. Although this article (Tootell et al., 2021) was conducted during the period of COVID-19, the conclusion does not indicate the relationship between the increased interpersonal distance and COVID-19. Therefore, we accept your kind suggestion to cite Holt et al. (2022) and add a reference to Lachini et al. (2021) to increase the persuasiveness of the previous study. The details of the references are as follows: Iachini, T., Frassinetti, F., Ruotolo, F., Sbordone, F. L., Ferrara, A., Arioli, M., ... & Ruggiero, G. (2021). Social distance during the COVID-19 pandemic reflects perceived rather than actual risk. International Journal of Environmental Research and Public Health, 18(11), 5504. Holt, D. J., Zapetis, S. L., Babadi, B., Zimmerman, J., & Tootell, R. B. (2022). Personal space increases during the COVID-19 pandemic in response to real and virtual humans. Frontiers in Psychology, 13, 952998. We also revised our manuscript. Reviewer Comments: “The authors should clearly specify the timing of data collection within the Methods section of the main text.” Author Reply: Thank you for your advice. Although the experiment period was referred to in the abstract, we added the timeline of data collection in the method- participants part of the main text as follows: The experiment period was from June 10, 2022, to January 23, 2023. Reviewer Comments: “Upon reviewing the raw data provided by the authors, I noticed that it includes 70 data. If I understood correctly, there should only be 68 data since 2 participants did not bring any belongings. Please check this.” Author Reply: What you understand is correct. Two of the participants did not take any of their belongings to take part in the experiment. Therefore, the experimental conditions were not met, and we excluded the data from these two participants. Moreover, we have mentioned the exclusion in the main text as follows: we collected data from 70 participants; of these, two participants were excluded since they did not bring any belongings. Reviewer Comments: “This study did not find any effect of the confederate's friendliness on the participants' behavior. The authors claims that this result is inconsistent with findings from Ariga (2006), potentially due to a ceiling effect. However, since the ANOVA revealed only a main effect of experimental timing and the interaction was not significant, it may be misleading to definitively state that the findings are inconsistent regarding the effect of the confederate's friendliness.” Author Reply: Our study indeed did not find a significant effect of the confederate's friendliness on the participants' behavior, as indicated by the lack of a significant interaction in the ANOVA. We acknowledged this finding and compared it with the results from Ariga (2006), where friendliness did have an effect. In our discussion, we suggested that the inconsistency with Ariga (2006) might be due to a ceiling effect. The ceiling effect suggests that participants may have already reached a maximum level of performance or behavior, making it difficult to observe any additional effect of the confederate's friendliness. While this is a plausible explanation, we agree that it should be presented as a hypothesis rather than a definitive conclusion. To address your concern about the conclusiveness of our statement, we propose revising our discussion to indicate that the findings are suggestive rather than conclusive. Here is the revised statement: “Intriguingly, our study did not find a significant effect of the confederate's friendliness on participants' behavior, as indicated by the lack of a significant interaction effect in the ANOVA. This result appears to be inconsistent with the findings from Ariga (2016). One possible explanation for this discrepancy could be a ceiling effect, where participants' behavior might have already reached its peak, limiting the observable impact of additional friendliness.”" } ] } ]	1	https://f1000research.com/articles/12-199
https://f1000research.com/articles/12-1441/v1	07 Nov 23	{ "type": "Research Article", "title": "Epidemiological profiles and causes of sudden deaths of various ages in Ethiopia: an autopsy-based study", "authors": [ "Alemayehu Shiferaw Lema", "Sesen Tsegaye Tekle", "Sesen Tsegaye Tekle" ], "abstract": "Background Sudden death is an important global public health issue. An autopsy is an important source of epidemiological data, as the considerable causes of sudden death remain hermetic until postmortem examination. This study is devoted to evaluating the sociodemographic, behavioral, clinical and pathological characteristics of sudden deaths of various ages in Ethiopia.\n\nMethods This is an observational, prospective, descriptive study that included all sudden deaths observed over 1 year at St. Paul’s Hospital and Millennium Medical College, Addis Ababa, Ethiopia.\n\nResults Sudden death (n = 568) accounted for 11.5% of all autopsied cases. There were 482 males and 86 females (M:F ratio of 5.6:1) and a mean age of 44.81±17.349. The peak age group was the fourth and fifth decades, accounting for 43.9% of the cases. Chronic substance abuse and a history of prior illness were declared in 40.1% and 38% of victims of sudden death, respectively. Cardiovascular (36.1%), respiratory (32.6%), and gastrointestinal system (19.5%) pathologies were the most common causes. The leading underlying causes of sudden death were ischemic heart disease and pneumonia. Most (86.6%) sudden deaths occurred outside of a hospital setting.\n\nConclusions Most of the causes of sudden death in Ethiopia can be prevented and treated. The majority of sudden deaths are silent without preexisting symptoms. Therefore, it is vital to develop public health measures that will help educate the community about the importance of recognizing the manifestation of various clinical conditions and the need to seek immediate clinical help. Furthermore, efforts should be made to make healthcare facilities accessible and affordable with adequate diagnostic and management capacity. Documentation of autopsy-based data could provide important epidemiological information to guide medical services, prevention efforts, and control measures.", "keywords": [ "Sudden death", "Sudden and unexpected natural death", "Sudden cardiac death", "Causes of death", "Autopsy", "Natural death", "Ethiopia" ], "content": "Introduction\n\nSudden death is an important global public health issue, especially when it occurs in apparently healthy individuals due to the bearing these losses have on individuals, families, communities and wider society. The definition of sudden death varies according to authorities and conventions.1 According to the World Health Organization (WHO), death is considered a sudden death (SD) when a nonviolent and unexpected death occurs within 24 hours after the commencement of a fatal illness.2 The frequency and pattern of sudden death in different parts of the world vary greatly due to the diversity of prevalent diseases in various nations and due to diverse genetic and environmental factors.3,4\n\nSudden unexpected natural death is often the initial clinical appearance of an underlying condition in people who had previously been asymptomatic and seemingly healthy.3,5 Furthermore, since many of these deaths are unwitnessed and unattended by clinicians, the extent of the problem is difficult to determine. In this circumstance, an autopsy is an initial and sole opportunity to determine and document the precise cause of death.1,4,6 In Ethiopia, SD is regarded as a type of medicolegal death for which an autopsy is required to determine the cause.\n\nPublic health authorities, therefore, depend heavily on vital statistics systems with a focus on the cause of death (COD) for formulating their programs, both curative and preventive specialist services. Mortality statistics are an essential component of the nation's vital statistics system. They are the ingredients to measure population growth and provide a demographic perspective for the planning of development in social services. Cause-specific mortality rates are crucial measures of population health trends. There are several challenges in interpreting epidemiological information in resource-limited settings, including a lack of uniformity and low quality of death certificates as well as the utilization of verbal autopsies.6–8 Thus, vital health information may not reach the national registry, which could prevent the implementation of crucial interventions and prevention measures. Accurate evidence on causes of death is necessary to recognize the general epidemiological profile of diseases in Ethiopia and to support decision-makers in prioritizing the public health agenda. An autopsy is an important source of epidemiological data, as the considerable causes of SD remain hermetic until postmortem examination.1 Therefore, epidemiological autopsy-based data on sudden death causes are vital to understand the characteristics of the affected population and customize public health programs. To our knowledge, this is the first study paper on SD in Ethiopia and is devoted to documenting the sociodemographic, behavioral, clinical and pathological characteristics of sudden death victims of various ages.\n\n\nMethods\n\nThis is an observational, prospective, descriptive study that included all sudden unexpected natural cases observed from July 1, 2019, to June 30, 2020, in the Department of Forensic Medicine and Toxicology of St. Paul’s Hospital and Millennium Medical College (SPHMMC), Addis Ababa, Ethiopia. SPHMMC is a tertiary hospital and medical college governed by a board under the Federal Ministry of Health. SPHMMC in Addis Ababa and Aider Hospital in the Tigray region were the only two centers in the country providing forensic medicine and toxicology services during the study period. The Department of Forensic Medicine and Toxicology, SPHMMC, offers postmortem services to almost all regions of Ethiopia, except cases from the Tigray region served by Aider Hospital.\n\nThis study included all SD cases (according to the WHO definition) brought for autopsy from July 1, 2019, to June 30, 2020. The WHO defines SD as death that occurs within 24 hours after the disease’s commencement in a person not known to have been diagnosed with a serious disease, accident, or poisoning.2 In consideration of this definition, two factors were considered: 1) the time of onset of terminal signs or symptoms until death and (2) the expectation of death at the time of occurrence. The definition of the onset of terminal signs or symptoms used in this study was the time when an individual had to change his activity because of the illness. The time of death was defined as the time an individual was pronounced dead. For unwitnessed deaths in which an individual was known to have been alive within 24 hours before the pronounced time of death, they were considered sudden death. The second factor in deciding whether or not the death was sudden was the unexpected nature of the occurrence. The degree of disability reported before death was used as a measure of the expectation of death at the time of the event. Individuals who died but were not confined to their homes, health facilities, or other related institutions due to illness for more than 24 hours before death were not considered unexpected deaths and were not included.\n\nPrincipal investigators and five well-trained medical doctors collected the data. Information on the biodata of the victims, clinical data and circumstances of the death was collected from all potential sources, such as police files, medical records, and direct interviews with the eyewitnesses, relatives, and friends of the victims. The duration of hospital stay before death was extracted from the hospital record, autopsy referral papers, and police requests.\n\nFull postmortem examinations were carried out in each instance using the Letulle evisceration procedure, systematically inspecting all cavities, including the cranial, cervical, thoracic, and abdominal cavities. Organs were dissected, examined and checked for signs of gross pathological changes and violence. Autopsied specimens (whole organs or organ pieces) were fixed in 10% formalin for histopathological examination. Multiple sections with thicknesses of 4-5 mm were taken. The tissues were processed, subjected to paraffin sectioning at a thickness of 4 micrometers and then stained using hematoxylin and eosin staining.\n\nA structured data collection form was used to obtain all relevant clinical, epidemiological and pathological data. The predesigned data collection form was pretested in 50 cases to maintain data quality, and the necessary amendment was made to the form before the actual data collection. Data entry was performed using Microsoft Excel 2016 and exported to the Statistical Package for Social Science (SPSS window version 26) for analysis. Descriptive summary measures were used to characterize sociodemographic, behavioral, clinical characteristics and circumstances of death. A chi-square test was used to compare categorical variables, and the level of significance was set at a p-value <0.05.\n\nEthics approval was obtained from the SPHMMC Institutional Review Board (Ethical clearance reference no: PM 23/188). The study was conducted as per the Declaration of Helsinki. All information was treated anonymously and confidentially using unique identification codes rather than individual names and identifications.\n\n\nResults\n\nA total of 4,942 medicolegal autopsies were performed during the study period, of which 568 cases were due to SD, accounting for 11.5% of the total autopsied cases. The youngest case was a 1-day-old male newborn, and the oldest was a 98-year-old man, with a mean age of 44.81±17.349. Males (n = 482/586) were predominant over females (n = 86/586) at a ratio of 5.6:1.27\n\nThe maximum number of sudden deaths (24.3%) was in the age group of 31-40 years, followed by 41-50 years, which represents 19.6% of all SD cases. SD was less prevalent in extreme age groups, less than 10 years (1.8%) and over 70 years (6.7%). Males outnumbered females in all age groups. The fourth decade was the most predominant age group seen in males and females, accounting for 23.9% and 26.7% of total sex-specific cases, respectively. The number of cases by age and sex is summarized in Figure 1.\n\nMore than two-thirds of the victims of SD (70%) belonged to urban areas, whereas 30% of victims were from rural areas. There was a statistically significant difference between the residence of the victims and sex (p<0.001). Most of the victims were from Addis Ababa city, the capital city of Ethiopia, accounting for 59.2% (n=336) of cases, followed by the Oromia region (23.6%), and the remaining 17.2% were from six other regions of the country. Table 1 summarizes the sociodemographic characteristics of the victims of sudden death.\n\n* SNNRS-Southern Nations Nationalities and Peoples’ Regional States.\n\nSubstance use was reported in approximately 40.1% (n=228) of all SD cases. Chronic alcohol use was reported in 24.3% of victims, followed by khat (Catha edulis) and cigarettes in 9.3% and 6.5%, respectively. Moreover, 10% of the victims use two or more of these substances. There was a statistically significant relationship between substance abuse and sex (p<0.001) and residence (p=0.004). A different distribution was observed for chronic alcohol use and sex (p<0.001).\n\nMore than one-third of cases (38%) had a history of prior chronic medical illness, and diabetes mellitus (n=97 cases, 17.1%) was the most common disease. In 5.8% of victims, there is a history of SD in first-degree relatives. There was a statistically significant relationship between the presence of a prior chronic illness and sex (p=0.022). Table 2 summarizes the clinical characteristics and habits of substance use and SD in first-degree relatives of victims.\n\nMore than three-quarters of the victims were found dead (68%, n=387/568 cases), followed by victims who died at the time of arrival or after a short period of arrival in health facilities (23.1%, n=131/568 cases). Approximately 6.3% (n=36 victims) died instantaneously. Prodromal signs and symptoms were reported in 178 victims of SD. Of these 178 victims, 70.8% (n=126) sought medical help. The most common terminal signs and symptoms of SD were chest pain (n=45 cases), followed by dyspnea (n=43 cases) and syncope (n=42 cases). Of the 178 victims, 42.1% died within 1 hour of the onset of symptoms, while 36% and 21.9% of the victims died between 1-6 hours and 6-24 hours of the onset of symptoms, respectively. The majority of sudden death incidents occurred at home in 34.9% (n=198) of the cases, followed by public places and health facilities in 30.3% and 23.4%, respectively.\n\nCardiovascular system diseases (CVS) were the leading causes of SD, accounting for 36.1% of all SD cases. This was followed by respiratory and gastrointestinal system pathologies, accounting for 32.6% and 19.5%, respectively. Central nervous system (CNS) and genitourinary system (GUS) pathologies were the least prevalent causes of death, accounting for 10.6% and 1.2%, respectively.\n\nMale cases were affected more than female cases in each system, except in the GUS, in which female cases were prevalent. There was a statistically significant difference between the causes of death by organ system and sex, p<0.004. Comparisons of COD by organ system and sex are summarized in Table 3.\n\n* Significant.\n\nIschemic heart disease (IHD) and pneumonia are the most common underlying causes of SD. The underlying COD in each organ system is detailed in Table 4. Pneumonia was the most common cause of sudden death in the first, third, and fourth decades of life and the second leading COD after the fifth decade following IHD. Ischemic heart disease was the most common COD in general and in both sexes, was the leading cause after the fifth decade and was the second most common COD in the age group of 21-40 years. Table 5 summarizes the common causes of SD by age group.\n\nThe most common COD among CVS was ischemic heart disease, accounting for 69.8% of CVS deaths and 25.2% of all sudden deaths, that is, the leading cause of SD overall and in both sexes. Cardiomyopathy was the second most common COD in the CVS category and caused 5.3% of all sudden deaths (Table 4). Only 4.4% of victims among these categories of sudden deaths had previously been diagnosed with cardiovascular disease.\n\nIn the cardiovascular category of sudden death, the modifiable cardiovascular risk factors (CVRFs) identified were diabetes mellitus in 31.7% (65/205) and hypertension in 17.6% (36/205) of the victims. Furthermore, a history of alcohol, khat, and smoking was declared in 45 victims. Chronic alcohol use was the most common substance used and was reported in 38 (18.5%) of 205 victims. This was followed by the use of khat and cigarettes, each of which was reported in 14 cases (6.8%).\n\nThe most common terminal symptoms reported among CVS victims of sudden death were syncope (n=39 cases) and chest pain (n=25 cases). In 61 of 205 cases (29.8%), there were no previous symptoms, and SD was the first manifestation of sudden cardiac death. There was a statistically significant difference between the CVS causes and sex (p=0.019).\n\nThe most common respiratory pathology was pneumonia in 57.2% of respiratory cases and 18.7% of all sudden deaths, that is, the second most common underlying cause of SD in general and in both sexes. This was followed by tuberculosis in 19.5% of respiratory cases and 6.3% of all sudden deaths (Table 4). A history of substance abuse was reported in 24.8% (n= 46 victims) of 185 victims of sudden death from respiratory pathology. Chronic alcohol use was the most common substance used and was reported in 37 (20%) of 185 victims. This was followed by smokers and chronic khat use, each reported in 13 cases. The most common terminal signs and symptoms reported among respiratory causes of sudden death were dyspnea (n=34 cases, 18.4%) and chest pain (n=20 cases, 10.8%).\n\nGastrointestinal system (GIS) pathologies were the third leading cause of SD, occurring in 97 (19.5%) cases. Liver and pancreatic diseases were the two most common causes of sudden death among GIS pathologies, accounting for 53.2% (n=59 cases) and 37.8% (n=42 cases), respectively (Table 4). A history of substance use was reported in 46.8% (n= 52) of 111 victims of sudden death from GIS pathology. Chronic alcohol use was the most common substance used and was reported in 45% (n=50/111) of victims, followed by khat and cigarettes in 19.8% and 4.5% of victims, respectively. The most common terminal signs and symptoms reported among the GIS causes of sudden death were abdominal pain (n=24 cases, 21.6%) and vomiting (n=7 cases, 6.3%).\n\nCNS pathologies were the fourth most common cause of SD, occurring in 10.6% (n=60 cases) of all sudden deaths. Subarachnoid hemorrhage and spontaneous intraparenchymal hemorrhage were the two common CNS pathologies, which occurred in 48.3% (29/60) and 31.7% (5/22) of cases, respectively (Table 4).\n\nThe least common cause of sudden death was related to GUS, which accounted for 1.2% of all sudden deaths. There was a statistically significant difference between the pathologies of GUS and sex, where p=0.48. There was a female preponderance of 71.4% and a mean age of 32.14±18.614 years. Pregnancy-related sudden deaths were the main cause of death in this group, occurring in five cases. Three of them died from obstetric bleeding (two cases of postpartum hemorrhage and one case of antepartum hemorrhage). A postpartum hemorrhage occurred after delivery at home in a rural area. Two cases of SD were due to rupture of ectopic pregnancy in 15- and 22-year-old single women, in which the family did not know the pregnancy status of the victims.\n\n\nDiscussion\n\nThis is the first study article on sudden deaths in Ethiopia and is devoted to evaluating the sociodemographic, behavioral, clinical and pathological characteristics of 568 sudden deaths of various ages in Ethiopia. The frequency and pattern of sudden death in different parts of the world vary greatly due to the diversity of prevalent diseases in various nations and due to various genetic and environmental factors.3,4 The present study reveals that sudden unexpected death with a known natural cause of death constitutes approximately 11.5% of all autopsy cases. This finding matches those of other developing countries.3 This finding is inconsistent with that reported in developed countries.5,9 It is challenging to compare the magnitude of SD in different parts of the globe because it varies mainly as a function of the diversity of prevalent diseases in various nations and due to diverse genetic and environmental factors.3,4 Furthermore, various definitions of SD, inclusion criteria and age groups that were evaluated in the study all contribute to the variation in SD incidence described in different studies.\n\nThe findings revealed a mean age of 44.8117.349 years. This is consistent with the studies conducted in Nigeria and Libya.3,4,10 The maximum number of sudden death cases (24.3%) was in the age group of 31-40 years, followed by 41-50 years, representing 19.6% of all SD cases. This finding matches various studies.11–13 All of these studies noted that middle age groups of 30 to 50 years are at high risk for SD. This finding appears to reflect behavioral and environmental factors that impact the health of society resulting from urbanization, the shift to a Western lifestyle, and the rapid nutritional transition and sedentary lifestyle with increased substance abuse habits.\n\nOf 224 sudden death cases, men (n = 482/586) were predominant over women (n = 86/586), with a ratio of 5.6:1. This finding is consistent with many similar studies.1,3,4,11,14,15 In our study, the majority (70%) of SD victims were from urban areas, which is consistent with other similar studies.4,11 This is due to the sedentary lifestyle and westernization with the increased smoking and alcohol consumption habits adopted by people in urban areas. In addition, the stress levels of urban and rural life are well known to differ.\n\nAccording to the current study, more than three-quarters of sudden deaths were unwitnessed. This could be because the shorter the survival period, the more likely it would go unnoticed, meaning that the likelihood of death being unwitnessed or unattended is directly correlated with the duration of survival.\n\nOur study found that chest pain, dyspnea, and syncope were the most common terminal symptoms reported in 68.6% of SD victims. These are the principal symptoms of cardiovascular and respiratory diseases, which were the two leading causes of SD. The finding of chest pain as the most common prodromal symptom coincided with a study in South Africa.14 In light of this, we advise emergency medical professionals to pay more attention to people who exhibit these prodromal symptoms.\n\nThe fact that 86.6% of all sudden deaths occurred outside of a hospital setting shows that the majority of these victims may not have known about their underlying medical problems or may not have been able to pay for the necessary medical care. This shows that most cases of SD are silent without preexisting symptoms. Therefore, it is vital to develop public health measures that will help educate the community about the importance of recognizing the manifestation of various clinical conditions and the need to seek immediate clinical help. Furthermore, efforts should be made to make healthcare facilities accessible and affordable with adequate diagnostic and management capacity. Two additional findings from this study further support this view. The first is that 34% of the SD victims had visits to medical facilities in the weeks before death, followed by deaths at home, which could be an indication that the diagnosis was incorrect, that therapy had failed, or that the victim lacked sufficient financial power to complete further investigation or management. The other reason is the high frequency of SD cases from chronic illnesses diagnosed for the first time at autopsy.\n\nThe occurrence of SD in males outnumbers females in all systems except GUS. Our findings coincided with those of the studies conducted in Tukey.4,15 In the current study, men were predominantly affected by cardiovascular causes of sudden natural death, and a significant association was observed between CVS disease and sex. Our findings coincided with the results of the United Kingdom.3,10,16 The fact that men are more frequently exposed to CVS pathologies can be attributed to the fact that estrogen hormone in women acts as a protective factor against most cardiovascular events, explaining the male preponderance that coexists with the high prevalence of CVS causes of sudden death.3,10 Furthermore, it could also be the result of men's higher rates of substance misuse compared to women, as well as higher levels of financial stress.\n\nCardiovascular and respiratory diseases are the most common causes of SD. These results are consistent with those of various studies conducted in different parts of the world.1,3,4,14,15,17 The fact that CVS pathologies are becoming the leading cause of SD could probably be the shift to the Western type of lifestyle that our societies are acquiring.\n\nThe most common underlying cause of SD is ischemic heart disease. This finding is consistent with those of various studies conducted in different parts of the world.1,4,5,14,15,17 Cardiomyopathy was the second most common COD in the cardiovascular system, accounting for 5.3% of all sudden deaths. This agrees with the result achieved in Libya.4\n\nIn many series, sudden cardiac death (SCD) is the initial manifestation of the condition in 20%–40% of cases.16,18 In the current study, 29.8% of victims of cardiovascular death had no antecedent symptoms, and SD was the first manifestation of sudden cardiac death in 29.8% of victims, which is consistent with many similar studies.16,18\n\nBecause SD is frequently the first sign of the disease, it is impossible to detect high-risk individuals, making the prevention of SCD considerably more challenging. Primary prevention is highly challenging because early identification of subjects in the community who are at a high risk of SCD is impossible owing to the significant percentage of SCD occurring in individuals with no previously known disease. However, sudden cardiac deaths have a relatively high prevalence of CVRFs. The risk of SCD in asymptomatic subjects with CVRFs is higher than that in the general population but lower than that of symptomatic patients with a diagnosed condition.16\n\nAs a result, early identification and management of modifiable CVRFs is one potential strategy to reduce the burden of sudden cardiac deaths in the community. In this study, significantly higher CVRF frequencies were observed in SCD victims, including diabetes mellitus (31.7%), hypertension (17.6%), and substance addiction (22%). Therefore, community education on preventive strategies, early detection, and control of CVRFs together with preventive strategies for substance abuse would be effective for the prevention of SD.\n\nRespiratory causes of SD accounted for 32.6% of cases in the current study. Pneumonia was the leading cause of death in the respiratory system, representing 18.7% of sudden death cases, making it the second most common cause of SD. This is closely followed by tuberculosis, comprising 6.3% of all sudden death cases. This is consistent with the results achieved in Libya and South Africa.4,14\n\nGastrointestinal pathologies were the third leading cause of SD, occurring in 111 (19.5%) cases. Liver and pancreatic pathologies were the two most common causes of sudden death among GIS pathology, accounting for 53.2% (n=59 cases) and 37.8% (n=42 cases), respectively. Hepatic and pancreatic pathologies together contribute to 90.1% of GIS causes of sudden death and are generally the third and fourth underlying causes of death, respectively. This finding is inconsistent with various similar studies showing that CNS pathologies are the third most common cause of SD.3,4,14,15,17 A possible explanation could be the high frequency of substance abuse reported among victims of GIS. A history of substance abuse was reported in 46.8% (n= 52) of 111 victims of sudden death from GIS pathology. Chronic alcohol use was the most common substance used and was reported in 50 (45%) of 111 victims, followed by khat and cigarettes in 19.8% and 4.5% of victims, respectively. Alcohol has a causative association with both liver and pancreatic diseases.19–22 Additionally, there is a growing body of evidence linking khat to the emergence of both acute and chronic liver disease.23–26 Khat (Catha edulis), a plant that is chewed for its psychedelic effects, is widely used in the eastern and southern parts of Ethiopia, but less frequently in the northern region.23\n\nCentral nervous system pathologies accounted for 10.6% of SD cases in this study. Cerebrovascular accidents were the most common causes (81.7% of all CNS causes), followed by infectious causes (15% of all CNS causes). This is in agreement with a study from Turkey.15 The number of male versus female cases in all organ systems was higher except for GUS. Our findings coincided with various studies.4,14,15 The reason is that in our study, a high frequency of maternal deaths was recorded.\n\n\nConclusions\n\nSudden death is an important global public health issue. Cardiovascular, respiratory and gastrointestinal system pathologies were the most common causes. The two main underlying causes of sudden death were ischemic heart disease and pneumonia. Although the causes of SD observed in the current study were comparable to those previously reported elsewhere, the rate of occurrence of certain conditions was different, particularly the higher frequency of liver and pancreatic pathologies. The association of these diseases with chronic alcohol and khat (Catha Edulis) abuse was also documented. Most of the causes of SD in Ethiopia can be prevented and treated. The majority of sudden deaths are silent without preexisting symptoms and occur outside a hospital setting. Therefore, it is vital to develop public health measures that will help educate the community about the importance of recognizing the manifestation of various clinical conditions and the need to seek immediate clinical help. Furthermore, efforts should be made to make healthcare facilities accessible and affordable with adequate diagnostic and management capacity. Documentation of autopsy-based data could provide important epidemiological information to guide medical services, prevention efforts, and control measures.\n\n\nConflicts of interest\n\nThe authors declare that they have no conflicts of interest.", "appendix": "Data availability\n\nFigshare: Epidemiological profiles and causes of sudden deaths of various ages in Ethiopia: an autopsy-based study, https://doi.org/10.6084/m9.figshare.24152004. 27\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nNofal HK, Abdulmohsen MF, Khamis AH: Incidence and causes of sudden death in a university hospital in eastern Saudi Arabia. E. Mediterr. Health J. 2011; 17: 665–670. Publisher Full Text Reference Source\n\nICD-10 Version: 2010: Other sudden death, cause unknown: (2010). [cited 2023 Feb 10]. Reference Source\n\nPelemo OE, Sabageh D, Komolafe AO, et al.: An autopsy review of sudden unexpected natural deaths in a suburban Nigerian population. Popul. Health Metrics. 2014 Dec; 12(1): 26. Publisher Full Text\n\nEl-Razik Mashali AA, Badr El Dine FM, Elmaguid Ahmed RA, et al.: The Application of the International Classification of Diseases among Autopsy Cases of Sudden Death in Tripoli, Libya. J. Forensic. Crime Investi. 2018; 2(1): 102.\n\nUdnoon J, Chirachariyavej T, Peonim V: Sudden unexpected deaths in different age groups at Ramathibodi Hospital, Bangkok, Thailand: a retrospective autopsy study during 2003-2007. Southeast Asian J. Trop. Med. Public Health. 2009 Jan 1; 40(1): 162–168. PubMed Abstract\n\nBasso C, Burke M, Fornes P, et al.: Guidelines for autopsy investigation of sudden cardiac death. Virchows Arch. 2008; 452(1): 11–18. Publisher Full Text\n\nReniers G, Araya T, Schaap A, et al.: Monitoring cause-specific adult mortality in developing countries: a comparison of data sources for Addis Ababa and its implications for policy and research. Soc. Sci. Med. 2005 Nov; 61(9): 1952–1957. PubMed Abstract \| Publisher Full Text\n\nGemechu T, Tinsae M, Ashenafi S, et al.: Most common causes of natural and injury-related deaths in Addis Ababa, Ethiopia. Pathol. Res. Pract. 2009 Jan 1; 205(9): 608–614. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nEscoffery CT, Shirley SE: Causes of sudden natural death in Jamaica: a medicolegal (coroner’s) autopsy study from the University Hospital of the West Indies. Forensic. Sci. Int. 2002; 129(2): 116–121. PubMed Abstract \| Publisher Full Text\n\nAkinwusi PO, Komolafe AO, Olayemi OO, et al.: Pattern of sudden death at Ladoke Akintola University of Technology Teaching Hospital, Osogbo, South West Nigeria. Vasc. Health Risk Manag. 2013; 9: 333–339. PubMed Abstract \| Publisher Full Text\n\nAnurupa C, Madhab BA, Himangshu D: Burden and commonest cause of sudden natural death among medicolegal autopsies in a tertiary care centre: a retrospective study. Int. J. Health Res. Medico. Leg. Prae. 2021 July-Dec; 7(2): 38–42. Publisher Full Text\n\nChoukimath DSM, Naik DMM: Causes of sudden death -autopsy review in a tertiary referral center. Trop. J. Pathol. Microbiol. 2020 Dec. 31; 6(8): 481–485. Publisher Full Text\n\nZanjad NP, Nanadkar SD: Study of sudden unexpected deaths in Medicolegal autopsies. J. Indian Acad. Forensic Med. 2006; 28: 27–30.\n\nTiemensma M, Burger EH: Sudden and unexpected deaths in an adult population, Cape Town, South Africa, 2001-2005. S. Afr. Med. J. 2012 Jan 27; 102(2): 90–94. PubMed Abstract \| Publisher Full Text\n\nAzmak AD: Sudden natural deaths in Edirne, Turkey, from 1984 to 2005. Med. Sci. Law. 2007; 47(2): 147–155. PubMed Abstract \| Publisher Full Text\n\nMorentin B, Audicana C: Population-Based Study of Out-of-Hospital Sudden Cardiovascular Death: Incidence and Causes of Death in Middle-Aged Adults. Rev. Esp. Cardiol. Engl. Ed. 2011 Jan 1; 64(1): 28–34. PubMed Abstract \| Publisher Full Text\n\nKumar V, San KP, Idwan A, et al.: A study of sudden natural deaths in medico legal autopsies in University Malaya Medical Centre (UMMC), Kuala Lumpur. J. Forensic Legal Med. 2007; 14(3): 151–154. PubMed Abstract \| Publisher Full Text\n\nEngdahl J, Holmberg M, Karlson BW, et al.: The epidemiology of out-of-hospital “sudden” cardiac arrest. Resuscitation. 2002 Mar; 52(3): 235–245. Publisher Full Text\n\nLankisch PG, Lowenfels AB, Maisonneuve P: What is the risk of alcoholic pancreatitis in heavy drinkers? Pancreas. 2002 Nov; 25(4): 411–412. PubMed Abstract \| Publisher Full Text\n\nPelli H, Lappalainen-Lehto R, Piironen A, et al.: Risk factors for recurrent acute alcohol-associated pancreatitis: a prospective analysis. Scand. J. Gastroenterol. 2008; 43(5): 614–621. PubMed Abstract \| Publisher Full Text\n\nKourkoumpetis T, Sood G: Pathogenesis of Alcoholic Liver Disease: An Update. Clin. Liver Dis. 2019 Feb; 23(1): 71–80. Publisher Full Text\n\nZhao P, Wang JG, Gao P, et al.: Sudden unexpected death from natural diseases: Fifteen years’ experience with 484 cases in Seychelles. J. Forensic Legal. Med. 2016 Jan; 37: 33–38. PubMed Abstract \| Publisher Full Text\n\nOrlien SMS, Sandven I, Berhe NB, et al.: Khat chewing increases the risk for developing chronic liver disease: A hospital-based case-control study. Hepatol. Baltim. Md. 2018 Jul; 68(1): 248–257. PubMed Abstract \| Publisher Full Text\n\nOrlien SM, Berhe NB, Morgan MY, et al.: Khat-related liver disease in sub-Saharan Africa: neglected, yet important. Lancet Glob. Health. 2019 Mar 1; 7(3): e310. PubMed Abstract \| Publisher Full Text\n\nOrlien SMS, Ismael NY, Ahmed TA, et al.: Unexplained chronic liver disease in Ethiopia: a cross-sectional study. BMC Gastroenterol. 2018 Feb 13; 18(1): 27. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPalacios Argueta P, Attar B, Sikavi C, et al.: Drug-Induced Liver Injury Caused by “Khat,” an Herbal Stimulant. ACG Case Rep. J. 2020 Nov; 7(11): e00480. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLema AS, Tekle ST: Epidemiological profiles and causes of sudden deaths of various ages in Ethiopia: an autopsy-based study. [Dataset]. figshare. 2023. Publisher Full Text" }	[ { "id": "244085", "date": "22 Feb 2024", "name": "Lorraine Du Toit-Prinsloo", "expertise": [ "Reviewer Expertise Forensic Pathology - Sudden Death", "Paediatric Pathology" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI am of the opinion that this article provides a good overview of the sudden deaths admitted to a Forensic Medicine Department.\n\nThe following comments are to be addressed by the authors: Replace the word victims with deceased / decedents throughout the manuscript Methods: - \" Autopsied specimens (whole organs or organ pieces) were fixed in 10% formalin for histopathological examination. Multiple sections with thicknesses of 4-5 mm were taken. The tissues were processed, subjected to paraffin sectioning at a thickness of 4 micrometers and then stained using hematoxylin and eosin staining.\" - replace this with ancillary investigations included whole organ retention, histological examination of tissue slides (were there any additional investigations such as microbiology or toxicology done?)\nCircumstances of death - The statement referring to 36 victims died instantaneously should be further explained in the context - there are only a few causes of death in the forensic setting in my opinion where we can indicate that the death occurred instantaneously.\nSome of the references pertaining to similar studies reporting on sudden death are more than 10 years old and it would be important to obtain more recent articles if available. It would also be interesting to expand on the nature of these investigations - a full post-mortem examination was conducted, but expanding on the types of ancillary investigations will add value.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13154", "date": "05 Feb 2025", "name": "Alemayehu S. Lema", "role": "Author Response", "response": "Dear Reviewer, We sincerely appreciate the time and effort you dedicated to providing such a comprehensive and constructive review. Your feedback has been extremely valuable in shaping the quality of this work. We have thoroughly reviewed and incorporated your suggestions throughout the manuscript. Please find our detailed responses to each comment below. Method section: Regarding ancillary investigations Response: Thank you for this valuable suggestion. We have revised the manuscript to include detailed descriptions of the ancillary investigations performed, as well as a discussion of the available limitations within our setting. Moreover, your insightful feedback has prompted us to provide detailed recommendations for improving autopsy facilities and future research efforts, which we believe will inform decisions and policies in our and similar contexts. Histopathological examination, largely using Hematoxylin and Eosin (H&E) staining, was performed in all sudden death cases. Toxicological, biochemical, and microbiological investigations are performed on a selective basis, as determined by the forensic pathologist. However, molecular autopsy facilities were not available in our context. Despite these limitations, our study represents the first nationwide, autopsy-based investigation to comprehensively analyze the epidemiological, clinical, and pathological characteristics of all sudden unexpected natural deaths over a one-year period. We rigorously gathered information from all available sources, performed postmortem autopsies, and collected samples for available ancillary investigations. We believe that this study provides valuable epidemiological insights crucial for planning medical services, prevention, control, education, and further research. Circumstances of death Response: Thank you for this critical and pertinent comment. We have clarified the circumstances surrounding the 6.3% (n=36/568) of all SD cases reported as \"instantaneous deaths.\" We have further detailed that, of these 36 cases, 88.9% (n=32) were attributed to cardiovascular (CVS) causes, particularly ischemic heart disease and cardiomyopathies, while the remaining cases involved spontaneous intracranial hemorrhage. Terminology Changes Response: Thank you for this important recommendation. We have replaced the term \"victims\" with \"deceased\" or \"decedents\" or Sudden death cases’’ or ‘’cases’’ throughout the manuscript as suggested. References Response: Thank you for this critical and pertinent suggestion. We have diligently updated the references, incorporating recent publications and replacing some earlier citations with their most current versions." } ] }, { "id": "270830", "date": "10 Jun 2024", "name": "Martina Modena", "expertise": [], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article addresses a major health problem such as sudden death, which has a dramatic impact on families and society. The authors provide an interesting descriptive study on sudden death in Ethiopia. The authors should address the following comments:\nMethods: -\n\n“Full postmortem examinations were carried out in each instance using the Letulle evisceration procedure […] Organs were dissected, examined and checked for signs of gross pathological changes and violence. Autopsied specimens (whole organs or organ pieces) were fixed in 10% formalin for histopathological examination. Multiple sections with thicknesses of 4-5 mm were taken. The tissues were processed, subjected to paraffin sectioning at a thickness of 4 micrometers and then stained using hematoxylin and eosin staining.”\n\nThe authors can provide more details on full postmortem examinations carried out? e.g. body weight and height have been collected? Concerning the histological analysis: was only the hematoxylin-eosin staining performed? the toxicology analysis was performed? The authors could include a small paragraph on heart analysis: e.g. pericardium, heart cavities, valves and coronary arteries have been checked?\n-\n\nConsidering the growing importance of molecular autopsy, have any EDTA blood or frozen tissue samples been kept for possible future analysis?\nResults:\nCauses of sudden unexpected deaths\n-\n\n“Cardiovascular system diseases (CVS) were the leading causes of SD, accounting for 36.1% of all SD cases. This was followed by respiratory and gastrointestinal system pathologies, accounting for 32.6% and 19.5%, respectively. Central nervous system (CNS) and genitourinary system (GUS) pathologies were the least prevalent causes of death, accounting for 10.6% and 1.2%, respectively.”\nAll described cases of sudden death are explained after autopsy by reaching a certain cause of death. This is surprising considering that in literature the cause of death remains in doubt even after an exhaustive autopsy in several sudden deaths. So, there is usually a proportion of cases remaining \"unexplained\".\nI suggest to authors to review the literature and guidelines (some references are more than 10 years old) and to review the results to be sure that all cases have been explained by autopsy. Do all cases have a definite diagnosis at autopsy? Particularly among cases of cardiac death, no probable arrhythmic death was found? Did all cases of sudden cardiovascular death have structural cardiac changes?\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13153", "date": "05 Feb 2025", "name": "Alemayehu S. Lema", "role": "Author Response", "response": "Dear Reviewer, We sincerely appreciate the time and effort you dedicated to providing such a comprehensive and constructive review. Your feedback has been extremely valuable in shaping the quality of this work. We have thoroughly reviewed and incorporated your suggestions throughout the manuscript. Please find our detailed responses to each comment below. Method section: Details of postmortem examinations procedure Response: Thank you for this valuable suggestion. We have revised the manuscript to include detailed descriptions of the postmortem examinations performed, the ancillary investigations conducted, and the limitations encountered within our setting. As suggested, we have also provided a more thorough description of the gross heart examination. Your feedback has prompted us to include recommendations for improving autopsy facilities and future research, which we believe will be valuable for informing decisions and policies in similar contexts, particularly for forensic pathologists working in resource-limited facilities. Result section: Sudden unexplained deaths Response: Thank you for this valuable suggestion. We have revised the manuscript to provide more detailed descriptions of the included cases. This study focused on all sudden unexpected deaths with a known natural cause. While our findings offer crucial epidemiological data for planning medical services, prevention, control, education, and further research, we acknowledge several limitations that could influence the interpretation of our results. Specifically, 6.2% of total autopsy cases remained undetermined due to the limitations of available resources and facilities, and these cases were therefore excluded from the study. Histopathological examination, largely using Hematoxylin and Eosin (H&E) staining, was performed in all sudden death cases. Toxicological, biochemical, and microbiological investigations are performed on a selective basis, as determined by the forensic pathologist. However, it is important to note that molecular autopsy facilities were not accessible, and tissue specimens were not preserved. This lack of molecular autopsy significantly limited our ability to determine the cause of death in cases of advanced putrefaction or incomplete ancillary examinations and this exclusion of cases with undetermined cause of death may affect the prevalence estimate. This limitation is explicitly discussed in the manuscript. Furthermore, we recognize that sudden unexplained deaths (SUDs) are frequently associated with underlying inherited arrhythmogenic cardiac diseases, which molecular autopsy can help identify. Identifying the cause of death via molecular autopsy is vital not only for medico-legal inquiries but also for guiding cascade genetic screening of the deceased's relatives. This screening is essential for risk prediction in family members and the appropriate management of those identified to be at risk. Your insightful feedback has prompted us to provide relevant recommendations regarding the need for a molecular autopsy facility. We believe that these recommendations will inform decisions and policies in our context and similar settings. As a short-term measure, considering the increasing importance of molecular autopsy, we recommend preserving DNA samples from all SUD cases to facilitate future investigations. These recommendations, we believe, will be particularly valuable for forensic pathologists and stakeholders working in resource-limited facilities. Despite these limitations, our study represents the first nationwide, autopsy-based investigation to comprehensively analyze the epidemiological, clinical, and pathological characteristics of all sudden unexpected natural deaths over a one-year period. We rigorously gathered information from all available sources, performed postmortem autopsies, and collected samples for available ancillary investigations. We believe that this study provides valuable epidemiological insights crucial for planning medical services, prevention, control, education, and further research. References Response: Thank you for this critical and pertinent suggestion. We have diligently updated the references, incorporating recent publications and replacing some earlier citations with their most current versions." } ] }, { "id": "287008", "date": "14 Jun 2024", "name": "Joseph Westaby", "expertise": [ "Reviewer Expertise Cardiovascular pathology", "sudden death", "various cardiac conditions", "anatomy of the heart" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article by Lema et al, is an observational study characterising all sudden deaths observed at a single forensic centre in Ethiopia. They report sudden death was 11.5% of all cases autopsied with 5.6 times as many males than females and a mean age of 45. Cardiovascular causes were most common with ischaemic heart disease as the leading cause. They highlight the importance of epidemiological data derived from autopsy studies to inform provision of medical services.\nThis is a study that adds to the literature on sudden death showing its causes from Ethiopia. There are a number of improvements that I recommend that the authors make and I would be happy to re-review the paper following their emendations.\nMethods Individuals who died but were not confined to their homes, health facilities, or other related institutions due to illness for more than 24 hours before death were not considered unexpected deaths and were not included. Do the authors mean not?\nResults Figure 1: It would be best not to display the last three bars labelled as total as it does not allow you to appreciate the differences between the decades of age\nThere was a statistically significant difference between the residence of the victims and sex (p<0.001). It is not made clear which sex lived more commonly where. Did males more frequently live in the city or the country?\nThere was a statistically significant relationship between substance abuse and sex (p<0.001) and residence (p=0.004). A different distribution was observed for chronic alcohol use and sex (p<0.001). It is not made clear what these relationships are? Was it more common in males and in the city? Was alcohol more common in males or females?\nThere was a statistically significant relationship between the presence of a prior chronic illness and sex (p=0.022). Were males or females more likely to have prior chronic illness?\nTable 3: It would be useful to put percentages for each sex for each cause so the differences between males and females are readily appreciable.\nThere was a statistically significant difference between the CVS causes and sex (p=0.019). Was it more common males?\nDiscussion The findings revealed a mean age of 44.8117.349 years. Giving the mean age as a whole number would be more appropriate\nOf 224 sudden death cases, men (n = 482/586) were predominant over women (n = 86/586), with a ratio of 5.6:1. This finding is consistent with many similar studies.1,3,4,11,14,15 Only two of these studies have a ratio of 5:1, most of these have ratios of 2:1 male:female which is more usual in the literature. Could the authors please speculate as to why they have such a high male to female ratio. Are females autopsied less than males? What percentage of the 4,942 medicolegal autopsies were female?\nThe occurrence of SD in males outnumbers females in all systems except GUS. Our findings coincided with those of the studies conducted in Tukey.4,15 Turkey is spelt wrong. They may wish to use its new name “Türkiye”. Reference four is from Libya not Turkey.\nOur findings coincided with the results of the United Kingdom.3,10,16 Refences are for two studies from Nigeria and one from Spain. None are from the UK. They should include references from the UK.\nCardiomyopathy was the second most common COD in the cardiovascular system, accounting for 5.3% of all sudden deaths. This agrees with the result achieved in Libya.4\nIt would be important to say that the cardiomyopathies may be inherited and therefore it is important to screen surviving blood relatives for these conditions. (Reference-1)\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13145", "date": "05 Feb 2025", "name": "Alemayehu S. Lema", "role": "Author Response", "response": "Dear Reviewer, We sincerely appreciate the time and effort you dedicated to providing such a comprehensive and constructive review. Your feedback has been extremely valuable in shaping the quality of this work. We have thoroughly reviewed and incorporated your suggestions throughout the revised manuscript. Please find our detailed responses to each comment below. Method section Response: The statement, \"Individuals who died but were not confined to their homes, health facilities, or other related institutions due to illness for more than 24 hours before death were not considered unexpected deaths and were not included,\" inadvertently used the phrase \"not confined.\" This was an error; the intended criteria were that individuals that were confined. We appreciate the reviewer for identifying this inaccuracy. The statement has now been amended to read: \"Individuals who died but were confined to their homes, health facilities, or other related institutions due to illness for more than 24 hours before death were not considered unexpected deaths and were not included.\" Result section 2.1. Figure 1 and table 3 Following your recommendations, we have made specific modifications to the presentation of results. In Figure 1, we've removed the \"total\" bars to improve the visual clarity of age-related trends, enabling a better appreciation of differences across decades. In Table 3, we have included sex-specific percentages for each cause, facilitating a direct comparison of male and female distributions. Statistical data presentation Response: Thank you so much, and comments are accommodated. All the statistical analysis and interpretation of the data have been meticulously clarified and elaborated upon, offering a more robust understanding of the findings. Mean age The mean age (±SD) is corrected to 44.8 ± 17.349 years. The previous version incorrectly presented the standard deviation within the mean, writing it as 44.8117.349 years. This has now been rectified. Discussion section 3.1. Male: female ratio Response: Thank you for this critical and insightful comment. We acknowledge the discrepancy in male-to-female ratios compared to some studies in the literature. The references for this section have been appropriately amended to reflect this. We have now included a detailed discussion of potential reasons for the observed gender disparity in our study. Issues regarding inherited cardiomyopathies Response: Thank you for this critical and pertinent suggestion. We agree that it is essential to highlight the potential for inherited cardiomyopathies. We have now included a statement in the discussion emphasizing the importance of screening surviving blood relatives for these conditions, and we have added the suggested reference. Issues regarding inherited cardiomyopathies Response: Thank you for this critical and pertinent suggestion. We have addressed all concerns regarding the citations and references. This includes updating the reference list to ensure accurate representation of study locations and replacing older references with more current literature, where possible. Additionally, we have incorporated many recent and all suggested references." } ] } ]	1	https://f1000research.com/articles/12-1441
https://f1000research.com/articles/12-1094/v1	01 Sep 23	{ "type": "Research Article", "title": "Food consumption and adherence to dietary guidelines among Jordanian children and adolescents", "authors": [ "Buthaina Alkhatib", "Huda Al Hourani", "Islam K. Al-Shami", "Ayoub Al-Jawaldeh", "Huda Al Hourani", "Islam K. Al-Shami", "Ayoub Al-Jawaldeh" ], "abstract": "Background: To evaluate the energy and macronutrient intake of Jordanian children and adolescents, and how closely they adhere to dietary recommendations. Methods: This cross-sectional study used data from Jordan's Population-based Food Consumption Survey, a household population-based study that was conducted in Jordan between 2021-2022 (561 children and adolescents 8-19 years). Dietary intake was assessed using the two non-consecutive 24-hour dietary recall method (24-h DR). The estimated food group and nutrient intakes were compared to nutritional recommendations, including MyPlate dietary guidelines. Results: The prevalence of overweight/obese individuals based on body mass index (BMI) was 44%, and the average waist-to-height ratio (WHtR) was 24.7%. Compared to MyPlate dietary guidelines, children and adolescents had a higher added sugar intake (57g/day). Also, the consumption of vegetables, fruits, and dairy fell short of MyPlate dietary guidelines. The total discretionary calorie intake in children and adolescents was approximately one-third of the total energy intake. Conclusion: The food consumption of Jordanian children and adolescents includes high intakes of discretionary calories, with a low intake of fruits, vegetables, and dairy products. The prevalence of overweight/obesity was elevated compared to international norms.", "keywords": [ "Food consumption", "discretionary calories", "energy intake", "MyPlate dietary guidelines", "added sugars", "saturated fats" ], "content": "Introduction\n\nFood habits formed early in childhood are likely to follow and form the foundation of adult eating patterns. Early-life food consumption patterns may affect children’s health by increasing susceptibility to developing non-communicable chronic diseases (NCDs) in adulthood.1,2 Many NCDs risk factors among children and adolescents, such as obesity, are caused by unhealthy eating behaviors and a lack of physical activity.3–5\n\nChanges in food consumption patterns in children and adolescents can be attributed to a variety of factors, including but not limited to being at school and interacting with peers during school days, the widespread availability of processed foods, availability of inexpensive food portions with family-size, eating out of home, and the ease of food delivery applications.6–8\n\nNumerous studies have examined how children and adolescents worldwide are adopting unhealthy eating habits, such as skipping meals like breakfast,9,10 unhealthy snacking which is composed of energy-dense foods,11–13 drinking sweetened beverages,14,15 eating fast foods,14,16 and consuming little fruits and vegetables.14,15,17 These unhealthy habits can lead to excessive or insufficient nutrient intake, defined as ‘Nutritional status deterioration’, and have serious health consequences.18 Increased risk of overweight and obesity among children and adolescents is one of these severe health problems. Childhood dietary intake plays a significant role in preventing and treating childhood overweight and obesity as it is a crucial factor in growth and development.19 Obesogenic eating patterns have been extensively investigated and linked to an increased risk of becoming overweight or obese.20 Among these eating patterns was the consumption of identified obesogenic foods (such as sweetened beverages, fast food, and snacks).21 An investigation in Greece found that children who consume obesogenic foods are more likely to be obese.22 In China, the modern dietary pattern was positively associated with future obesity in children and adolescents.23 Moreover, a higher intake of vegetables in childhood has been connected with a lower chance of having mental health disorders later in life,24 such as depression. Moreover, a nutritious diet can help prevent cardio-metabolic multi-morbidities, which are frequently observed in adult patients with neuropsychiatric problems.25 To maintain a regular immune response, lower the risk of adverse mental health disorders and associated co- and multi-morbid conditions later in life, and maintain a regular immune response, dietary changes made as early as during childhood and adolescence represent a promising therapeutic strategy.26\n\nOver the past 40 years, the consumption of discretionary or luxury snack foods has increased globally,27 and it has been linked to overweight/obesity prevalence and increasing chronic disease risk as a consequence.28 Discretionary foods have been defined as food and beverages that contain added fat, sugar, and sometimes salt and are not considered necessary for a healthy diet, and contribute to excessive energy intake and displace core foods and essential nutrients.29,30 Although some recommendations have been made, most dietary guidelines around the world discourage the consumption of these foods. For American children and adolescents, the discretionary calorie allowance ranges between 8% and 20% for all sex-age groups.31 The recommended maximum discretionary foods and beverages for Australian children and inactive adolescents are 0-1/2 servings/day, which equals 143 kcal.32\n\nThere has been little research on Jordanian children’s and adolescents’ dietary habits, and there is only sporadic data to suggest that certain food groups or individual items are consumed insufficiently or excessively.33 This study aimed to 1) characterize the food consumption of Jordanian children and adolescents and 2) assess their adherence to dietary guidelines, especially MyPlate.\n\n\nMethods\n\nThis study received ethical approval from the Institutional Board Review (IRB) committee, reviewed and approved the survey protocol at The Hashemite University (No.7/13/2020/2021). Following the head of the household’s oral permission, one of the participant’s parents signed an informed consent form for children and adolescents under the age of 16. A written consent form was signed by adolescents over 16 years, and data collection began during the first visit in the presence of one of the parents.\n\nThe current study is based on the Jordan’s Population-based Food Consumption Survey (JPFCS), which was conducted between October 2021 and March 2022. The JPFCS was created to collect dietary habits, eating patterns, and nutritional status among children, adolescents, adults, and the elderly, individuals aged eight years and older who live in Jordan. A representative sample of 701 households was invited to participate. The number of agreed-upon households to participate was 632, with a 90.2% response rate drawn randomly from Jordan’s three major regions (Central, Northern, and Southern). A total of 2,721 household members were approached, and 2,145 participants agreed to participate. The total number of children and adolescents who took part was 617 (28.7%). Children and adolescents with chronic diseases, physical disabilities, food allergies and intolerance, or cognitive impairment were excluded from the study. A study protocol has been described in detail by Al-Shami et al. (2023).34\n\nThe current study included JPFCS children and adolescents divided into two age groups: children (8-12 years) and adolescents (13-19 years). Obtaining food intake for children under eight during the past 24 hours is challenging, especially while they are away from home (food eaten in kindergarten or daycare centers).34 As a result, data reliability is higher for children aged eight and above. Outlier values for participants’ energy intake were calculated by excluding any value that increased or decreased by 2.5 standard deviations of the group mean, as outliers can have a big impact on statistical analyses, and skew the results of any hypothesis test if they are inaccurate. As a result, from 617 JPFCS participants, the final net sample size for the current analysis was 561 participants eligible. Following the head of the household’s oral permission, one of the participant’s parents signed an informed consent form for children and adolescents under the age of 16, a written consent form was signed by adolescents over 16 years, and data collection began during the first visit in the presence of one of the parents.\n\nIt was announced on the university’s website about the need for nutritionists to work in data collection, and they were selected after personal interviews and based on their experience, and they were subsequently trained. The abovementioned trained nutritionists conducted a face-to-face interview with the head of the household to obtain dietary and anthropometric measurements, particularly for children (see extended data35). Dietary data were collected from the children (<12 years) with parents’ help, while older participants were those who answered their dietary questions. The aforementioned data was gathered via a structured questionnaire completed during the interview. An experienced nutritionist used established methods to measure anthropometric measurements of children and adolescents, including height (cm) using Seca portable stadiometer), weight (kg) (using Tanita digital weighing scale), and waist circumference (WC) (cm) (using Seca measuring tape). Participants’ body weight and height were recorded to the nearest 0.1kg and 0.1cm. A flexible anthropometric tape was used to measure the participant’s WC while standing. Body mass index (BMI) was calculated ’as weight (kg) divided by the square of the height (m2).36 Moreover, the BMI-for-Age Z-Score (BAZ) was calculated. For the association of BMI-for-age with overweight and obesity, values > +1 SD represent overweight, and values > +2 SD represent obesity according to WHO reference curves. Values between +1 SD and -2 SD were considered ‘normal’. In comparison, values > -2 SD were considered ‘thinness’. The waist-to-height ratio (WHtR) was calculated by dividing the participant’s waist circumference by their height. A WHtR cutoff of ≥ 0.5 is generally accepted as a universal cutoff for obesity in children.37\n\nTwo non-consecutive 24-hour dietary recalls (24-h DR) were obtained to assess food intake on one weekday and one weekend. Furthermore, the child’s parents were asked to be present during the collection of the 24-hour DR. The first 24-h DR was collected during the interview, while the second recall was obtained via phone. Participants were asked to recall and list all foods and beverages they consumed from midnight to midnight the previous day, along with their quantity, preparation method, and most popular food brand names. A photographic food atlas was also created to simplify the estimation of consumed food portion size; this tool contains over 150 foods and composite recipes consisting of high-definition colored photos of various foods and meals commonly consumed in Jordanian diets. The survey was introduced in Arabic language; then it was translated into English before the analysis.35\n\nThree food composition databases were used to estimate nutrient intake in children and adolescents. The consumed foods collected by 24-DR were entered into a Computerized Nutrient Analysis Program: ESHA’s Food Processor®, Nutrition Analysis Software (version 11:0; ESHA Research), Composition of Local Jordanian Food Dishes,38 and Lebanon Food Composition Data: Traditional Dishes, Arabic Sweets, and Market Foods.39 Furthermore, based on MyPlate dietary guidelines, consumed foods were classified into five food groups (grains, vegetables, fruits, protein, and dairy), with a specified number of consumed servings of each food group. According to the Essential Guide to Nutrient Requirements, published by the Institute of Medicine in the national academies press in 2019, it also was approved and recommended by the USDA Dietary Guidelines for Americans, 2020-2025, which reflects the Acceptable Macronutrients Distribution Ranges (AMDR).40 The mean recommended energy intake for children and adolescents based on the MyPlate Dietary Guidelines and AMDR were 1800 and 2200, regardless of gender.5 The recommended daily intake of fruits and vegetables based on the Joint FAO/WHO Expert Consultation on Diet, Nutrition and the Prevention of Chronic Diseases is a minimum of 400 g of fruits and vegetables/day; an equivalent of ≥5 servings/d.41\n\nAnalysis was conducted using SPSS software (IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp) (https://www.ibm.com/products/spss-statistics). PSPP (https://www.gnu.org/software/pspp/), a freely accessible software, is capable of running the same analysis used in this study. All analyses were stratified by gender and age group. Anthropometric characteristics were described using frequencies and percentages for categorical variables. The energy and macronutrient intake distribution was reported as means and standard deviation (Mean ± SD). An Independent sample t-test was used to compare differences between boys and girls within each age group. The normality of the distributions was assessed through the Kolmogorov-Smirnov test and Kurtosis and Skewness values. Differences were considered significant at p < 0.05.\n\n\nResults\n\nA total of 561 Jordanian children and adolescents participated in this study, of whom 217 (38.7%) were children and 344 (61.3%) were adolescents.69 The general characteristics of the study population are presented in Table 1. Although boys and girls accounted for almost equal proportions within the children group, adolescent girls accounted for the disproportionation when compared to boys within the same age group (57% vs. 43%, respectively). For the overall children group, participants who consumed dietary supplementations accounted only 6%, with no significant difference between boys and girls. A higher proportion of adolescents were using dietary supplements (any vitamins or minerals or herbs that are consumed as capsules, tablets, or drinks, instead of the diet) (12.5%), with a significant difference between both genders. Adolescent girls were found to be the most frequent group in using nutritional supplements (16.3%) when compared to boys (7.4%) from the same group (p = 0.014). When compared to other regions in Jordan that were distributed according to their geographic distribution, the central regions had higher proportions of either children or adolescents of both genders (children: 61.8% of boys and 53.3% of girls; adolescents: 56.1% of boys and 62.2% of girls).\n\n* Bold p-value: < 0.05 considered statistically significant (2-tailed) between genders within each age group.\n\n† BMI-for-age values > +1 SD represent overweight, values > +2 SD represents obesity, values between +1 SD and -2 SD were considered “normal”, while values > -2 SD were considered “thinness”.\n\n†† WHtR ≥ 0.5 is generally accepted as a universal cutoff for obesity in children and adolescents.\n\nFindings related to the participant’s anthropometric characteristics stratified by age and gender are presented in Table 1. Most of the adolescents were classified as normal weight (64.5%), and about half of the children were also within the normal weight category (52.3%). Without significant differences between both genders among each age group; children boys had the highest overweight/obesity prevalence (46.3%), followed by girls in the same age group (41.5%), then adolescent boys (33.8%), and the lowest prevalence was for adolescent girls (30.6%). About a quarter of the children’s boys had abnormal WHtR (25.5%), and 23.8% of the same group of girls too; however, 30.4% and 21.4% of adolescent boys and girls, respectively, were also classified as having abnormal WHtR, with no significant differences. On the other hand, based on the household analysis, there were 4.5 people per family on average. Additionally, nearly 50% of the sample under study (JPFCS original sample) stated that their household’s overall income is less than 500 JD.\n\nTable 2 categorizes the most common food items consumed by Jordanian children and adolescents into five food groups, as well as the recommended number of servings for each food group for both age groups, based on 1800 kcal needs for children and 2200 kcal needs for adolescents. The reference MyPlate dietary guidelines image was presented for children in Figure 1 and adolescents in Figure 2.\n\nIn children, the entire group consumes less than the recommended number of servings from all food groups, as well as girls of the same age group. On the other hand, children’s boys almost consumed the recommended amount of grains (30.6% vs. 30% of the standard plate), while all other food groups were lower than the recommended number of servings, as shown in Figure 1. Mismatching between real and recommended intake based on the standard plate has been indicated. As shown in Figure 1, a higher gap has been found among children girls’ intake of dairy, protein, and fruits (11%, 9.6%, and 6.8%, respectively) when compared to boys from the same age group (13%, 12.4%, and 8.7%; respectively) (Figure 1). Furthermore, Jordanian adolescents overall or according to gender differences consumed less than the recommended serving number of each food group (Figure 2), based on 2200 kcal/day as the average total energy requirement (Table 2). In girls, the actual intakes of grains, fruits, vegetables, and proteins were 22%, 7.3%, 7.8%, and 11%, respectively, which did not agree with the recommended reference plate. This discrepancy was also observed in boys with their consumption of fruit and vegetables (6.1% and 9.1%, respectively). However, there appears to be less mismatch in grain and protein intake (28.8% and 15.1%, respectively) (Figure 2). It’s interesting to note that both age groups showed the same outcome in terms of gender differences because there was a significant difference in their intake of grains and proteins (p-value < 0.05) among all the food groups.\n\nThe mean daily energy and macronutrient intake of the study population, stratified by age and gender, is shown in Table 3. In the children’s group, the mean total energy intake was: 1796.4 ± 557.1 kcal/day, with a significant difference between boys and girls; the mean total energy intake for boys was 1950 kcal/day compared to 1638 kcal/day for girls (p < 0.001). Similar results were shown in the adolescent group, with a significantly higher mean energy intake in boys compared to girls (2116.3 kcal/day vs. 1688.5 kcal/day) (p < 0.001), while the average total intake of the group was 1872. 6 ± 579.1 kcal/day.\n\n* p-value < 0.05 is considered statistically significant (2-tailed).\n\nTable 3 further examines the various types of fat consumed; the mean saturated fat (SFA) intake was nearly equal for both age groups and rounded to 16 g/day (Table 3), which was within an acceptable amount when compared to the MyPlate dietary guidelines allowed amounts of 20 g/day and 22 g/day for children and adolescents, respectively (Table 2, Figure 1, and Figure 2). Boys of both ages consumed significantly more saturated fats than girls of the same age (children: 18.3 g/day vs. 14.3 g/day, and adolescents: 18.7 g/day vs. 14.5 g/day, for boys and girls, respectively) (p < 0.001) (Table 4).\n\n* p-value < 0.05 is considered statistically significant (2-tailed). EI: energy intake.\n\nMoving in sequence, the mean intake of polyunsaturated (PUFA) and monounsaturated fats (MUFA) was nearly equal in both age groups; however, boys in both age groups consumed significantly more than girls (p < 0.05) (Table 3). Trans fat (TFA) intake was significantly higher in adolescent boys than in girls (0.81 g/day vs. 0.45 g/day) (p = 0.006). Irrespective of gender-specific differences, the mean cholesterol intake of the adolescents was higher than that of the children’s group (168.1 ± 150.1 mg/day vs. 133.2 ± 93.7 mg/day; respectively). Also, mean cholesterol intake was significantly higher in boys than in girls in the child group (148 mg/day vs. 118 mg/day (p = 0.02) and in adolescents (219 mg/day for boys vs. 130 mg/day for girls) (p < 0.001). In addition, the intake of omega-3 and omega-6 fatty acids was significantly higher in boys than in girls in both age groups (Table 3).\n\nAccording to the MyPlate dietary guidelines objectives that make every bite count and choose options full of nutrients, some foods and beverages were recommended to be explicitly limited; added sugars and saturated fats/added fat. Foods that were analyzed as added sugars and saturated fats were listed in Table 2, as well as their typical serving sizes, and the maximum allowed amount to consume for each age group were presented in the same table.\n\nAge differences in mean intake from added sugar were almost equal to 57 g/day, and this means higher than MyPlate dietary guidelines allowed amounts which were <45 g/day and <50 g/day for children and adolescents, respectively (Table 4, Figure 1, and Figure 2). Although no significant difference between boys and girls was found within the children group, adolescent boys significantly consumed higher amounts of added sugars when compared to girls from the same group (60.87 g/day vs. 53.28 g/day, respectively) (p = 0.015). Moreover, children and adolescent boys consumed significantly higher amounts of total added fats than girls (39.33 g/day, 38.92 g/day vs. 32.7 g/day, and 31.42 g/day (p = 0.007; 0.001; respectively) (Table 4). For children and adolescents, total discretionary calorie intake (added sugar and fat) accounted for approximately 30.7% and 28.6% of total energy intake, respectively; which is considered higher than the recommendations (<10% of total energy intake).\n\n\nDiscussion\n\nThe food consumption of Jordanian children and adolescents has never been studied before. Furthermore, the COVID-19 pandemic is a significant contributor to the shift in dietary intake globally toward obesogenic food choices, besides decreased physical activity, increased screen time, and leading to weight gain.42,43\n\nThe present study’s findings showed that the overall prevalence of generalized overweight/obesity among the studied sample was 36.6%. The prevalence of overweight/obesity was higher in children than in adolescents (44.3% vs. 32%). About 1/5 to 1/4 of participants from all age groups were classified as overweight. Globally, overweight and obesity have increased dramatically among children and adolescents aged five to 19, from 4% in 1975 to just over 18% in 2016.44 In Jordan, the image was not dissimilar to other countries worldwide. Zayed et al. (2016) reported that analysis by gender showed that obesity was more prevalent among Jordanian males, with 18.9% obese compared to 11.2% of females.45 Jordanian obesity prevalence and its related gender patterns appear consistent with what has been reported in the literature.\n\nAnother obesity index, WHtR, revealed that nearly a quarter of the children’s boys (25.5%) and 23.8% of the same group of girls had abnormal WHtR; however, 30.4% and 21.4% of adolescent boys and girls, respectively, were also classified as having abnormal WHtR. WHtR was not used to assess abdominal obesity in Jordanian children and adolescents earlier. A few studies on WHtR as an indicator of obesity in the Eastern Mediterranean region reported similar results; in the United Arab Emirates (UAE), 27.2% of subjects had abnormal WHtR,46 and in Lebanon, 38.3% had abnormal WHtR.47\n\nObesity as a result of diet has been extensively studied. Fast food and sugar-sweetened beverages are directly linked to the childhood obesity epidemic. The initial findings on the prevalence of obesity were primarily related to food intake. This study found that adolescents engaged in eating behaviors associated with an increased risk of being overweight and obese.\n\nThe MyPlate dietary guidelines were created in 2011, indicating how much of the plate should be allocated to protein foods, grains, fruits, and vegetables. The current study’s findings revealed that children’s girls consumed fewer than the recommended number of servings from all MyPlate dietary guidelines groups. On the other hand, children’s boys nearly consumed the recommended amount of grains (30.6% vs. 30% of the plate), while all other food groups consumed less than the recommended number of servings. However, adolescents’ intake was off-balance in all recommended servings of MyPlate dietary guidelines, regardless of gender.\n\nCompared with studies in the Eastern Mediterranean countries, 28% of Emirati adolescents met the recommended daily fruit and vegetable intake, with significantly more males than females.48 A multinational comparison study of eleven Eastern Mediterranean countries revealed that 19.4% of adolescents reported consuming fruits and vegetables ≥5 times/day.49 In Iran, a study found that only 30.3% and 34.6% of adolescents consumed the recommended amount of fruit and vegetables, respectively.50 In Egypt, 45.9% of children and adolescents have fruits and vegetables 1-6 times daily.51 In the UAE, around 50% of school-age adolescents had less than five servings of fruits and vegetables.46 Similar findings were reported among Saudi children, with 69% and 71% of the samples not consuming fruits and vegetables daily.52 Furthermore, a review of the dietary patterns and nutrient intakes of children (5-10 years) and adolescents (10-19 years) in the Eastern Mediterranean Regions revealed that their diet was poor, with fruits, vegetables, and dairy products.53 According to current study findings and studies from Eastern Mediterranean countries, Western countries did not achieve better results in this area. In Belgium, adolescents were the least likely to follow food-based dietary recommendations compared to the youngest children and adults.37 As well as, a study in 33 countries from European and North America reported that a large proportion of adolescents do not eat fruit and vegetables daily.54\n\nAlthough most studies reported low consumption of fruits and vegetables among children and adolescents worldwide, it is important to note that the methods used to assess their intake vary; some studies rely on self-reporting food frequency, while others rely on face-to-face 24-DR.\n\nAlthough the current study’s findings showed a low consumption of fruits, vegetables, and dairy groups, the mean energy intake was within the normal range of requirements for age and gender. The mean total energy intake among the children was 1796.4 ± 557.09 kcal/day, with a significant difference between boys and girls. Similar findings were shown among the adolescent group; a significantly higher mean energy intake among boys compared to girls (2116.34 kcal/day vs. 1688.5 kcal/day; respectively) (p < 0.001), while the average overall group intake was 1872.57± 579.06 kcal/day.\n\nThe present findings indicated that means of macronutrient percentages were found to comply with the AMDRs for both carbohydrates and protein. Fat was high among Jordanian children and adolescents (36.33±6.05 % and adolescents 36.05±6.6%; AMDRs for both groups: 25-35%). Similar results were observed in a previous study conducted among Jordanian adolescents aged 14-18 with a fat intake of around 37% of EI.55 Such findings are comparable to those reported in other countries in the region, including Lebanon (39.2% of EI for 4-13 years),56 and Palestine (39.8% of EI for boys 11-16 years).57 The picture appears similar to what has been reported in Western countries including Spain, where about 43.4% of boys and 46.9% of girls between 4 and 17 years exceeded the AMDR in total fat intake,58 while the mean contribution of fats to EI was 36.9% and 37.2% in Italian boys and girls; respectively (teenagers: 10-17.9 years).59 Remarkably, the results of our study were consistent with those of other studies, showing that the pattern of energy and macronutrient intake has become a popular choice for trendy styles among children and adolescents worldwide.\n\nDiscretionary calories, including added fat and sugar, are unnecessary for health. These foods contribute excess energy to the diet by displacing nutritious foods and should be consumed in moderation. The total intake of discretionary calories in the current study exceeded the recommendations for both age groups by three times (30.7% and 28.6% of total EI for children and adolescents, respectively), considering that the recommendation is <10% of the total EI.60 These results are comparable to those of other countries worldwide. Discretionary foods and beverages accounted for more than a third of the daily energy intake of Australian children aged 2 to 18.32 The same findings were found in Pakistan, where adolescents consumed 31.3% of their energy needs from discretionary foods.61 On average, about 14% of total EI in American children and adolescents was from added sugars.62\n\nDespite adequate carbohydrate intake, the average intake of added sugars was nearly 57 g/day (about 13% and 12% of total EI for children and adolescents, respectively), and these averages were higher than the levels allowed by the MyPlate dietary guidelines and WHO guidelines. These findings might be related to the frequent consumption of sweet snacks, including cakes, pastries, and sweets/chocolates. Adolescents in some Middle Eastern countries tuned increased daily consumption of sweets and desserts, such as in Sudan and Kuwait.53,63 Consistently, the German Child and Adolescent Study results were no better than the present results, reporting that 50% of carbohydrate intake came from added sugars (23.5%) and total sugars, (28.1%).64 In addition, the percentage of energy contribution from added sugars in US children and adolescents was 14.3% at 2-8 years and 16.2% at 9-18 years, while the primary sources are sweetened beverages, candy, and sweet baked goods.65 The main sources of added sugars in the present study were sweetened beverages such as carbonated beverages, canned juices (fruit beverages), many types of sweetened ready-to-drink beverages, and sweetened tea; chocolate, cakes, as well as various kinds of Arabic sweets such as baklava, as well as Western desserts.\n\nContrary to previously published studies, saturated fats mean intake in the present findings was almost equal for both age groups and rounded at 16 g/day; it was within an acceptable amount compared to the MyPlate dietary guidelines allowed amounts. Notably, boys from both age groups consumed significantly higher amounts of cholesterol, saturated, polyunsaturated, and monounsaturated-fatty acids than girls from the same age group. Many Middle Eastern countries, including Lebanon,56 Iran,50 Palestine,57 and Saudi Arabia,66 had average saturated fat intakes (10.7%,10.3%, 10.3%, and 11.3%, respectively) that exceeded the recommendations (AMDR upper limit for saturated fat is 10% of total EI). A similar pattern of results was obtained in Western countries such as Italy (11.5%) the UK (13.2%), France (15%), and Spain (12.3%).58,59,67,68\n\nSome issues must be addressed to clarify the findings of this study. The large representative sample from a population-based study, the careful data quality control methods by reducing dietary intake misreporting, evaluating overweight and obesity by using WHtR (indicating central obesity) rather than BMI (indicating overall obesity), and the repaint of the specific MyPlate dietary guidelines for all age groups were major strengths of our study. One of the current study’s limitations was that it was cross-sectional, which hindered the observation of causal effects. Furthermore, there is a lack of evaluation of physical activity, nutrition-related blood tests, and blood pressure.\n\nThe findings of this study make several noteworthy contributions in depicting the food consumption patterns and food and nutrient intakes following the COVID-19 pandemic and its consequences; the disease’s effect occurred in two stages: first, during the lockdown, and second, afterward. An enormous amount of scientific literature focuses primarily on the negative changes in food habits, food consumption quality and quantity, body weight, and physical activity in people of all ages, particularly children and adolescents. Jordan experienced lockdowns and school closings like any other country, eventually replaced by e-learning. These negative changes in children and adolescents could last longer until adulthood and increase NCDs’ prevalence.\n\nSome issues must be addressed to clarify the findings of this study. The large representative sample from a population-based study, the careful data quality control methods by reducing dietary intake misreporting, evaluating overweight and obesity by using WHtR (indicating central obesity) rather than BMI (indicating overall obesity), and the repaint of the specific MyPlate dietary guidelines for all age groups were major strengths of our study. One of the current study’s limitations was that it was cross-sectional, which hindered the observation of causal effects. Furthermore, there is a lack of evaluation of physical activity, nutrition-related blood tests, and blood pressure.\n\nIt appears that fat and added sugar consumption must be controlled; policymakers and health professionals must take appropriate steps to address this issue. It is recommended that families, children, and adolescents receive nutrition education about the components of MyPlate dietary guidelines and the adverse health effects of obesogenic diets. Implementing community education programs about healthy eating habits requires cooperation between governmental and non-governmental organizations.\n\n\nConclusions\n\nIn conclusion, the prevalence of overweight/obesity approached about half of children, and a third of adolescents were classified as overweight/obese. On the other hand, about a quarter of the children and adolescents had abnormal WHtR. Notably, children and adolescents mismatched the intake of all recommended servings of MyPlate dietary guidelines (except grain intake in ’boys’ children). Despite the mean energy intake being within the estimated recommendations, children and adolescents consumed a slightly higher fat proportion than the AMDRs. Noticeably, the mean intake of added sugar was higher than MyPlate dietary guidelines allowed amounts, while the saturated fats mean intake was within an acceptable MyPlate dietary guidelines amount for both groups. Moreover, about 1/3 of energy consumed was from discretionary calories. Remarkably, boys consumed higher amounts of cholesterol, saturated, polyunsaturated, and monounsaturated fats than girls.", "appendix": "Data availability\n\nZenodo: Food consumption and adherence to dietary guidelines among Jordanian children and adolescents. https://doi.org/10.5281/zenodo.8159227. 69\n\nThe project contains the following underlying data:\n\n• SPSS JPFCS children and Teenagers 2023. sav. (Anonymised participant’s data used in this study).\n\nZenodo: Food consumption and adherence to dietary guidelines among Jordanian children and adolescents. https://doi.org/10.5281/zenodo.8240928. 35\n\nThis project contains the following extended data:\n\n• A study of the rate of food consumption using 24-hour memory for a sample of Jordanian society.docx (English version of data collection survey including two sheets for 24-hour recall).\n\n• دراسة معدل استهلاك الطعام باستخدام التذكر ل 24 ساعة لعينة من المجتمع الأردني النسخة العربية .docx. (Arabic version of data collection survey including two sheets for 24-hour recall).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0)\n\n\nReferences\n\nUauy R, Kain J, Mericq V, et al.: Nutrition, child growth, and chronic disease prevention. Ann. Med. 2008; 40(1): 11–20. Publisher Full Text\n\nYan Y, Mi J: Noncommunicable chronic disease prevention should start from childhood. Pediatr. Investig. 2021; 5(1): 3–5. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAl-Jawaldeh A, Abbass MMS: Unhealthy Dietary Habits and Obesity: The Major Risk Factors Beyond Non-Communicable Diseases in the Eastern Mediterranean Region. Front. Nutr. 2022; 9: 817808. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPuwar T, Saxena D, Yasobant S, et al.: Noncommunicable Diseases among School-going Adolescents: A Case Study on Prevalence of Risk Factors from Sabarkantha District of Gujarat, India. Indian J. 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Publisher Full Text" }	[ { "id": "204311", "date": "12 Sep 2023", "name": "Lana Agraib", "expertise": [ "Reviewer Expertise My areas of research are obesity", "chronic disease", "and dietary patterns" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThanks to the authors, this article is well-written and the figure and table are well-drawn and easier to read and understand helping in getting the idea more easily. The article addresses the food consumption pattern among Jordanian children and adolescents. It addresses an important topic in Jordan, especially indicating the consumed food group that may affect children and adolescents’ health, as the prevalence of obesity among this age group is rising dramatically.\nIn more detail, Alkhatib and colleagues highlighted that the intakes of fruits, vegetables, and dairy products were low among the study group, while the consumption of additives specifically sugar and fat which was defined using the term \"discretionary calorie\" was high, and this may explain the increasing in obesity rate. It should make an important contribution to children and adolescent health programs which in consequence reduce obesity and the associated adulthood diseases that increase the burden in the health sector.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] }, { "id": "223002", "date": "27 Nov 2023", "name": "Sarah Ibrahim", "expertise": [], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for submitting this paper. An interesting and important study appreciating the impact nutrition has on NCDs.\n\nPlease find my feedback for some revisions below:\n\nAbstract\nThe background is an articulation of the study purpose. Would be helpful to include some background information to substantiate the purpose of conducting this study- situate the problem first and then proceed to indicate the purpose of the study.\nBackground\nPerhaps including a little bit of information on the current overweight and/or obesity-related challenges in Jordan, that would have also sparked the interest to conduct this study.\nMethods\nReword: This study received ethical approval from the Institutional Board Review (IRB) committee, reviewed and approved the survey protocol at The Hashemite University (No.7/13/2020/2021). To: Institutional Research Ethics Board approval was obtained from the Hashemite University (No.7/13/2020/2021).\nFurther clarification on where was data collected conducted?\nWhat type of sampling method was used? Further elaboration warranted.\nRationale for excluding children with chronic disease warranted.\nSurvey Tool\nThe following statement is unclear in this subsection: It was announced on the university’s website about the need for nutritionists to work in data collection, and they were selected after personal interviews and based on their experience, and they were subsequently trained.\nRecommend re-writing this section; as it stands, it is not entirely clear (semi-structured interviews, face-to-face interviews, various tools used)- particularly the first few sentences.\nWas the nutritionist present during the recall?\nData Analysis\nShould be written as stratified based on sex (and not gender).\nDiscussion\nRecommend condensing the discussion further (a number of studies are summarized here), and very little information provided on the implications section, which is important. Recommend highlighting key research articles in the discussion to substantiate your findings etc. and flush out the implications section further.\nA section on the limitations is warranted.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "10666", "date": "18 Sep 2024", "name": "Buthaina Alkhatib", "role": "Author Response", "response": "Thank you for submitting this paper. An interesting and important study appreciating the impact nutrition has on NCDs. Response: Many thnaks Please find my feedback for some revisions below: Abstract The background is an articulation of the study purpose. Would be helpful to include some background information to substantiate the purpose of conducting this study- situate the problem first and then proceed to indicate the purpose of the study. Response: (It has been modified) Background Perhaps including a little bit of information on the current overweight and/or obesity-related challenges in Jordan, that would have also sparked the interest to conduct this study. Response: (It has been modified) Methods Reword: This study received ethical approval from the Institutional Board Review (IRB) committee, reviewed and approved the survey protocol at The Hashemite University (No.7/13/2020/2021). To: Institutional Research Ethics Board approval was obtained from the Hashemite University (No.7/13/2020/2021). Response: it has been modified. Further clarification on where was data collected conducted? Response: it has been written in details in the section” study design and sample selection’, also the details were published in the protocol manuscript Al-Shami et al. (34) What type of sampling method was used? Further elaboration is warranted. Response: simple random sampling for households. ( it has been provided) The rationale for excluding children with chronic disease warranted. Response: the study aimed to investigate the children and adolescents in the whole apparently healthy population, the exclusion of those with chronic diseases was to neutralize the effect of the disease on food intake and to reduce the effect of the medications taken on the dietary pattern and food consumption. Survey Tool The following statement is unclear in this subsection: It was announced on the university’s website about the need for nutritionists to work in data collection, and they were selected after personal interviews and based on their experience, and they were subsequently trained. Recommend re-writing this section; as it stands, it is not entirely clear (semi-structured interviews, face-to-face interviews, various tools used)- particularly the first few sentences. Response: “The university's website stated that nutritionists were required to assist with data collection. Based on their experience, they were chosen through in-person interviews, and they were then trained.” Was the nutritionist present during the recall? Response: YES, for the first 24-hour recall, then the other recall was obtained by phone call. It has been clarified in the first 4 lines on the “dietary assessment” section Data Analysis Should be written as stratified based on sex (and not gender). Response: (It has been modified) Discussion Recommend condensing the discussion further (a number of studies are summarized here), and very little information is provided on the implications section, which is important. Recommend highlighting key research articles in the discussion to substantiate your findings etc. and flush out the implications section further. Response: it has been modified and highlighted with red color. A section on the limitations is warranted. Response: it is available in the paragraph before the implications, and it has been separated into a single paragraph." } ] } ]	1	https://f1000research.com/articles/12-1094
https://f1000research.com/articles/13-1251/v1	18 Oct 24	{ "type": "Research Article", "title": "Influence of spin-off decision on financing risk: Empirical insight from Indonesian Islamic banks", "authors": [ "Zulfikar Bagus Pambuko", "Jaka Sriyana", "Akhsyim Affandi", "Abdul Hakim", "Jaka Sriyana", "Akhsyim Affandi", "Abdul Hakim" ], "abstract": "Background Spin-offs play a significant role in organizational development strategies, particularly in Islamic banking, by fostering entrepreneurship, innovation, and Shariah-compliant management practices. Indonesia stands as a pioneer in implementing the dual banking system and has established a spin-off policy to foster the growth of Islamic banking. This study investigates whether the spin-off decision has a significant impact on financing risk in Indonesian Islamic banks.\n\nMethods Financing risk is measured by the non-performing financing ratio, while the spin-off decision is represented by a dummy variable equal to 1 for the post-spin-off period and 0 for the pre-spin-off period. This study utilizes data from semi-annual reports of 35 Indonesian Islamic banks and analyzes it using a dynamic panel model with the Generalized Method of Moments (GMM).\n\nResults The findings reveal that spin-offs significantly reduce financing risk, thereby enhancing the financial resilience and boosting investor appeal. Notably, this implies that Islamic banks operating as Islamic windows exhibit a higher level of financing risk compared to fully-fledged Islamic banks. Furthermore, a noteworthy pattern emerges that spin-off Islamic banks with substantial assets demonstrate greater risk in comparison to their counterparts with more modest assets. System GMM also confirmed the result.\n\nConclusions Islamic banks can significantly reduce their financing risks by establishing independent Islamic banks, or spin-offs. Unlike Islamic windows, which are typically integrated within conventional banks and face higher risk levels, standalone Islamic banks offer greater flexibility and control over their operations.", "keywords": [ "Islamic Banks", "Non-Performing Financing", "Financial Resilience", "Government Policy" ], "content": "Introduction\n\nIslamic banking has emerged as a vital component of the global financial landscape, offering a unique alternative based on principles grounded in ethical and Shariah-compliant practices (Al Ansari & Alanzarouti, 2020; Jaafar & Brightman, 2022). Islamic banks dominate 70% of the total assets in the global Islamic finance sector, signifying a growth of 17% compared to the previous period. The primary driving force behind this accomplishment is the significant contribution of countries with Muslim-majority populations, particularly in the GCC, MENA, and Southeast Asia regions. This progress is primarily supported by effective governance and well-suited policies (ICD IsDB, 2022). In Indonesia, a prominent Muslim-majority nation, the Islamic banking sphere has showcased notable expansion and adaptability, establishing its role as a crucial element within the nation’s financial framework (Trinugroho et al., 2018). Within this period of growth, the spin-off policy has been contemplated as a strategy to navigate the complexities of contemporary banking while adhering Shariah principles (Pambuko & Sriyana, 2023; Trinugroho et al., 2021).\n\nThe phenomenon of spin-off becomes the one of the key dynamics influencing the financial performance of Indonesian Islamic banks (Pambuko & Sriyana, 2023; Trinugroho et al., 2021). As a strategy, this refers to the process of establishing separate entities from the parent institution, often with distinct business focuses (Chai et al., 2018). According to Article 68 of Law 21 of 2008, all Islamic windows are required to undergo a spin-off after 15 years or if their assets have exceeded 50% of their conventional parent bank’s assets (Nurkarim et al., 2021; Pambuko, 2019; Rokhmawati et al., 2022). These spin-offs were achieved through various methods, including pure spin-offs, conversions, mergers, and acquisitions (Al Arif, Masruroh, et al., 2020a). The rationale behind such spin-offs often involves streamlining operations, improving risk management, optimizing organizational structures, enhancing efficiency, fostering growth, and complying with sharia law (Al Arif, 2014; Al Arif et al., 2018; Hamid, 2015).\n\nThe Financial Services Authority of Indonesia (2023) reports a significant increase in Islamic banking institutions as of May 2023. There are now 13 Islamic commercial banks and 20 Islamic windows, compared to just 5 commercial banks and 27 windows before the spin-off policy’s implementation. This law, enacted in 2008, mandated all Islamic windows to become full-fledged Islamic banks by 2023 (Pambuko et al., 2024). However, many Islamic windows haven’t completed this process, highlighting the need for further study on how spin-offs impact Islamic banking performance and their adherence to Sharia principles. Furthermore, the issue of spin-offs has also become one of the key strategies to enhance the contribution of Islamic banking in other countries. As reported, Pakistan, Bahrain, Kuwait, and Afghanistan are among the countries earnestly implementing this issue in the development of Islamic banks (ICD IsDB, 2022). Therefore, Indonesia, as a pioneer of the implementation of spin-off strategy in the Islamic banking sector, deserves to be a benchmark in the implementation of this strategy, particularly as an effort to sustain the Islamic banking industry.\n\nIn the last decade, many researchers have directed their attention toward identifying the impact of spin-off policies on the performance of Islamic banks. Several indicators of financial performance have been focused on, including profitability (Hamid, 2015; Nurkarim et al., 2021), efficiency (Al Arif et al., 2018; Al Arif, Mufraini, et al., 2020b; Al Arif & Nabilah, 2022; Hadziq et al., 2022; Pambuko, 2019; Rusydiana et al., 2019), market share (Al Arif, 2017; Al Arif et al., 2023), asset growth (Al Arif, 2015a; Al Arif et al., 2017), financing growth (Al Arif, 2015b), deposit growth (Al Arif, 2014, 2018b, 2018a; Al Arif et al., 2024), and market power (Rayyani et al., 2022). While there’s been a lot of research on spin-offs, how they affect a bank’s risk of financing risk (bad loans) has not been well-studied. This is an important gap to address, especially considering the recent Basel III framework from the Basel Committee on Banking Supervision (BCBS). These new global regulations aim to make banks worldwide more stable by considering all their risks, both from loans they’ve made (on-balance sheet) and from their commitments (off-balance sheet exposures) (Abdurraheem et al., 2023).\n\nConcurrently, the management of bad financing or non-performing financing (NPF) presents a critical challenge for Islamic banking institutions in Indonesia (Imaduddin, 2008; Nugroho et al., 2018; Soekapdjo et al., 2018). Non-performing financing, characterized by loans or financing contracts in default or at risk of default, can have far-reaching implications on the stability and credibility of financial institutions (Hernawati et al., 2021). In traditional banking, its known as non-performing loan (NPL). The existence of financing risk can hinder the stability of Islamic banking entities, potentially jeopardizing their capacity to facilitate economic growth and foster financial inclusivity (Banna et al., 2022). Considering the distinct characteristics of Islamic finance, rooted in risk-sharing and asset-backed principles, a comprehensive exploration of how spin-off decisions influence financing risk, specifically non-performing financing, requires further investigation.\n\nStudies on NPF in Islamic banks or NPL in conventional banks are still hotly discussed. Research suggests that external factors play a bigger role in NPLs for conventional banks, while both internal and external factors impact NPFs in Islamic banks (Loang et al., 2023; Setiawan et al., 2017). Furthermore, despite some inconsistencies in results, from a bank-specific perspective, an increase in non-performing financing is influenced by bank size, operating efficiency ratio, liquid asset ratio, financing to deposit ratio, and foreign ownership (Havidz & Setiawan, 2015; Hosen & Muhari, 2019; Osunkoya et al., 2023; Rahim & Zakaria, 2013; Saw et al., 2022; Zheng et al., 2019). On the other hand, the decrease in non-performing financing is influenced by an increase in net operating profit, capital adequacy ratio, return on assets, cost to income ratio, deposit funds growth, return on equity, loan growth, and market concentration (Hartanto & Samputra, 2023; Hosen & Muhari, 2019; Muhammad et al., 2020; Rahim & Zakaria, 2013; Zheng et al., 2019). Similarly, macroeconomic conditions also impact changes in banking’s financing risk. Exchange rates, inflation, and economic policy uncertainty contribute to an increase in non-performing financing (Firmansyah, 2014; Hosen & Muhari, 2019; Karadima & Louri, 2021; Osunkoya et al., 2023; Zheng et al., 2019), while GDP and unemployment contribute to a decrease in non-performing financing (Ferhi, 2018; Hassan et al., 2019; Hernawati et al., 2021; Le & Diep, 2020; Zheng et al., 2019). A surplus in foreign exchange reserves can also trigger a financing boom, which in turn can affect financing quality (Kuncoro, 2024).\n\nThis scientific paper aims to bridge these knowledge gaps by offering an empirical analysis of the relationship between spin-off decision and the prevalence of financing risk in the Indonesian Islamic banking sector. While previous research suggests spin-off decisions can improve financial performance, the potential effect on financing risk has been overlooked. This study will address this gap by examining how spin-offs influence financing risk. By untangling these linked factors, we aim to provide valuable insights for both academics and Islamic bankers, fostering a deeper understanding of how strategic restructuring impacts the financial soundness of Islamic banks. Moreover, given the intricate relationships between spin-off strategies and financing risk, policy implications and strategic recommendations stemming from this study could serve as a catalyst for informed decision-making within the Islamic banking industry.\n\n\nMethods\n\nTo examine the impact of spin-off decisions on financing risk, this study utilizes semi-annual bank-level data from 2006 to 2022 for Islamic banks in Indonesia. The bank-specific data, derived from the financial statements of 35 Islamic banks, were acquired from the Islamic Banking Statistics which is reported by Indonesian Financial Services Authority (FSA). The sample consists of 16 full-fledged Islamic banks and 19 Islamic windows. Macroeconomic data were sourced from Statistics Indonesia, Bank Indonesia, and OPEC basket price. We employed an unbalanced panel dataset encompassing 1032 observations.\n\nTable 1 explains the data we used in this study. We looked at the ratio of non-performing financing (NPF) to total financing, which is a common measure of bad loans in Islamic banks (Saw et al., 2022). Spin-off is a proxy for spin-off decisions, represented by a dummy variable where 1 denotes post-spin-off time and 0 signifies pre-spin-off time. The bank-specific factors include bank size (log total assets of each Islamic bank) and market share, assessed by the individual Islamic bank’s asset over the total asset industry of Islamic banks. To understand the economic climate, we looked at the Consumer Price Index (CPI) for inflation and the Industrial Production Index (IPI) for economic growth. The variable OIL is based on the OPEC basket price, which represents the per-barrel oil price.\n\nThis study utilizes a dynamic panel regression model with individual fixed effects to assess the impact of spin-off decisions on financing risk for Islamic banks in Indonesia. The dynamic panel approach addresses both unobserved bank-specific characteristics and potential endogeneity issues that might bias the results. To further account for potential simultaneity and correlation between variables, the study employs the Generalized Methods of Moment (GMM) estimation technique. Equation (1) details the empirical model used in this analysis, which incorporates the spin-off decision as the main independent variable. Additionally, control variables such as bank size, market share, and macroeconomic factors like inflation, economic growth, and oil price are included to account for their potential influence on financing risk.\n\nWhere Yit is the non performing financing (NPF) for bank i and year t; Spinofft is a dummy variable, it is one if the period after spin-off decision, zero otherwise; BankSpecifici,t is control variable consisting of bank size dan market share; MacroEconomict is control variable consisting of inflation, economic growth, and oil price; and εi,t is the error term. The first lag of the dependent variable has been integrated into the model as an independent variable to address the possible persistence of NPF changes in time. Our analyses utilized a difference GMM Arellano-Bond estimator. To ensure robustness, we conducted a two-step System GMM estimator for further validation.\n\nThen we analyze the impact of bank size on the interaction between spin-off decisions and non-performing financing. We created an interaction variable in the form of SpinofftSizeit for this purpose. The equation (2) represents the estimation model.\n\nData analysis was conducted using EViews 12 by S&P Global. Prior to interpretation, diagnostic tests were performed. The Sargan test was employed to assess the validity of the instruments, while the Arellano-Bond test was used to detect the presence of autocorrelation. A well-specified model should exhibit valid instruments and no autocorrelation.\n\n\nResults and Discussion\n\nTable 2 presents descriptive statistics for the variables spanning from 2006 to 2022. The average value of NPF as a financing risk proxy stands at 3.10%. This value remains below the designated upper limit of 5.00. The lowest NPF value, at 0.00%, indicates that certain Islamic banks have no risky financing, although the highest NPF value recorded is 53.27%. This relatively high variability is supported by a standard deviation of 4.17%. Regarding assets and market share, the lower mean values compared to the standard deviation suggest that Islamic banks in Indonesia are still dominated by a few larger banks.\n\nThe analysis commenced by identifying the issue of multicollinearity among the independent variables. Table 3 displays the correlation scores among the independent variables. A correlation score of < 0.8 was indicative of the absence of multicollinearity (Mukhibad, Nurkhin et al., 2023b; Rizvi et al., 2020). The highest correlation between independent variables was 0.5678 (correlation between SIZE and IPI), followed by SIZE and MS (0.5592). These findings signify the absence of multicollinearity within the model.\n\nThe subsequent analysis examines the impact of spin-off decisions on the financing risk of Islamic banks. Table 4 presents the outcomes of the difference GMM and system GMM. Difference GMM estimator is depicted in regressions (1)-(4), while system GMM estimator in regressions (5)-(8). Regressions (1) and (5) only incorporate bank-specific variables, consisting of assets (SIZE) and market share (MS). In regressions (2) and (6), we include additional control variables such as inflation (CPI), economic growth (IPI), and global oil prices (OIL). In regressions (3), (4), (7), and (8), we introduce interaction variables, specifically spin-offsize. Towards the end of the table, it is indicated that no issues of instrumental validity and autocorrelation were found. To elaborate, the results of the Sargan test reject the null hypothesis, confirming the validity of the instruments. Furthermore, the results of the Arellano-Bond autocorrelation test, AR(2), also reveal the absence of autocorrelation in the model.\n\n* p<0.01.\n\n p<0.05.\n\n* p<0.1.\n\nThe findings from the analysis provide compelling evidence regarding the influence of the lagged dependent variable, NPF(-1), which consistently exhibits a statistically significant positive effect across all models at the 1% significance level. This outcome substantiates the notion that the financing risk experienced in the preceding period contributes to an increase in the non-performing financing ratio during the present period. This result underscores a significant challenge in the Islamic banking sector, suggesting that the mechanisms in place to address the issue of bad financing have not yet achieved optimal effectiveness. This aligns with previous research conducted by Mukhibad, Jayanto et al. (2023a), who reached similar conclusions in their study. Notably, the finding underscores the persisting complexity of managing NPF in Islamic banking and emphasize the need for more refined strategies to mitigate such risks. Interestingly, the result contrasts with those of Hartanto & Samputra (2023), whose research indicated a potential improvement in the non-performing financing situation from period t-1 to period t. This variation emphasizes the intricate and many-sided aspects of how financing risk behaves in Islamic banking.\n\nRegarding the main focus of this study, it becomes apparent that the spin-off decisions undertaken by Islamic banks wield a substantial and statistically significant impact, consistently evident at the 1% significance level across all models. This pervasive influence, however, diverges in models (1) and (2). Specifically, the majority of models reveal a noteworthy negative effect resulting from the strategic choice of Islamic banks to embark on spin-offs. This intriguing discovery underscores a pivotal insight – that the judicious adoption of spin-off strategies by Islamic banks yields a salutary outcome, effectively tempering the levels of financing risk. This outcome resonates with the emerging understanding that Islamic banks’ autonomy in resource management holds the potential to substantially shape their risk profile. This profound effect echoes the findings of a distinct study, where a compelling revelation was made that full-fledged Islamic banks exhibit a more adept ability to mitigate non-performing financing as compared to Islamic windows (Pambuko & Pramesti, 2020; Pernamasari, 2020). These findings collectively affirm the advantageous influence of spin-off decisions in fostering improved risk management practices and enhancing the overall stability of Islamic banking entities.\n\nWe also investigated the impact of size on financing risk. The analysis results reveal that size has a significant positive impact on non-performing financing, except in model (3) where it has a negative impact. The finding indicates that an increase in the asset size will increase financing risk. The result supports the finding of Hosen and Muhari (2019) and Saw et al. (2022). It is also validated the ‘bad management theory’ proposed by Berger and DeYoung (1997). Within this theoretical framework, the orchestration of poor management practices within banking institutions leads to lower loan quality and increases the level of non-performing loans. Furthermore, these results are corroborated by the estimations of the interaction variable (spinoff*size), which significantly influences non-performing financing. Thus, larger Islamic banks that undergo spin-offs carry a higher financing risk compared to smaller banks.\n\nFurther analysis concerning the impact of market share on the financing risk of Islamic banks was conducted. Across all models, a positive relationship between market share and non performing financing is revealed, except in models (6) and (8), where the relationship is significant at the 5% and 10% levels, respectively. The finding strengthens the previous estimations indicating that greater asset dominance increases the potential for non-performing financing. As for the control variables, we only found robust and negatively correlated estimates for NPF and OIL. This negative relationship explains that an increase in global oil prices will decrease financing risk for Islamic banks. With a certain level of oil price increase, related product prices become more competitive, stimulating business sectors and lowering financing risk. As Abimanyu et al. (2023) pointed out, Indonesia’s policy aims to ensure that global oil price movements contribute positively to the state’s finances and trade, while minimizing inflationary risks. The result also supports the findings of Ryandono et al. (2022) dan Al Jabri et al. (2022). On the other hand, economic growth and inflation exhibit inconsistent results across each model.\n\n\nConclusion\n\nThis study investigates the impact of spin-off decision – the separation of Islamic windows from their conventional parent banks to become full-fledged Islamic banks – on financing risk in Indonesian Islamic banks. We estimate over a substantial timeframe in the journey of Islamic banks in Indonesia, spanning from 2006 to 2022. Our findings reveal that Islamic windows carry a higher risk compared to full-fledged Islamic banks that undergo spin-offs. We also discover that spin-off Islamic banks with larger assets are more exposed to risk than those with smaller assets. This notice is supported by the regression that financing risk increases with the growth of assets and market share. In essence, our study not only contributes to the empirical understanding of Islamic banking dynamics but also advances the discourse surrounding prudent risk management strategies in financial systems governed by ethical and Shariah-compliant principles.\n\nThese findings yield several policy implications. We have strong evidence that the independence of Islamic banks makes them more sensitive to risk and adept at mitigating it. Therefore, the mandatory spin-off policy to be implemented for all Islamic windows by the end of 2023 is a viable approach. Moreover, the potential rise in market dominance by Islamic banks, which could amplify financing risk, calls for complementary policies to mitigate the potential negative outcomes.\n\nThis study does not involve human participants, animal subjects, or plant specimens.", "appendix": "Data availability\n\nZenodo: Influence of spin-off decision on financing risk: Empirical insight from Indonesian Islamic banks https://doi.org/10.5281/zenodo.13879461 (Pambuko, 2024).\n\nThe project contains the following underlying data:\n\n− dataset financing risk.xlsx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nThe data used in this research is open-access and can be downloaded from the following website: Indonesian Banking Statistics on Financial Service Authority Website: https://www.ojk.go.id/en/kanal/perbankan/data-dan-statistik/statistik-perbankan-indonesia/Default.aspx; BPS-Statistics Indonesia: https://www.bps.go.id/en/statistics-table/2/MjA3NyMy/indeks-produksi-bulanan-industri-besar-dan-sedang-menurut-kbli-2-digit--kbli-2020---2010-100-.html; Bank Indonesia: https://www.bi.go.id/en/statistik/indikator/data-inflasi.aspx; and OPEC Basket Price: https://www.opec.org/opec_web/en/data_graphs/40.htm.\n\n\nReferences\n\nAbdurraheem AA, Alam MM, Nadzri FAA: Financing concentration and credit risks: Empirical study on the islamic banks in Malaysia. 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Part A: Economics and Business. 2021; 1(2): 93–101. Publisher Full Text\n\nOsunkoya M, Ikpefan O, Olokoyo F: Macroeconomic and bank-specific determinants of non-performing loans in Nigeria. WSEAS Transactions on Business and Economics. 2023; 20: 1153–1166. Publisher Full Text\n\nPambuko ZB: Kebijakan spin-off dan efisiensi perbankan syariah di Indonesia. Ihtifaz: Journal of Islamic Economics, Finance, and Banking. 2019; 2(1): 21–38. Publisher Full Text\n\nPambuko ZB: Dataset of financing risk for islamic banking in Indonesia (semi-annual 2006-2022). [Dataset]. Zenodo. 2024. Publisher Full Text\n\nPambuko ZB, Medias F, Dewi VS, et al.: Restructuring strategy: A performance review of spin-off Islamic banks in Indonesia. E3S Web of Conferences. 2024; 500: 05008. Publisher Full Text\n\nPambuko ZB, Pramesti DA: The effectiveness of Bank Aceh Syariah conversion decisions. Economica: Jurnal Ekonomi Islam. 2020; 11(1): 1–23. Publisher Full Text\n\nPambuko ZB, Sriyana J: Islamic banking spin-offs decision: A bibliometric review. Cogent Business & Management. 2023; 10(2). Publisher Full Text\n\nPernamasari R: Analysis performance of Islamic bank in Indonesia: Before and after the spin off. European Journal of Business and Management Research. 2020; 5(5): 1–7. Publisher Full Text\n\nRahim SRM, Zakaria RH: Comparison on stability between Islamic and conventional banks in Malaysia. Journal of Islamic Economics, Banking and Finance. 2013; 9(3): 131–149. Publisher Full Text\n\nRayyani WO, Abbas A, Ayaz M, et al.: The magnitude of market power between SCBs and SBUs: the root cause of stagnancy of the growth in Islamic banking industry and spin-off policy as its solution. Ikonomika: Jurnal Ekonomi Dan Bisnis Islam. 2022; 7(1): 97–120.\n\nRizvi SAR, Narayan PK, Sakti A, et al.: Role of Islamic banks in Indonesian banking industry: an empirical exploration. Pacific-Basin Finance Journal. 2020; 62: 101117. Publisher Full Text\n\nRokhmawati A, Desy, Halim EH: Does spin-off obligation of sharia business units from its parent commercial banks enhance their performance? Iranian Economic Review. 2022; 26(4): 819–832.\n\nRusydiana AS, Devi A, Hasib FF, et al.: Spin-off policy of sharia bank: Is it profitable? Al-Iqtishad: Jurnal Ilmu Ekonomi Syariah. 2019; 11(2): 265–288. Publisher Full Text\n\nRyandono MNH, Imron MA, Wildan MA: World oil prices and exchange rates on Islamic banking risks. International Journal of Energy Economics and Policy 2022; 12(4): 409–413. Publisher Full Text\n\nSaw ATW, Ooi AY, Yap WK, et al.: Bank ownership and non-performing loans of Islamic and Conventional banks in an emerging economy. International Journal of Economics and Management. 2022; 16(3): 339–349. Publisher Full Text\n\nSetiawan C, Hasan T, Hassan MK, et al.: Non-performing loans and bank efficiency of conventional and Islamic banks in the Organization of Islamic Cooperation (OIC) countries. Journal of Islamic Economics, Banking and Finance. 2017; 13(4): 18–43. Publisher Full Text\n\nSoekapdjo S, Nugroho L, Badawi A, et al.: Bad debt issues in Islamic bank: Macro and micro influencing (Indonesia cases). International Journal of Commerce and Finance. 2018; 4(1): 10–26.\n\nTrinugroho I, Risfandy T, Ariefianto MD: Competition, diversification, and bank margins: Evidence from Indonesian Islamic rural banks. Borsa Istanbul Review. 2018; 18(4): 349–358. Publisher Full Text\n\nTrinugroho I, Santoso W, Irawanto R, et al.: Is spin-off policy an effective way to improve performance of Islamic banks? Evidence from Indonesia. Research in International Business and Finance. 2021; 56(November 2020): 101352. Publisher Full Text\n\nZheng C, Bhowmik PK, Sarker N: Industry-specific and macroeconomic determinants of non-performing loans: A comparative analysis of ARDL and VECM. Sustainability. 2019; 12(1): 325. Publisher Full Text" }	[ { "id": "336316", "date": "07 Nov 2024", "name": "Azharsyah Ibrahim", "expertise": [ "Reviewer Expertise Islamic management", "banking", "and finance" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary This paper investigates the impact of the spin-off decision (Islamic windows separating from conventional banks to become independent Islamic banks) on financing risk in Indonesian Islamic banks. Using semi-annual data from 2006-2022 for 35 Islamic banks, the study employs a dynamic panel model with Generalized Method of Moments (GMM) estimation. The key finding is that spin-offs significantly reduce financing risk, particularly for larger banks. The study also finds that larger Islamic banks and those with a higher market share generally face higher financing risk. The negative correlation between oil prices and non-performing financing suggests that increasing oil prices may indirectly benefit Islamic banks by stimulating the economy. Evaluation\nIs the work clearly and accurately presented and does it cite the current literature? Partly. While the presentation is generally clear, some areas could benefit from more precise language and further elaboration. The literature review, while extensive, could be structured more thematically to better highlight the existing research gaps and the study's contribution. Some cited works appear very recent (2023-2024) and I am unable to verify their accessibility/existence given my current knowledge cutoff. It's important to ensure all cited works are publicly accessible. Is the study design appropriate and is the work technically sound? Partly. The use of a dynamic panel model with GMM is appropriate for addressing potential endogeneity. However, the justification for using the OPEC basket price as a sole indicator of global oil prices could be strengthened. A broader measure or a combination of indicators might be more representative. Additionally, more detail on the specific GMM implementation (e.g., lag selection, instrument validity tests beyond Sargan) would enhance the technical soundness. Are sufficient details of methods and analysis provided to allow replication by others? Partly. While the data sources are mentioned, the specific variables used within the model (e.g., how \"market share\" is calculated) could be more explicitly defined. The provided dataset link on Zenodo was checked and is accessible. However, clear instructions on how to merge the bank-specific data with the macroeconomic data are necessary for full replication. More detail on the GMM implementation is also needed (as mentioned above). If applicable, is the statistical analysis and its interpretation appropriate? Partly. The interpretation of the results generally aligns with the findings. However, the discussion of the inconsistent results for economic growth and inflation could be improved. Exploring potential reasons for these inconsistencies or considering alternative model specifications might provide more robust insights. Furthermore, while the Sargan test is reported, more comprehensive diagnostics related to the GMM estimation would strengthen the analysis. Are all the source data underlying the results available to ensure full reproducibility? Yes. The data sources are listed and the Zenodo link provides the bank-level data. The macroeconomic data sources are also publicly accessible. However, as noted above, clearer instructions on data merging are needed. Are the conclusions drawn adequately supported by the results? Partly. The main conclusion regarding the positive impact of spin-offs on reducing financing risk is supported by the findings. However, the claim that larger spin-off banks are more exposed to risk needs further clarification. While the results show that size increases risk in general, it's not entirely clear from the presented analysis whether this effect is amplified after the spin-off, or if larger banks simply start at a higher risk level pre-spin-off. More nuanced analysis and discussion are needed to fully support this specific conclusion.\nSpecific Recommendations for Improvement:\nLiterature Review: Organize the literature thematically and clearly articulate the research gap being addressed. Verify the accessibility of all cited works. Methodology: Provide a stronger justification for the choice of oil price indicator. Elaborate on the specific GMM implementation details (lag selection, instrument details, and robustness checks). Data and Replication: Provide clear definitions of all variables, including calculations. Include detailed instructions on how to merge the datasets used. Statistical Analysis: Explore reasons for the inconsistent results of control variables. Provide more comprehensive GMM diagnostics. Conclusion: Refine the discussion about the impact of size on risk for spin-off banks. Provide clearer evidence to support the claim of increased risk for larger spin-off banks compared to smaller ones. Consider separating the impact of size on risk in general from the specific impact on spin-off banks.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "13176", "date": "04 Feb 2025", "name": "Zulfikar Bagus Pambuko", "role": "Author Response", "response": "We would like to warmly thank you for reading our manuscript and your valuable comments which would substantially improve our paper. We have followed carefully all your comments in the preparation of the revised version of the paper. Our revisions are summarized below. Reviewer’s Suggestion 1: Is the work clearly and accurately presented and does it cite the current literature? Partly. While the presentation is generally clear, some areas could benefit from more precise language and further elaboration. The literature review, while extensive, could be structured more thematically to better highlight the existing research gaps and the study's contribution. Some cited works appear very recent (2023-2024) and I am unable to verify their accessibility/existence given my current knowledge cutoff. It's important to ensure all cited works are publicly accessible. Authors’ Response: We would like to express our gratitude for your valuable feedback in enhancing the quality of our article. In response to your suggestion, we have incorporated a dedicated section on literature review as follows: “Literature Review The management of bad financing or non-performing financing (NPF) presents a critical challenge for Islamic banking institutions in Indonesia (Imaduddin, 2008; Nugroho et al., 2018; Soekapdjo et al., 2018). Non-performing financing, characterized by loans or financing contracts in default or at risk of default, can have far-reaching implications on the stability and credibility of financial institutions (Hernawati et al., 2021). In traditional banking, its known as non-performing loan (NPL). The existence of financing risk can hinder the stability of Islamic banking entities, potentially jeopardizing their capacity to facilitate economic growth and foster financial inclusivity (Banna et al., 2022). Considering the distinct characteristics of Islamic finance, rooted in risk-sharing and asset-backed principles, a comprehensive exploration of how spin-off decisions influence financing risk, specifically non-performing financing, requires further investigation. Bank-specific factors influencing financing risk Research on NPF in Islamic banking and NPL in conventional banking reveals that various internal and external factors influence financing risk. For conventional banks, external factors such as macroeconomic conditions play a dominant role in shaping NPL levels, while in Islamic banks, both internal and external factors significantly affect NPF (Loang et al., 2023; Setiawan et al., 2017). Among bank-specific factors, an increase in NPF is associated with variables such as bank size, operating efficiency ratio, liquid asset ratio, financing-to-deposit ratio, and foreign ownership (Havidz & Setiawan, 2015; Hosen & Muhari, 2019; Osunkoya et al., 2023; Rahim & Zakaria, 2013; Saw et al., 2022; Zheng et al., 2019). Conversely, factors that contribute to a reduction in NPF include higher net operating profit, capital adequacy ratio, return on assets, cost-to-income ratio, deposit fund growth, return on equity, loan growth, and market concentration (Hartanto & Samputra, 2023; Hosen & Muhari, 2019; Muhammad et al., 2020; Rahim & Zakaria, 2013; Zheng et al., 2019). Macroeconomic factors influencing financing risk Macroeconomic conditions also significantly impact the level of financing risk in Islamic banks. Negative economic indicators such as exchange rate fluctuations, inflation, and economic policy uncertainty have been found to increase NPF levels (Firmansyah, 2014; Hosen & Muhari, 2019; Karadima & Louri, 2021; Osunkoya et al., 2023; Zheng et al., 2019). On the other hand, positive macroeconomic trends such as GDP growth and reduced unemployment contribute to a decrease in NPF (Ferhi, 2018; Hassan et al., 2019; Hernawati et al., 2021; Le & Diep, 2020; Zheng et al., 2019). Additionally, a surplus in foreign exchange reserves can trigger a financing boom, which may subsequently affect financing quality and contribute to increased NPF levels (Kuncoro, 2024).” Reviewer’s Suggestion 2: Is the study design appropriate and is the work technically sound? Partly. The use of a dynamic panel model with GMM is appropriate for addressing potential endogeneity. However, the justification for using the OPEC basket price as a sole indicator of global oil prices could be strengthened. A broader measure or a combination of indicators might be more representative. Additionally, more detail on the specific GMM implementation (e.g., lag selection, instrument validity tests beyond Sargan) would enhance the technical soundness. Authors’ Response: We have added an explanation regarding the use of the OPEC basket price in the “Method” section. “This price serves as a crucial benchmark in determining crude oil prices in the global market, including Indonesia, although it is merely one of many indicators influenced by various complex factors.” Additionally, we have provided a more detailed explanation of lag selection in GMM estimation. “A lag order of one (lag 1) was used for estimation” Reviewer’s Suggestion 3: Are sufficient details of methods and analysis provided to allow replication by others? Partly. While the data sources are mentioned, the specific variables used within the model (e.g., how \"market share\" is calculated) could be more explicitly defined. The provided dataset link on Zenodo was checked and is accessible. However, clear instructions on how to merge the bank-specific data with the macroeconomic data are necessary for full replication. More detail on the GMM implementation is also needed (as mentioned above). Authors’ Response: Thank you for the suggestion. Supplementary information regarding the variables has been provided in Table 1. “Non-performing financing is the ratio of bad financing by total financing” “Inflation is measured using the Consumer Price Index (CPI), which compares the total cost of a fixed basket of goods and services in the current period to the cost of the same basket in a base period” “Economic growth is measured using the Industrial Production Index (IPI), which is calculated by dividing the value of production in a specific period by the value of production in the base year 2010.” The data used in this study is a combination of panel data (internal data from Islamic banks) and time series data (macroeconomic data). For the macroeconomic data, we ensured that the estimation periods aligned, and duplicated the time series data for each Islamic bank observation. Given the unbalanced nature of the panel data, macroeconomic data was only added to complete Islamic bank observations. Reviewer’s Suggestion 4: If applicable, is the statistical analysis and its interpretation appropriate? Partly. The interpretation of the results generally aligns with the findings. However, the discussion of the inconsistent results for economic growth and inflation could be improved. Exploring potential reasons for these inconsistencies or considering alternative model specifications might provide more robust insights. Furthermore, while the Sargan test is reported, more comprehensive diagnostics related to the GMM estimation would strengthen the analysis. Authors’ Response: Following the reviewer’s suggestion, we have enhanced the discussion of economic growth and inflation in the “empirical results” section. Furthermore, we have provided a more detailed statistical analysis to elucidate the differences between the difference GMM and system GMM estimators. “On the other hand, economic growth and inflation exhibit inconsistent results across different model specifications. Inflation generally exerts a positive influence on financing risk, as observed in models 2, 6, and 8. This finding aligns with previous studies, which suggests that inflation can reduce purchasing power, leading to increased loan defaults (Awdeh et al., 2024; Patiu & Eleazar, 2024). However, the impact of economic growth on financing risk is more nuanced, with negative effects observed in the difference GMM estimation and positive effects in the system GMM estimation. This discrepancy might be attributed to the non-linear relationship between economic growth and NPF, where difference GMM captures short-term effects while system GMM captures long-term effects. The positive relationship in the system GMM, which is considered to provide more robust estimates, may reflect the potential for credit booms during periods of economic expansion, leading Islamic banks to loosen lending standards (Castro, 2013; Huizinga & Laeven, 2019; Mongid et al., 2023). Furthermore, this divergence in results may be explained by the finite sample bias in difference GMM, which relies solely on differences across time periods and excludes the level data.” Reviewer’s Suggestion 5: Are all the source data underlying the results available to ensure full reproducibility? Yes. The data sources are listed and the Zenodo link provides the bank-level data. The macroeconomic data sources are also publicly accessible. However, as noted above, clearer instructions on data merging are needed. Authors’ Response: Thank you for the suggestion. The data used in this study is a combination of panel data (internal data from Islamic banks) and time series data (macroeconomic data). For the macroeconomic data, we ensured that the estimation periods aligned, and duplicated the time series data for each Islamic bank observation. Given the unbalanced nature of the panel data, macroeconomic data was only added to complete Islamic bank observations. Reviewer’s Suggestion 6: Are the conclusions drawn adequately supported by the results? Partly. The main conclusion regarding the positive impact of spin-offs on reducing financing risk is supported by the findings. However, the claim that larger spin-off banks are more exposed to risk needs further clarification. While the results show that size increases risk in general, it's not entirely clear from the presented analysis whether this effect is amplified after the spin-off, or if larger banks simply start at a higher risk level pre-spin-off. More nuanced analysis and discussion are needed to fully support this specific conclusion. Authors’ Response: The conclusion that larger spin-off banks are more exposed to risk is derived from the interaction variables between the spin-off and size variables (spinoffsize), as detailed in the fifth paragraph of the \"Empirical Results\" section. “Furthermore, these results are corroborated by the estimations of the interaction variable (spinoffsize), which significantly influences non-performing financing. Thus, larger Islamic banks that undergo spin-offs carry a higher financing risk compared to smaller banks. As highlighted by Trinugroho et al., (2021), the multifaceted nature of financing contracts in Islamic banking substantially elevates the risk of non-performing financing.” Specific Recommendations for Improvement: Reviewer’s Suggestion 7: Literature Review: Organize the literature thematically and clearly articulate the research gap being addressed. Verify the accessibility of all cited works. Authors’ Response: Please refer to response number 1. Reviewer’s Suggestion 8: Methodology: Provide a stronger justification for the choice of oil price indicator. Elaborate on the specific GMM implementation details (lag selection, instrument details, and robustness checks). Authors’ Response: Please refer to response number 2. Reviewer’s Suggestion 9: Data and Replication: Provide clear definitions of all variables, including calculations. Include detailed instructions on how to merge the datasets used. Authors’ Response: Please refer to response number 4. Reviewer’s Suggestion 10: Statistical Analysis: Explore reasons for the inconsistent results of control variables. Provide more comprehensive GMM diagnostics. Authors’ Response: Based on the literature review, our implementation of the GMM model adheres to the established guidelines. While inconsistencies in the estimation results between difference GMM and system GMM for some variables are common, the inconsistencies in the spin-off, size, and IPI variables might be attributed to endogeneity issues better addressed by system GMM or measurement errors in difference GMM. This can be explained by the inherent differences between the two estimators. Difference GMM uses first differences to eliminate fixed effects, whereas system GMM combines instruments from both first differences and levels, allowing it to capture more of the variability in the data (The preceding explanation offers a more in-depth analysis of response number 4). Reviewer’s Suggestion 11: Conclusion: Refine the discussion about the impact of size on risk for spin-off banks. Provide clearer evidence to support the claim of increased risk for larger spin-off banks compared to smaller ones. Consider separating the impact of size on risk in general from the specific impact on spin-off banks. Authors’ Response: we have explained separately in the last 2 paragraphs in the Results and Discussion section related to the general impact of size on NPF, followed by a specific examination of the interaction between spin-off and size on NPF. The positive interaction term between spin-off and size (spinoff*size) on Table 4 suggests an increased risk of NPF for larger spin-off banks. we have also added a supporting statement, “As highlighted by Trinugroho et al., (2021), the multifaceted nature of financing contracts in Islamic banking substantially elevates the risk of non-performing financing.”" } ] }, { "id": "353263", "date": "10 Jan 2025", "name": "Mutamimah Mutamimah", "expertise": [ "Reviewer Expertise Economics", "Management", "Financial Management" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article is well written and meets the rules for good articles. The problem formulation is based on research gaps from previous research results. Apart from that, the research method is also appropriate, including the indicators, and statistical analysis and results. However, researchers need to attach the year in which the Islamic banking spin-off was carried out, because each Islamic banking spin-off is different. In table 2 about Descriptive analysis of variables, the description of each variable should be explained well. Furthermore, in conclusion, it must have limitations and future research agenda. It would be good to explain why the research did not analyze financing risks before the spin-off, so there will be a difference between before the spin-off and after the spin-off. Good luck!\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13175", "date": "04 Feb 2025", "name": "Zulfikar Bagus Pambuko", "role": "Author Response", "response": "We would like to warmly thank you for reading our manuscript and your valuable comments which would substantially improve our paper. We have followed carefully all your comments in the preparation of the revised version of the paper. Our revisions are summarized below. Reviewer’s Suggestion 1: The article is well written and meets the rules for good articles. The problem formulation is based on research gaps from previous research results. Apart from that, the research method is also appropriate, including the indicators, and statistical analysis and results. However, researchers need to attach the year in which the Islamic banking spin-off was carried out, because each Islamic banking spin-off is different. Authors’ Response: Following your insightful suggestion, we have revised the Method section to provide a more comprehensive overview of the restructuring processes within the Indonesian Islamic banking industry. The newly added paragraph, which details historical data on spin-offs, conversions, and mergers, directly addresses your feedback regarding the need for more specific examples. “The Indonesian Islamic banking landscape has witnessed various restructuring strategies. Pure spin-offs were employed by banks such as Bukopin Syariah (2008), BNI Syariah (2008), BRI Syariah (2010), BJB Syariah (2010), and Bank Nano Syariah (2024). Conversion, another common approach, was adopted by BTPN Syariah (2014), Bank Aceh Syariah (2016), BPD NTB Syariah (2018), and BPD Riau Kepri Syariah (2022). The formation of Bank Syariah Indonesia in 2021 marked a significant merger in the sector. Moreover, a combination of acquisition and conversion was utilized sequentially by banks including Bank Panin Dubai Syariah (2009), Bank Victoria Syariah (2010), BCA Syariah (2010), and Bank Aladin Syariah (2010).” Reviewer’s Suggestion 2: In table 2 about Descriptive analysis of variables, the description of each variable should be explained well. Authors’ Response: Thank you for your valuable feedback. We have addressed your concerns regarding variable descriptions in the descriptive analysis. “Table 2 presents descriptive statistics for the variables spanning from 2006 to 2022. The average value of NPF, as a financing risk proxy, stands at 3.10%, remaining below the generally accepted upper limit of 5.00%. The lowest NPF value, at 0.00%, indicates that some Islamic banks exhibit no risky financing, while the highest recorded NPF value is 53.27%. This relatively high variability is supported by a standard deviation of 4.17%. SPINOFF, a dummy variable, has a mean of 0.27, indicating that spin-off events are relatively rare. Its standard deviation of 0.45 suggests moderate variability in occurrence. Regarding assets and market share, the lower mean values compared to the standard deviation suggest that Islamic banks in Indonesia are still dominated by a few larger banks, reflecting differences in institutional capacity and market reach. Similarly, the Consumer Price Index (CPI) and Industrial Production Index (IPI) show moderate variability, with standard deviations of 2.70 and 18.33, respectively, reflecting macroeconomic conditions that influence Islamic banking performance. Oil prices (OIL), a critical variable for resource-dependent economies, have a mean of IDR 0.86 million per barrel, with relatively stable fluctuations (standard deviation of 0.28). This stability contrasts with the high variability observed in institutional size and non-performing financing. Overall, the descriptive analysis underscores significant heterogeneity in institutional characteristics and economic factors, suggesting the need for tailored strategies in managing Islamic banks. Institutions must address wide disparities in size and market share, ensuring resilience to external economic conditions such as inflation, industrial output fluctuations, and oil price volatility.” Reviewer’s Suggestion 3: Furthermore, in conclusion, it must have limitations and future research agenda. It would be good to explain why the research did not analyze financing risks before the spin-off, so there will be a difference between before the spin-off and after the spin-off. Good luck! Authors’ Response: We appreciate your insightful comments. We have added the limitations and future research opportunities to the conclusion section. “The present study has identified several limitations. The utilization of a dummy variable to assess the impact of spin-offs on financing risk, while effective in capturing the immediate effects of regulatory policies, may not fully account for the nuanced dynamics at play. Moreover, the study's scope is constrained by the use of semi-annual data up to 2022 and its focus on the Indonesian Islamic banking industry. To address these limitations, future research could benefit from employing a difference-in-differences analysis to more precisely estimate the causal impact of spin-offs. Furthermore, incorporating a broader range of internal and external variables, as well as expanding the analysis to include Islamic banks in Southeast Asia or OIC countries, would provide a more comprehensive understanding of the phenomenon.”" } ] } ]	1	https://f1000research.com/articles/13-1251
https://f1000research.com/articles/13-657/v1	18 Jun 24	{ "type": "Research Article", "title": "The dynamics of financial performance and market performance in the context of Indian banking industry", "authors": [ "Ashok Sar", "Kshirod Panigrahi", "Kshirod Panigrahi" ], "abstract": "Background This study aims to gain insight into the effect of banks’ financial performance on their market performance. We conceptualized the research subject on the assumption that the financial performance of an organization is the most important criterion for triggering movement in its stock price. We explored various models and parameters to evaluate financial performance of banks and found CAMELS being one of the most comprehensive and appropriate model. We considered share price growth of banks to measure their stock market performance\n\nMethods We collected financial and stock market data pertaining to 32 listed Indian banks for the period 2018 to 2022. The study has employed multiple linear regression analysis of panel data for evaluating the relationship between independent and dependent variables. We adopted panel regression for data analysis and used the Prais- Winsten regression with panel corrected standard errors, as the data suffers from contemporaneous cross-sectional correlation.\n\nResults The results show that net non-performing assets, net interest margins, and return on capital have a significant negative impact on share price growth. The capital adequacy ratio and the current and savings account deposit ratios have a positive insignificant impact. The liquid asset-to-total asset ratio has a negative, insignificant impact. The coefficient of determination indicates that the share price growth of banks is more dependent on other factors which are not included in the regression analysis of this study.\n\nConclusion This study helps investors and bankers understand the limited impact of financial parameters on banks’stock prices and to look for other parameters which explain the stock price movement better.", "keywords": [ "financial performance", "stock market performance", "capital adequacy ratio", "net non- performing asset", "CASA ratio", "return on capital employed", "net interest margin", "liquid asset to total asset", "growth in share price" ], "content": "1. Introduction\n\nDespite the global issues of inflation and recession resurfacing, rallies in Indian banking stocks have continued. The banking sector is the foundation of the Indian economy as it channelizes the surplus in the form of investment to entrepreneurs in the form of credit. With the introduction of cutting-edge technology-driven business models, Indian banking has undergone transformation. Additionally, the government has been working to clean up the stressed balance sheets of public-sector banks. The “Make in India” initiative and the ongoing push for infrastructure investment are expected to increase credit demand. Banks will benefit substantially from this huge upsurge in credit-off takes. In 2022, the Nifty Bank index gained more than 11%, whereas the benchmark Nifty gained only 1.56%. Some of the most crucial measures for evaluating banking stock include net interest margins, credit-to-deposit ratios, capital adequacy ratios, return on equity ratios, and return on asset ratios. As the prospects of banks are heavily influenced by macro events and growth cycles, banking sector stocks can be highly volatile. One should invest in banking businesses if one is comfortable with the risks involved. Despite the fact that a slowdown in the global economy appears imminent, Indian banking stocks have been defying global trends. Accelerating credit demand and improving asset quality are anticipated to be favorable factors for these stocks. However, prior to making an investment, comprehensive research is required to avoid getting carried away by the excitement.\n\nIt has been a matter of great concern for investors to determine the most important factors influencing stock prices. Investors are engaged in analyzing the volume of data to detect predictable patterns of stock price movements. Ramakrishnan and Toppur (2016) state that stock prices are volatile, uncertain, complex, and ambiguous. Therefore, predicting the future performance of stocks is difficult and almost impossible. Anwaar (2016) maintains that stock prices are largely influenced by financial, monetary, and foreign trade policies, as well as other macroeconomic factors. He emphasized that investors make investment decisions mostly because of the financial information of a firm. Pradhan et al. (2014) find a causal relationship between economic, financial, and political risk factors and stock prices. Narayan et al. (2014) observed that industrial production, which was a surrogate for economic growth and the rate of exchange (currency depreciation), had a positive impact, whereas interest rate increase had an adverse impact on stock prices. Given the riskier nature of stock investments, it is imperative to understand the market dynamics and price determinants of a particular stock. Sharif et al. (2015) observed that internal factors, such as firm performance, management capability, corporate planning, and strategy, which are firm-specific, and external factors, such as macroeconomic parameters, government regulations, and market conditions, decide the price of a stock.\n\nThe price of a stock can be determined based on the current financial performance, consistency of past performance, and future revenue-generating potential of the firm. Consequently, the reaction of the market to financial performance should be linear across the firm, subject to other factors remaining constant. From this notion, we can reasonably assume that the financial performance of banks and their stock prices are strongly associated. We need to check the extent of the overall correlation and evaluate each financial performance dimension with respect to its impact on stock prices.\n\nThe Indian stock market is evolving rapidly, keeping pace with growing GDP. The market is maturing and offers new avenues of investment for both retail and institutional investors. Businesses find it easy to mobilize equity funding through the market. Against this backdrop, it is essential to understand the details of market performance and the dynamics thereof. This understanding will help investors make informed decisions about their portfolios. There has been more than 100 percent growth in the number of dematerialized accounts in just two years. The number was 40.9 million in March 2020, which has become 108.0 million in December 2022. As per the current market statistics, retail investors conduct 52% of daily transactions as against 29% and 19% by domestic and foreign institutional investors, respectively.\n\nThis study intends to assess the impact of the financial results of banks listed on the Indian stock exchange on the performance of their stock. The Indian banking industry has been chosen purposefully, as it is moving towards consolidation. Mergers of state-owned banks have resulted in a decrease in the number of public-sector banks and an increase in the size and business volume of anchor banks. As India is poised to register higher economic growth in the next ten years leveraging high domestic demand, Indian banks will play a significant role. Two Indian banks already appear on the list of the top 20 banks in terms of market capitalization. This number is expected to rise further as India is on the cusp of becoming 3rd largest GDP by 2030, overtaking Japan and Germany, as per the S&P Global and Morgan Stanley report.\n\nThe second section covers previous studies and their contributions to the subject. The design, method, and approach are discussed in section. section explains the result of the study. A thorough discussion and analysis of the findings are covered in the fifth part. The conclusions of this study are discussed in the final section.\n\n\n2. Literature review\n\nSar (2017, 2018, 2019) states that a firm’s financial performance is assessed at the aggregate level using return on invested capital (ROIC), return on equity (ROE), the spread between ROE and the cost of equity, or the spread between ROIC and weighted average cost of capital (WACC). A firm is said to have superior financial performance if its ROE, ROIC, or economic rate of return compare well with a benchmark. Financial performance has a wider connotation, and can be evaluated using various parameters. Suhadak et al. (2019) suggest that financial performance is an indicator of the effectiveness and efficiency of an organization. Effectiveness indicates the capability of management to select the correct objective and tools to accomplish the objective. Efficiency refers to the optimum input utilization to produce the desired output. Previous studies have used several financial ratios, such as liquidity, leverage, activity, profitability, growth, and valuation, to evaluate financial performance.\n\nThe CAMELS rating system is an internationally acknowledged and accepted risk rating system employed by the central bank to evaluate the overall health of banks. Regulators and rating agencies use these to assess the strength of banks. Venkatesh and Suresh (2014) mention that the framework was first used in 1979 by the Federal Financial Institutions Examination Council (FFIEC). As stated by Banu and Vepa (2021) this model was recommended for measuring financial strength and weakness of banks by the Basel committee on banking supervision of the Bank of International Settlements’ (BIS) in 1988. In 1997, the model was expanded to include a sixth parameter, which is sensitive to market risk. In 1995, the Padmanabhan Committee recommended implementing the model in Indian Banks.\n\nThe model comprises six parameters: capital adequacy, asset quality, Management, Earnings, Liquidity, and Sensitivity\". The strength of this model lies in its comprehensiveness in assessing capital sufficiency, operational efficiency, managerial capability, profit-generating ability, and financial stability. Unlike other ratings or regulatory ratios, the CAMELS rating is not made public. The regulatory authorities and top management of the respective banks use it only to understand and control potential risks. The Indian Reserve Bank of India (RBI), which is the central bank, uses a five-point rating system of five point scale, with one representing the highest rating and five representing the lowest.\n\nNguyen et al.(2020) narrating on the efficacy of the model articulated that the model was being adopted by three U.S. watchdogs. Nhan et al. (2021) emphasized the importance of this model as a barometer to check the overall performance and risk mitigation capability of banks. Describing the significance of the model, Handorf (2016) explained this as the most effective test to measure the soundness of a bank, and Dang (2011) considered this to be the most reliable tool for checking the health and safety of banks. The CAMELS model was chosen because it is the most acceptable and comprehensive framework for evaluating a bank’s financial performance and vulnerability to risk.\n\nSar (2019) maintains that the market performance of a public limited company is assessed using measures associated with the performance of its shares in stock markets. Hobarth (2006) stated that market value versus book value and Tobin's ratio are measures used to evaluate a company's market performance. Market value to book value ratio indicates the market valuation of a company in comparison to its book value. Tobin’s Q is the ratio between the total market capitalization and the book value of an enterprise’s assets. He uses the following mathematical formula to measure the market performance of a company:\n\nThis formula calculates the share price growth of a company in percentage terms from t-1 to t1. This is the most common indicator used to evaluate market performance. The stock price of a firm is the true value, as the buyer of the stock paid the price for owning the share of that company. Though speculators manipulate stock prices in the short run, the price reflects the real value of the stock in the long run. The market performance of an enterprise is accurately reflected in its share price, as is the outsider’s view of the company. Unlike financial performance, market performance is an investor’s perspective on the company and industry. Stowe et al. (2010) mentioned two types of return from an investment in equity: capital gain, which is the amount of appreciation in the stock price, and dividends earned from equity during the ownership period of equity. Sharpe (1964) and Lintner (1965) propounded the capital asset pricing model (CAPM) based on the premise that stock prices are a function of the risk attached to it. The model explains that the expected yield from a stock or portfolio of stocks is the sum of the risk-free rate and risk premium attached to the risk of that stock or portfolio. The theory assumes that markets are efficient and investors are rewarded with a return equivalent to the quantum of risk. This model measures the systematic risk of a stock using its beta coefficient, which refers to the sensitivity of the return of a particular stock to the market portfolio. The CAPM model was challenged by Basu (1977), who found that CAPM failed to predict returns accurately for stocks with a high price earnings (PE) ratio because it underestimated the returns of those stocks. Banz (1981) also observed that the CAPM underestimated the average return of stocks with smaller market capitalization. Bhandari (1988) maintains that, for stocks, with a high debt-equity ratio, the actual return is higher than the return estimated based on the market beta. Rosenberg et al. (1985) and Stattman (1980) state that the average yields of equity with high book-to-market ratios are higher than those indicated by their betas. Fama and French (1992) commented on the empirical failure of CAPM and observed that the estimation of the expected return forecast by market beta is supplemented by factors such as size, PE ratio, debt equity and book to market ratio.\n\nSarjono and Suprapto (2020) in an attempt to assess the impact of CAMEL rating model on bank’s share price in Indonesian stock exchange found that movement of stock price is positively correlated with capital adequacy ratio (CAR), return on asset (ROA), return on equity (ROE) and net interest margin (NIM). In another study on the Indonesian stock exchange, Nugroho et al.(2020) found that, except for capital adequacy, the other four variables representing CAMELS have a negligible impact on stock prices. Ikechukwu and Owualah (2022) observed that, while capital adequacy, asset quality, and earnings have no impact, management capability and liquidity have significant negative influences on share prices. While conducting an impact assessment study of the CAMELS model on the share prices of Jordanian banks, Awwad (2022) found that asset quality, sensitivity, and liquidity have positive and substantial impacts. However, capital adequacy, management ability, and earnings have no impact.\n\nRiani et al. (2020) observed that net profit margin, price-earnings ratio, total assets turnover ratio, and return on equity have a positive and significant relationship with share price, whereas debt equity and the current ratio have an insignificant impact on stock prices. Sumantri (2020) finds that stock prices are substantially impacted by ROE and ROA. Wuryani et al. (2021) discover that capital adequacy affects stock prices, whereas profitability and liquidity do not. Awalakki and Archanna (2021) analyzed the impact of 11 independent variables on stock returns and concluded that price to book value (PB) and ROE are two parameters which have positive and significant impact on performance of stock.\n\nSharif et al. (2015) assessed the impact of eight variables on share prices and found that all eight variables have a positive and significant relationship with dividend yield (DY), which has a negative relationship. Anwaar (2016) examined the relationship between five independent variables displaying a firm’s performance and one dependent variable, stock returns, and found that return on assets (ROA) and net profit margin (NPM) have significant and positive effects on stock performance.\n\nNureny (2019) found that the (CAR) has a significant impact on share prices. In a similar study on the Indonesian stock exchange, Rusdiyanto et al. (2019) found that CAR and non-performing loans (NPL) have a substantial impact on stock prices. Benyamin and Endri (2019) and Al-qudah (2020) found that share price is strongly and positively impacted by Return on Equity (ROE).\n\nHatem (2017) considered share price growth an appropriate parameter to measure stock market returns. He observed that growth in share price (SPG) was positively and strongly impacted by return on equity (ROE). However, a similar relationship was not found between return on asset (ROA) and SPG. Jape and Pauldhas (2021) conducted a study to understand the impact of economic variables such as the G-sec coupon rate, FII funds flow, and exchange rate on stock price movement. Trần Nha Ghi (2015) and Fathony et al. (2020) sought to determine the impact of a company's financial success on its stock return. In a similar effort to evaluate how different financial ratios affect stock returns, Chabachib et al.(2020) used “growth in share price” to measure stock performance.\n\nA review of past studies sheds light on the relationship between return on stocks and financial performance of various industries, including banks, using two to three sets of dependent variables. Many of these studies have suggested expanding the work in future research by using a greater number of variables. For further research, Rusdiyanto et al. (2019) suggested including more variables to determine stock price movement. Awalakki and Archanna (2021) find it very difficult to rely on a few parameters or a fixed model to predict stock prices. The results vary and financial parameters do not appear to have a uniform impact on stock prices. Although studies have measured the financial strength of Indian banks using the CAMELS parameters, the model has not been used to measure the impact on stock prices in the Indian banking industry. Many of these studies have suggested extending the use of the CAMELS model to assess market performance dynamics. Although the model has been extensively used to evaluate the overall performance of banks, it has not been used to assess the stock market performance of Indian banks.\n\nBased on result of past studies, we formulated the following hypothesis:\n\n- There is no relationship between financial parameters consisting of CAMELS model and performance of stocks of Indian banks.\n\n\n3. Methods\n\nDespite global macroeconomic issues such as rising inflation, rising interest rates, and sluggish growth, the Indian banking industry is showing all healthy symptoms, such as adequate capital, rising profit, and steep fall in nonperforming assets. There are 12 state-owned banks, 22 private sector banks, 46 foreign banks, 12 small finance banks, four payment banks, and 43 regional rural banks. The total banking sector deposit is INR 177.34 trillion and bank credit is INR 133.04 trillion as on December 2022.\n\nThe Bombay Stock Exchange (BSE) and the National Stock Exchange (NSE) are the two Indian stock exchanges from which we obtain our sample. While collecting data, we found that there are a total of 32 banks listed on these two stock exchanges for at least five years. Therefore, the sample size for the study was equal to that of the whole population. For five years, stock market data were not available for the other banks, and they were not considered for the study.\n\nSix independent variables were selected based on the CAMEL model. The last parameter of the CAMELS model - sensitivity to risk–has not been considered for the analysis, as appropriate data were not readily available for this parameter. The remaining five CAMEL parameters are measured using six financial ratios. Stock performance is measured by growth in share prices. Detail structure of the Table 1.\n\nBrief description of each variable is mentioned below.\n\nCapital Adequacy Ratio: This ratio computes overall capital as a proportion of the bank's total risk-weighted assets. A higher ratio indicates better health. Capital acts as a shock absorber for banks during a liquidity crisis.\n\nNet NPA: NPA stands for Non-performing assets, which are any asset that does not generate income for a stipulated period, as per the guidelines issued by the RBI. We obtain the Net NPA by deducting provisions from Gross NPA. Gross NPA consists of substandard, doubtful, and lost assets. A lower net NPA value is better for banks. The net NPA is always shown as a percentage of the total asset portfolio to understand the quality of a bank’s asset portfolio.\n\nCASA Ratio: The ratio of demand deposit (current and savings) to the total deposit (demand plus term deposit) of a bank. A higher CASA ratio is desirable because demand deposits are less costly than time deposits. Therefore, a bank with a higher CASA ratio has a lower funding cost and a higher interest margin. The bank must provide a customized solution to capture the flow of funds and augment its service quality and product range to mobilize high-demand deposits. This reflects the efficiency of management.\n\nReturn on Capital Employed: This ratio signifies the earning capacity of a firm. Total earnings before interest and taxes are expressed as a percentage of the total capital employed. Total capital is computed by deducting current liabilities from total assets. A higher ROCE ratio indicates that companies efficiently utilize capital to obtain higher return.\n\nNet Interest Margin: It calculated by deducting interest expenses from a bank’s interest income. It is computed by dividing the gap between investment returns and interest expenses by average earnings assets. This ultimately determines a bank’s profitability.\n\nLiquid Asset to Total Asset: This ratio of current assets to total assets. The current asset indicates a bank’s liquidity strength. A higher liquidity ratio is considered to be healthier for banks.\n\nGrowth in share price: This measures the percentage growth in share price over the last year’s price. Growth was calculated based on the closing price of the stock.\n\nThe data were collected from 32 Indian banks listed on either of the two Indian stock exchanges.\n\nNSE and BSE for 5 year time period from 2018 to 2022. Since we need six years of data to calculating 5 years share price growth, the closing share price of each bank from 2017 to 2022 was collected for the computation of stock price growth. Information was collected from the following websites: a list of 32 banks is given in Table 2.\n\nhttps://www.moneycontrol.com/; https://economictimes.indiatimes.com/; /https:/www.nseindia.com/; https://www.bseindia.com/.\n\nKeeping in view the nature of the data, a panel regression model was chosen to evaluate the effect of Indian Banks’ financial results on stock market performance. This study adopted a multiple linear regression analysis of panel data to measure the relationship between the explanatory and predictor variables. The regression equation is constructed using share price growth as the dependent variable and the six CAMEL parameters as independent variables.\n\n(i = 1,2,3 … . 32 and t = 2018, 2019, … . 2022)\n\nspgit refers to the share price growth of bank i for period t. where Î ± is the intercept of the regression model. β1 to β6 are the slope coefficient for the independent variables and Ɛit is the error term.\n\n\n4. Results\n\nThe observable explanatory variables were carefully chosen to ensure that they did not suffer from multicollinearity. It is known that multicollinearity adversely impacts the efficacy of the regression model, reduces the accuracy of estimation of the coefficient, and produces a distorted p-value that cannot be relied upon. Therefore, to determine the extent of correlation among the explanatory variables, a multicollinearity test using Variance Inflation Factors (VIF) was performed. Four variables with a VIF score of > 3 were eliminated, and six variables with VIF scores of < 3 and mean VIF score of 1.78. were considered for the regression analysis. The VIF details are given in Table 3.\n\nWe ensured that the data did not suffer from heteroscedasticity, contemporaneous cross-sectional correlation, or autocorrelation in the residuals, as the presence of these elements in the standard error could produce biased statistical inference. Cameron and Trivedi (2005) suggest that independent observations provide better information than correlated observations. Therefore, we cannot ignore the possible correlation between regression disturbances over time and between subjects. Bera et al. (2000) maintained that the standard error component model also addresses the serial correlation problem. Baltagi (2005) also confirmed that it addresses heteroscedasticity.\n\nIn our research, the data included time-series data. We must verify the degree of correlation between the values of the same variable over successive periods. This is known as an autocorrelation or serial correlation. The dataset exhibits first-order autocorrelation as per the Wooldridge test for autocorrelation. The associated details are presented in Table 4.\n\nRegression analysis assumes that the residuals or errors are homogeneous. The absence of this condition is known as heteroscedasticity. To ensure that the random error components are identically and independently distributed across the independent variables, we must verify the heteroscedasticity present in the collected data. The presence of heteroscedasticity in the panel data was validated using a modified Wald test for group-wise heteroscedasticity in a fixed-effect regression model, as suggested by Greene (2000). The associated details are presented in Table 5.\n\nAnother important assumption of the panel data model is that the disturbances or errors available in the cross-section are independent. The cross-sectional dependence in the panel data is attributed to unobserved common elements in the error term. We used the CD test, as suggested by Pesaran (2004), to determine cross-sectional dependence. The test results demonstrate a high degree of dependence among cross-sectional data. Since the p-value is less than 0.001, we can reject the null hypothesis that there is weak cross-sectional dependence. If we assume that the unobserved common elements that are responsible for the cross-sectional dependence have no relationship with the independent variables, then the standard fixed-effects (FE) and random-effects (RE) models could be used, and the bias in the standard errors could be corrected by adopting the method of Driscoll and Kraay (1998). On the contrary, if these unobserved common elements that are responsible for the cross-sectional dependence are found to be correlated with the independent variables, then the FE and RE estimators will be unreliable or inconsistent and biased, and the approach proposed by Pesaran (2006) will be used as per De Hoyos and Sarafidis (2006). However, when the relationship between the two is not known, the choice of method is not clear.\n\nBeck and Katz (1995) used Monte Carlo simulations to test the accuracy of panel corrected standard errors (PCSE) and to verify the efficiency of ordinary least squares (OLS) estimators. They were in favor of using OLS with PCSE instead of FE and RE models as well as the generalized least squares (GLS) estimator for panel data sets showing both heteroscedasticity and cross-sectional dependence.\n\nSince all three problems (heteroscedasticity, contemporaneous cross-sectional correlation, and autocorrelation) are found in the error structure of our data, the ordinary least squares (OLS) with Therefore, PCSE was not appropriate for our study. Ardizzi et al. (2014) used the Prais–Winsten regression with Panel-Corrected Standard Errors (PCSE) when similar issues are observed in panel data. Therefore, we adopted the same model to adjust the standard errors appropriately.\n\nThe outcome demonstrates that the model is statistically significant because the p-value is less than 0.05. The regression model was a good fit for this study. Because the p-value of 0.0209 was < 0.05, the null hypothesis was rejected. This leads us to believe that there is a relationship between the CAMEL parameters and stock returns in Indian banks. The R2 value signifies that 21.27% of the variance in share price growth is explained by six independent variables, whereas 78.73% of the variance is explained by variables not included in the regression model. The combined effect of all CAMEL parameters has a moderating effect on share price growth in the banking industry.\n\n\n5. Discussion and further research\n\nCAR has a regression coefficient of 0.0316 with a p-value of 0.10, which is > 0.05. This implies that for a 1% increase in the (CAR) the share price growth (SPG) will be impacted by 3.16%. Because the p-value is greater than 5%, the relationship is not significant. The NNPA has a regression coefficient of -0.0499 with a p-value of 0.04, which is < 0.05. This result indicates that a 1% increase in net Non-performing Asset (NNPA) causes a 4.99% change in share price growth (SPG). The negative sign indicates that when NNPA increases, the SPG is negatively impacted. The relationship between NNPA and SPG was significant, with a p-value > 0.05. The CASA has a positive impact on share price growth, but the relationship between the two is insignificant. ROCE, NIM, and LATA have a negative impact on SPG, and the relationship between ROCE and NIM with SPG is significant, as the p-value is < 0.05. The relationship between LATA and SPG was insignificant.\n\nThe findings of our analysis with respect to CAR are corroborated by the results of Sarjono and Suprapto (2020), Nugroho et al.(2020), Ikechukwu and Owualah (2022), and Nureny (2019). Our results regarding NNPA match those of Sarjono and Suprapto (2020) and Rusdiyanto et al. (2019). Ikechukwu and Owuala (2022) discovered a negative correlation between asset quality and share price. However, the relationship was found to be insignificant, whereas our results show that it is significant. The findings regarding LATA are supported by those of Anwaar (2016). Similar to our findings, Ikechukwu and Owualah (2022) also found a negative relationship between liquidity and share price, but unlike ours, their relationship is statistically significant. Our findings on managerial efficiency (CASA) and earning ability (ROCE and NIM) do not come from previous studies.\n\nThis study recommends further research on the subject to understand the key factors responsible for the performance of banking stocks. The study was not able to include sensitivity to market risk parameters in the CAMEL model. It also does not consider other important macroeconomic parameters, such as inflation and exchange rates, which are expected to impact stock returns. The impact of structural changes, such as the merger of public sector banks and COVID-19, was not included in the study. Stock market correlation and co-movement across geographies are also important factors that influence stock price movement, as illustrated by Evans and McMillan (2009) and Dos Santos and Lagoa (2017).\n\n\n6. Conclusion\n\nBased on the results, the predictor variables selected for the study as per the CAMEL model have a moderate impact on the explanatory variable, that is, share price growth. This implies that there are other variables not considered in our study that are responsible for share price growth in the banking industry in India. As evident from the regression estimation, Net Non-performing asset (NNPA) measuring asset quality has a negative and significant impact on share price growth. This inference is statistically proven and commonsensical, as we know that any increase in nonperforming assets results in erosion of banks’ earnings. The net interest margin (NIM) and return on capital (ROCE) have negative and significant impacts. Surprisingly, these two variables, identified to measure earning ability, have a negative impact. This could be attributed to structural issues such as mergers in public sector banks and pandemics, which might have influenced stock prices. The impact of capital adequacy ratio (CAR) and CASA ratios is positive, but insignificant. A threshold Capital adequacy ratio being the regulatory requirement, and almost all banks maintain a reasonable level of CAR. Therefore, it might not be a powerful indicator of stock prices. The CASA ratio influences the cost of funds and the earnings of a bank. A higher CASA ratio entails lower interest expenses and lower cost of funds. However, the impact is positive but negligible. Liquid assets to total assets (LATA), which measures liquidity, has a negative and insignificant relationship with stock prices. The major takeaway is to make the research more comprehensive and include more valid explanatory variables to better predict stock prices.\n\n\nEthics and consent\n\nEthical approval and written informed consent were not applicable.", "appendix": "Data availability statement\n\nFigshare: Banking Industry Performance.xlsx, https://doi.org/10.6084/m9.figshare.25859644.v1 (Sar, 2024)\n\nData is available under the terms of CC By 4.0\n\n\nReferences\n\nAl-qudah HA: The Impact of Financial ePrformance of Stock Prices of Jordanian Islamic Banks (During Period from 2010 to 2018). Int. J. Econ. Financ. Issues. 2020; 10(1): 228–234. Publisher Full Text\n\nAl Zaidanin J: A Study on Financial Performance of the Jordanian Commercial Banks using the CAMEL Model and Panel Data Approach. Int. J. Financ. Bank. Stud. 2020; 9(4): 111–130. Publisher Full Text\n\nAnwaar M: Impact of Firms’ Performance on Stock Returns (Evidence from Listed Companies of FTSE-100 Index London, UK). 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Publisher Full Text\n\nIndrajaya D, Astuti M, Maulidizen A, et al.: The Effect of Third-Party Funds, Capital Adequacy Ratio, Casa Ratio, Bi Rate, And Inflation Towards The Distribution of Credit Banking in Indonesia. Int. J. Econ. Dev. Res. 2022; 2(3): 171–185. Publisher Full Text\n\nJape S, Pauldhas M: A STUDY AND ANALYSIS OF SELECTED STOCKS OF BANKING SECTOR LISTED ON BSE/NSE INDIA DURING CRISIS. Int. J. Manag. 2021; 12(2): 929–937. Publisher Full Text\n\nKhan Q, Naz A: The Impact of Capital Structure and Financial Performance on Stock Returns “A Case of Pakistan Textile Industry”. Middle-East J. Sci. Res. 2013; 16(2): 289–295. Publisher Full Text\n\nLintner J: The valuation of risk assets and the selection of Risky investments in stock portfolios and capital budgets. Rev. Econ. Stat. 1965; 47(1): 13–37. Publisher Full Text\n\nMaude FA, Tijjani MS, Muazu SM, et al.: Effect of CAMELS Financial Indicators on Profitability of Systemically Important Banks (SIBs) in Nigeria. Sokoto J. Manag. Stud. 2020; 1–21. Publisher Full Text\n\nMuriithi LK: The effect of financial performance on stock price volatility of commercial bank listed at Nairobi Stock Exchange. University of Nairobi; 2018; pp. 22–34. Research project.\n\nNarayan PK, Narayan S, Singh H: The determinants of stock prices: New evidence from the Indian Banking Sector. Emerg. Mark. Financ. Trade. 2014; 50(2): 5–15. Publisher Full Text\n\nNguyen AH, Nguyen HT, Pham HT: Applying the CAMEL model to assess performance of commercial banks: empirical evidence from Vietnam. Banks Bank Syst. 2020; 15(2): 177–186. Publisher Full Text\n\nNhan DT, Kim-Hung P, Van Anh DT , et al.: The saftey of banks in Vietnam using CAMEL. Adv. Decis. Sci. 2021; 25(2): 1–34. Publisher Full Text\n\nNugroho M, Halik A, Arif D: Effect of CAMELS Ratio on Indonesia Banking Share Prices. J. Asian Finance Econ. Bus. 2020; 7(11): 101–106. Publisher Full Text\n\nNureny: Financial Performance and Share Prices of Banks of State-Owned Enterprises in Indonesia. Jurnal Ilmiah Ilmu Administrasi Publik. 2019; 9(2): 315–326. Publisher Full Text\n\nPesaran M: Estimation and Inference in Large Heterogeneous Panels With a Multifactor Error Structure, CESIFO working paper No. 1331.2006; pp. 6–16.\n\nPesaran MH: 'General Diagnostic Tests for Cross Section Dependence in Panels', Discussion Paper No. 1240.2004; pp. 2–42.\n\nPradhan RP, Hall JH, Filho F d SP, et al.: Risk ratings and stock prices: The causal nexus in BRICS countries Risk ratings and stock prices. Int. J. Bank. Account. Financ. 2014; 5(4): 435–439. Publisher Full Text\n\nRamakrishnan PR, Toppur B: 'A Study of Banking Stocks in India to Develop a Model for Prudent Investment. Univers. J. Manag. 2016; 4(9): 477–487. Publisher Full Text\n\nRiani M, Muda I, Rini ES: The Analysis of the Influence of Financial Performance on Stock Prices with Earning Growth as a Moderating Variable in Infrastructure, Utility and Transportation Sector Companies Listed on the Indonesia Stock Exchange. Int. J. Innov. Res. Sci. Res. Technol. 2020; 5(8): 897–904.\n\nRosenberg B, Reid K, Lanstein R: Persuasive evidence of market inefficiency. J. Portf. Manag. 1985; 11(3): 9–16. Publisher Full Text\n\nRusdiyanto, Soetedjo S, Susetyorini, et al.: 'The Effect of Capital Adequacy Ratio (CAR), Net Profit Margin (NPM), Return on Assets (ROA), Non-Performing Loans (NPL), and Loan-to-Deposit Ratio (LDR) to Stock Prices in Banking Companies on the Indonesia Stock Exchange. Int. J. Sci. Res. 2019; 8(7): 1499–1510.\n\nSar AK: Competitive advantage and performance: an analysis of Indian downstream Oil and Gas Industry. Acad. Account. Financ. Stud. J. 2017; 21(2): 21–34.\n\nSar AK: Competitive advantage and performance: an analysis of Indian FMCG industry. Acad. Account. Financ. Stud. J. 2018; 22(1): 1–8.\n\nSar AK: Impact of Competitive Advantage and Risk on Market Performance: A Study of Top 20 Companies as per Market Capitalization. Int. J. Fin. 2019; 13(4): 16–28. Publisher Full Text\n\nSarjono H, Suprapto AT: CAMEL ratio analysis of banking sector share price in Indonesia stock exchange. Pal Arch. J. Egypt. 2020; 17(7): 2213–2222.\n\nSathyamoorthi CR, Mapharing M, Ndzinge S, et al.: Performance Evaluation Of Listed Commercial Banks In Botswana: The Camel Model. Arch. Bus. Res. 2017; 5(10): 142–158. Publisher Full Text\n\nSharif T, Purohit H, Pillai R: Analysis of Factors Affecting Share Prices: The Case of Bahrain Stock Exchange. Int. J. Econ. Financ. 2015; 7(3): 207–216. Publisher Full Text\n\nSar A: Banking Industry Performance.xlsx. Dataset. figshare. 2024. Publisher Full Text\n\nSharpe WF: Capital asset prices: A theory of market equilibrium under conditions of risk. J. Financ. 1964; 19(3): 425–442.\n\nStattman D: Book Values and Stock Returns'. The Chicago MBA: A Journal of Selected Papers. 1980; 4(1): 25–45.\n\nStowe JD, Robinson TR, Pinto JE, et al.: Equity Asset Valuation.2010; pp. 144–154. Reference Source\n\nSuhadak K, Handayani SR, Rahayu SM: Stock return and financial performance as moderation variable in influence of good corporate governance towards corporate value. Asian J. Account. Res. 2019; 4(1): 18–34. Publisher Full Text\n\nSumantri MB: The influence of financial performances toward stock's price of state owned bank listed on the indonesia stock exchange. Pal Arch. J. Egypt. 2020; 17(10): 3046–3053.\n\nThisaranga K, Ariyasena D: 'Effect of CAMEL model on bank performance: with special reference to listed commercial banks in Sri Lanka', Conferenec paper. International Conference on Business Research, University Of Moratuwa, Sri Lanka. 2021; pp. 188–213.\n\nTrân Nha Ghi: The impact of capital structure and financial performance on stock returns on the firms in Hose. Int. J. Inf. Res. Rev. 2015; 2(6): 734–737.\n\nTrivedi JC: Performance Analysis of Bankex Banks Through Camel Model. Manag. Dyn. 2013; 13(2): 1–13. Publisher Full Text\n\nVenkatesh DJ, Suresh MC: Comparative performance evaluation of selected commercial banks in kingdom of Bahrain using CAMELS method'. Risk Management & Analysis in Financial Institutions EJournal. 2014; 1–42. Publisher Full Text\n\nWuryani E, Handayani S, Mariana: The Effect of Financial Performance and Bank Size on Banking Stock Prices. Proc. Int. Jt. Conf. Art. Humanit. 2021; 618: 975–979." }	[ { "id": "314161", "date": "26 Aug 2024", "name": "Baranidharan Subburayan", "expertise": [ "Reviewer Expertise Dr. S. Baranidharan", "specializes in financial analytics", "stock market analysis", "financial econometrics", "and economics. The practical applications of financial theories", "including the use of advanced statistical models and econometric techniques to analyze market trends", "manage financial risks", "and optimize investment strategies. He is also deeply involved in the study of derivatives markets", "hedging strategies", "and the development of financial tools for decision-making in uncertain environments." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary of the Article - The dynamics of financial performance and market performance in the context of Indian banking industry The article examines the intricate relationship between financial performance and market performance in the Indian banking industry. By analyzing various financial metrics such as profitability, liquidity, and capital adequacy, alongside market indicators like stock prices and market capitalization, the authors aim to understand how these factors interact and influence each other. The findings suggest that financial performance significantly impacts market performance, with implications for both investors and banking institutions.\nStrengths of the Article Comprehensive Coverage The article covers a wide range of financial metrics, providing a holistic view of the banking industry’s financial health and its impact on market performance. This comprehensive approach adds depth to the analysis.\nNovelty and Relevance The study addresses a relevant and timely issue in the Indian banking sector, which is crucial given the ongoing changes and challenges in the industry. The focus on the dynamics between financial and market performance adds a fresh perspective to the existing literature.\nMethodological Rigor The methodology is sound, with clear articulation of the data collection process, analytical techniques, and statistical methods used. The use of appropriate models to analyze the relationship between financial and market performance enhances the study’s credibility.\nWeaknesses of the Article Literature Review One of the significant weaknesses of the article is the literature review, which relies on research up to 2021. While the literature review is thorough, it lacks the inclusion of more recent studies that could provide updated insights and strengthen the foundation of the research. The use of present tense in some parts of the literature review is inconsistent with academic writing norms, where past tense is typically used to discuss previous research. This inconsistency may detract from the article’s professionalism and clarity.\nImplications for Practice and Research\n\nThe article would benefit from a more explicit discussion of the implications of the findings for both practitioners in the banking industry and future researchers. Adding this section before the conclusion would help to contextualize the findings and provide actionable insights.\n\nConstructive Suggestions for Improvement Update the Literature Review The authors should consider including more recent studies, particularly those published after 2021. This would make the research more relevant and ensure that it reflects the latest trends and developments in the field. Consistency in Tense Usage Revising the literature review to ensure consistent use of past tense when referring to previous studies will improve the article’s readability and adherence to academic standards.\nImplications Section Introducing a section that discusses the managerial and research implications of the findings would greatly enhance the article. This would provide practical insights for industry professionals and highlight areas where further research is needed.\nThe article makes a valuable contribution to the understanding of how financial performance influences market performance in the Indian banking industry. The comprehensive analysis and novel focus on this dynamic relationship are commendable. However, the inclusion of more recent literature, consistent tense usage, and a discussion of the practical and research implications would significantly strengthen the paper. The decision to approve the article with reservations is appropriate, given the need for these improvements. The suggestions provided here are intended to help the authors refine their work and ensure that it meets the highest academic standards.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13124", "date": "13 Jan 2025", "name": "Ashok Sar", "role": "Author Response", "response": "I have addressed the three sets of suggestions in the revised manuscript." } ] }, { "id": "328301", "date": "18 Nov 2024", "name": "Rizky Yudaruddin", "expertise": [ "Reviewer Expertise finance and banking" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary of the Article This study aims to understand the effect of banks' financial performance on their market performance, based on the assumption that financial performance is a key driver of stock price movement. Using the CAMELS model to assess financial performance, the study analyses financial and market data from 32 listed Indian banks over the period 2018 to 2022 through multiple linear regression on panel data. Strengths of the Article The strength of this article lies in the use of the CAMELS model to measure the impact of financial performance on stock price movements in the Indian banking industry. Weaknesses of the Article 1. Important variables such as the health crisis (COVID-19) have been ignored by the author 2. Endogeneity problem 3. Using stock performance measurements with the percentage growth in share price over the last year's price, completely ignores the dynamics of stock price fluctuations.\nConstructive Suggestions for Improvement 1. The research period 2018-2022, is the period before and during COVID-19. The author needs to involve control variables such as COVID-19. 2. The author needs to explain the existence of Endogeneity problems and how to overcome them 3. The author needs to use daily data 4. The author needs to do a robustness check 5. The author needs to prepare a clear statement about the contribution of this study\n\nDharani, M. et al., 2023 (Ref 1)\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "13125", "date": "31 Jan 2025", "name": "Ashok Sar", "role": "Author Response", "response": "I have addressed the 5 constructive suggestions in the revised manuscript. Size of the bank as a Control variable has been incorporated. Endogeneity problem has been discussed. Daily data for independent variables is not available as the financial parameters are available in the balance sheet and profit and loss statement of banks. With respect to robustness check Multiculinearity test through Variance Inflation Factors (VIF) was done. CD test as suggested by MH Pesaran (2004) has been done to find out the cross sectional dependence. Contribution of this study has been mentioned in a separate section." } ] }, { "id": "339596", "date": "03 Dec 2024", "name": "Cacik Rut Damayanti", "expertise": [ "Reviewer Expertise Corporate governance", "accounting and finance", "sustainability." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntroduction:\nThe paragraph should have references, especially when the authors describe data in the banking sector. The introduction should clearly describe the research problem in India, whether India has an issue with financial and market performance, to justify the importance of conducting research in this country. The research gaps and novelty of this research should be illustrated in the introduction, such as how the CAMELS model has been under utilized for market performance analysis in the Indian banking sector. While the abstract mentions the CAMELS model as a tool for assessing financial performance, it needs to justify why this model is particularly suitable for the study or how it stands out compared to other approaches. Avoid generalizations, such as \"Indian banking stocks have defied global trends,\" without providing data or citations to support these claims.\nLiterature Review\nThe review needs a more precise thematic structure. Discussions on financial performance, market performance, and the CAMELS model are scattered, making it hard for readers to follow the logical progression. I suggest organizing the literature review into clearly defined themes, such as: (a) Financial performance metrics. (b) Market performance and stock price determinants. (c) Prior studies using the CAMELS model. (d) Studies specific to the Indian banking sector. The author should discuss the CAMELS model and how its application in past studies has been explored in depth. The review mentions the model but needs to evaluate its application across various contexts or its limitations critically and provides a detailed analysis of how the CAMELS model has been used in different studies to assess financial performance and market behavior. Highlight its strengths, weaknesses, and gaps in its application, especially in the Indian context. The literature review primarily summarizes prior studies without critically analyzing their methodologies, findings, or relevance to the current research. The review relies heavily on generalized studies, with limited inclusion of studies specific to the Indian banking sector or stock market.\nMethods\nThe chapter briefly mentions the data sources (e.g., NSE and BSE websites) but does not provide enough detail on verifying the data’s accuracy or completeness. There is also no mention of handling potential biases in the data. I suggest including a detailed discussion of data quality assurance, such as cross-checking data across multiple sources or handling missing or outlier data points. I recommend conducting robustness checks, such as using alternative models (e.g., fixed effects, random effects, or dynamic panel models) or testing the results on different time frames or subsets of data to assess the reliability of the findings. While the CAMELS model is central to the study, the chapter needs to adequately justify why specific variables (e.g., NNPA, ROCE) were selected or how they align with the study objectives. The chapter mentions 32 listed banks as the sample but needs to discuss their representativeness or provide details about sample characteristics (e.g., public vs. private banks, size, regional focus).\nResult\nWhile the statistical significance of variables (e.g., NNPA, ROCE, and NIM) is discussed, the meaning of these findings in the context of the Indian banking sector is minimally interpreted. Variables such as CAR, CASA, and LATA are found to be statistically insignificant, but their implications are not adequately explored. The results are not compared with findings from previous studies, making it hard to contextualize the significance of the current study. The chapter reports significance levels (p-values) but does not discuss their thresholds, the potential for Type I or Type II errors (e.g., 0.05 or 0.10), and the likelihood of false positives or negatives. The chapter focuses on statistical findings but needs to discuss their practical implications for stakeholders like investors, policymakers, or bankers. Summarize the results in the context of the hypotheses (e.g., \"H0 is rejected for NNPA and NIM but not for CAR\"). The negative impact of ROCE and NIM is surprising but should be discussed in more detail. I suggest discussing unexpected findings thoroughly, including potential reasons and their implications for the banking sector. The chapter does not acknowledge any limitations in the results, such as potential biases, omitted variables or model restrictions.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [] } ]	1	https://f1000research.com/articles/13-657
https://f1000research.com/articles/13-386/v1	25 Apr 24	{ "type": "Research Article", "title": "Development and validation of an interprofessional collaborative educational module on the self-management of foot for individuals with type II diabetes mellitus", "authors": [ "Sushma Prabhath", "Harihara Prakash Ramanathan", "M Ganesh Kamath", "Gagana Karkada", "Ganesh Handady", "Ciraj Ali Mohammed", "Arun G. Maiya", "Sushma Prabhath", "Harihara Prakash Ramanathan", "M Ganesh Kamath", "Gagana Karkada", "Ganesh Handady", "Ciraj Ali Mohammed" ], "abstract": "Background Insufficient awareness of foot self-care among diabetic individuals results in diabetic foot ulcers. The management of diabetes and diabetic foot ulcers demands a well-coordinated approach that involves multiple healthcare providers (HCPs). The present study aims to develop and validate an interprofessional collaborative (IPC) educational program involving HCPs to efficiently oversee and instruct the public on appropriate strategies for self-managing diabetic foot health.\n\nMethods The research group worked on creating an educational module titled ‘An Interprofessional Collaborative Educational Module on Self-Management of Foot for Individuals with Type II Diabetes Mellitus.’ The objective of this module was to promote the adoption of proper practices in self-managing foot health for individuals with type 2 diabetes mellitus. A panel of 13 experts participated in a two-stage validation process using the Delphi method to assess the module and its educational resources. Subsequently, the module was tested on a group of 30 participants, i.e., individuals with diabetes, with its efficacy evaluated through conversation analysis and in-depth interviews.\n\nResults The three-month-long module included three sessions • 1: Diabetes and its health implications • 2: Diabetic foot and self-management • 3: Interprofessional education in diabetic foot care The mode of content delivery was via Whatsapp, and the educational resources, in the form of pamphlets, flowcharts, handouts, case-based cartoons, and videos on diabetes, including diabetic foot, its risks, and self-management, were shared regularly. All participating experts consensually validated the module and educational resources. Analysis of in-depth interviews revealed that the module immensely benefitted the participants and helped them improve their knowledge and practices of foot care in diabetes.\n\nConclusions The study concludes that IPC educational modules can enhance adherence to proper diabetic foot care practices, potentially reducing the occurrence of foot ulcers and amputations, and ultimately improving the quality of life for individuals with diabetes.", "keywords": [ "Interprofessional", "collaborative", "educational module", "diabetic foot self-management", "development", "validation" ], "content": "Introduction\n\nFoot ulcers represent persistent issues that arise as a result of diabetes. People with diabetes face a significant lifetime risk, possibly reaching 25% of developing a foot ulcer. Alarmingly, it is estimated that every half a minute, a lower limb is lost globally due to diabetes-related complications.1\n\nDiabetic foot ulcers (DFUs), if severe, may lead to lower limb amputations and even death. It can thus disrupt the quality of life for the person involved and their family.2\n\nIn 2017, the worldwide prevalence of diabetes mellitus impacted almost 425 million individuals, and it is projected to increase to 629 million by the end of 2045.3 In India, over 77 million people currently have diabetes, and this number is expected to surge to 35.7 million by 2045. Diabetes affects approximately 8.9% of the Indian population and is associated with an estimated one million deaths annually.4,5\n\nThe worldwide occurrence of DFUs varies between 5% and 7.5% among individuals with diabetic neuropathy. In India, a survey conducted within the community found the prevalence of diabetic foot ulcers to be 6.38%. Approximately 15% of DFUs probably deteriorate, ultimately resulting in lower extremity amputations, a problem that poses significant global clinical management challenges and places a substantial economic burden on society.6\n\nResearch findings indicate that around 25% of people with diabetes in India are anticipated to experience DFUs.7,8 This situation could be exacerbated by insufficient general awareness, limited medical facilities, and economic constraints.9,10 India’s population comprises various ethnic and genetic groups with distinct cultural beliefs and hygiene practices.11 This diversity can significantly impact the causes of diabetes, its outcomes, such as diabetic foot ulcers, and individuals’ responses to diabetes treatments.4,12\n\nDiabetic care-related practices may also vary based on ethnicity, lifestyle practices, socio-economic status, and the prevalence of diabetes. It may further contribute to an increase in the occurrence of DFUs in India.13,14\n\nResearch has revealed that individuals with diabetes frequently overlook self-care measures for their feet and tend to implement foot-care practices only after complications have already developed.1\n\nInsufficient awareness about diabetes-related foot issues and self-care practices among diabetes patients stands as a significant contributor to the development of diabetic foot ulcers. Inadequate control of blood sugar levels, non-compliance with dietary guidelines, and a lack of exercise exacerbate this issue. Inadequate knowledge and poor foot care practices are noteworthy risk factors for foot complications in diabetes.15\n\nSurveys in Indian populations have also revealed an evident gap between foot care knowledge and practices among diabetic individuals.14,16,17 These studies have further highlighted the need for increasing awareness about proper foot care practice in diabetic patients to reduce the incidence of complications. They further added that it can be achieved by educating individuals with diabetes about self-foot care and other essential practices.16,17\n\nImplementing an educational program focused on self-managing diabetic foot issues could be a viable solution.18\n\nEducating self-managing diabetic foot conditions has enhanced foot care practices, lowering the chances of developing diabetic foot ulcers.19,20 Individual patient education of five to six minutes helped improve foot care practices, as reported among the diabetic rural population of Puducherry, India.21 The study added that such educative sessions, when consistently reinforced, are likely to result in healthy habit formation, prevent disabilities, and reduce medical expenses in the long run.21 However, there is a paucity in the available literature regarding such attempts, i.e., prolonged and continuous educational interventions on self-management of diabetic foot in the Indian scenario.\n\nTherefore, there is an urgent necessity to introduce nationwide diabetes foot self-management educational initiatives in India. The primary objective is to raise awareness about preventing diabetic foot-related issues and enhance the management of diabetic foot care. These efforts have the potential to mitigate the frequency of foot amputations and alleviate the burden of ‘diabetic foot’ across the nation.22\n\nDiabetic foot self-management practices must be adequately and effectively communicated to individuals with diabetes. The complexity of this disease is such that it needs a collaborative approach involving various healthcare providers (HCPs) to achieve desired outcomes. This concern could be addressed through an interprofessional (IP) team-based approach.\n\nAn IP team of HCPs such as physicians, endocrinologists, surgeons, physiotherapists (including an orthotist, and podiatrist), nursing faculty, and nutritionists can collaboratively focus on comprehensive diabetic foot care and its management.23,24 An IP team-based approach is recommended as the most effective method for educating the population about the correct techniques of diabetic foot self-management.23,24 Engaging an IP team in designing the educational intervention to disseminate optimal practices of diabetic foot self-management is likely to yield positive results. However, in countries like India, where a physician-centered or multidisciplinary approach to patient care is more common, the efficacy of the IP team-based approach has yet to be extensively investigated.\n\nEngaging HCPs and creating an interprofessional collaborative educational module focusing on the correct methods of diabetic foot self-management while ensuring its accessibility to individuals with diabetes could be a successful strategy. This approach will facilitate comprehensive and ongoing education, encompassing all critical aspects of diabetic foot self-management. As a result, it has the potential to decrease diabetic foot issues and their associated complications in people with diabetes, ultimately contributing to an enhanced quality of life for these individuals.\n\nThis current study aims to create and verify an interprofessional collaborative (IPC) educational module with the involvement of HCPs. This module is intended to efficiently instruct the population on appropriate strategies for self-managing diabetic foot issues.\n\n\nMethods\n\nThe study has been designed in adherence to the Declaration of Helsinki and has received approval from the Institutional Ethics Committee of Kasturba Medical College and Kasturba Hospital (IEC No 698-2020 dated Wednesday, 11th November 2020). It was additionally registered in the Clinical Trials Registry of India (CTRI/2021/03/031629 dated Monday, 1st March 2021). Written informed consent has been obtained from the participants recruited in the study. The study was conducted between April 2021 to November 2022.\n\nA focused group discussion (FGD) was arranged for the members of the IP team to discuss the development of the educational module. The IP team included HCPs involved in diabetic foot care and management. The HCPs identified were a general physician, an endocrinologist, a surgeon, a physiotherapist, a dietician, and a nursing professional. The IP team also included an anatomist experienced in health professions education. The IP team was previously constituted after seeking the perceptions of the HCPs related to importance of interprofessional collaboration in teaching diabetic foot self-management.23 The HCPs were aware about the benefits of IP team-based approach in diabetic foot care. They further expressed their willingness to work as part of an IP team and suggested appropriate teaching methods for diabetic foot self-management.23 This study thereby led to the conduct of the present study, i.e., Development and validation of an interprofessional collaborative educational module on the self-management of foot for individuals with type II diabetes mellitus.\n\nDuring the course of the current study, the FGD was arranged online via Microsoft Teams (Microsoft Corporation, United States). Insights were obtained from each IP team member for the development of the interprofessional collaborative educational module.\n\nThe educational module was then developed by the research team involving the following components:\n\n• Mode of delivery\n\n• Level of learner (study population)\n\n• Duration of the session\n\n• Domains of learning\n\n• Level of proficiency expected\n\n• Educational resources\n\n• Assessment and evaluation methods\n\nThe educational resources were developed after reviewing the literature on the following databases: Medline, Johns Hopkins Medicine, World Diabetes Foundation, Healthline, World Health Organization (WHO), Joslin Diabetes Centre, WebMD, National Institute of Health-National Institute of Diabetes and Digestive Kidney Diseases, Google. The educational resources were developed in English and the local language, i.e., Kannada.\n\nIdentification of validators/review experts\n\nA total of 11 validators (five internal and six external) were involved in validating the educational module and resources. The internal validators were the members of the IP team who were previously involved in the discussion for developing the IPC module. External validators were HCPs and experts in the field of medical education. The latter were unrelated to the IP team and the development process of the educational module.\n\nTwo-step validation of the IPC educational module and resources was carried out using the Delphi method.25\n\nThe first consensus stage was obtained via a validation tool (research instrument) adapted from Ribeiro and Spadella, 201826 [Annexure 1 in extended data]. Appropriate permissions were obtained for its modification and usage in the current context.\n\nThe validation tool had two parts.\n\nPart 1: Validation tool for the educational module\n\nPart 2: Validation tool for educational resources\n\nBoth parts included the basic details of the validators, i.e., age, gender, and years of professional experience.\n\nPart 1 of the validation tool assessed domains-concept, didactic-pedagogical, operational, and adhesion features. Part 2 of the validation tool assessed the following components of the educational resources developed: concept, language, illustration, layout, and motivation39 [Annexure 1 in extended data].\n\nThe evaluation tool was administered online via Microsoft Forms (Microsoft Corporation, United States).\n\nThe experts examined the assessment/dimension components, giving ratings ranging from zero to 10, where zero indicated complete disagreement and 10 signified total agreement. Each segment included three open-ended questions to gather suggestions for additions, revisions, or removals and feedback regarding errors and misunderstandings.\n\nThe assessments conducted by experts were examined, and the scores were recorded in a Microsoft Excel spreadsheet (Microsoft, Corporation, USA). This process included determining the mean value for each item to evaluate its perceived significance or suitability and calculating standard deviations to assess the degree of agreement among the experts. The established cut-off values were as follows: items with a mean ≥7 were considered important or adequate, while items with a mean <7 were considered minor or appropriate. Additionally, items with a standard deviation of <3 were considered to be in consensus, whereas those with a standard deviation ≥3 were deemed non-consensual. Subsequently, this data matrix served as a guide for refining the initial versions.26 The validated items had close-to-cut-off results and increased the importance level.\n\nAfter incorporating the required suggestions and making the necessary improvements and inclusions, the module and resources were again shared with the validators for review, and the second stage of consensus was obtained.\n\nAfter approval and validation, the implementation of the educational module was planned with the consensus of the members of the IP team.\n\nStudy population\n\nThe study population included individuals with type 2 diabetes.\n\nInclusion and exclusion criteria\n\nInclusion criteria\n\n• The individuals with type 2 diabetes of any duration were considered. The study participants were recruited from the Centre for Diabetic Foot Care and Research (CDFCR) Department of Physiotherapy, Kasturba Hospital Manipal.\n\n• The participants comfortable in using the “WhatsApp”, i.e. a social media tool were preferred.\n\nExclusion criteria\n\n• Patients with type 1 diabetes, impaired fasting glucose, impaired glucose tolerance, and gestational diabetes were excluded from the study.\n\n• Patients who have developed diabetic foot ulcers were also not be considered.\n\nThe sample size calculation was carried out to access a small effect (Change). The calculation was done with G*power 3.1.9.4 software for sample size calculation based on t tests - Means: Difference between two dependent means (matched pairs).\n\nSample size calculation\n\nTo check its effectiveness, the module was initially implemented only a pilot (small) group of study participants (N=30), i.e., individuals with type 2 diabetes. The participants were recruited after explaining the entire process of educational intervention and obtaining the written informed consent. A flow chart showing the implementation steps of the IPC educational module is represented in Figure 1.\n\nFeedback was sought from the study participants regarding the usefulness of the educational module by inviting them to express their views over the chat.\n\nThe statement read this way:\n\n“Hope you like the way in which the session is being conducted. Hope the resources that are shared here is useful. We have changed the settings for you to reply.\n\nKindly give a or or type YES if this session is useful to you. You may also add your suggestions (if any) for further improvement of the session. You can also send a voice message.”\n\nThe settings that were initially changed to “only admins can edit the group info” while sharing the educational resources were changed to “all participants can send messages to this group” enabling the participants to express their views.\n\nThe module’s effectiveness was further analysed by inviting the study participants for a questionnaire-based telephonic interview. The interview guide was self-developed and validated by five medical and IP education experts. The interview guide is shared as Annexure 2 in the extended data.39 Each interview lasted for 45-60 minutes and was audio recorded. The interviewees’ responses were subjected to thematic analysis, and themes were identified.\n\nThe interview recordings were transcribed to text, and the final transcripts were verified for clarity and correctness by members of the study team. Participants in the research were categorized as participants 1, 2, 3, and so on to guarantee anonymity and de-identification. The transcripts were then imported for processing using MAXQDA Analytics Pro 2020 (VERBI GmbH, Berlin, Germany) The free trial version of the software was used.\n\nThematic analysis was performed on the participant replies. The authors coded the material after reading and rereading the participant replies. The codes were then examined to find the pattern, and the themes were identified. To identify the topics, an inductive and semantic technique was used.\n\nThe authors created an initial coding scheme with the first two transcripts, which was enhanced by examining two more transcripts. The codebook was improved further iteratively with consecutive transcripts until consensus was attained. The coding was reviewed within and between transcripts.\n\nThe entire research team approved the final codebook and applied it to all transcripts. Following coding, comments were evaluated for frequency by topic matter.\n\n\nResults\n\nConsidering the input provided by the members of the IP team, the research team dedicated their efforts to creating an IPC module titled ‘An Interprofessional Collaborative (IPC) Educational Module on Self-Managing Foot Health in Individuals with Type II Diabetes Mellitus.’\n\nThe objective of the module was to instill self-management practices for foot care in individuals with type 2 diabetes mellitus.\n\nThe module was designed to run for three months, consisting of three sessions.\n\n• 1: Diabetes and its Health Implications\n\n• 2: Diabetic Foot and Self-Management\n\n• 3: Interprofessional Education in Diabetic foot care\n\nConsidering the ease of accessibility, the IP team unanimously suggested that the mode of delivery should be online. It was decided that the resources would be shared regularly via WhatsApp.\n\nThe learning outcomes, domains of learning involved, level of proficiency expected, educational resources, assessment methods, and evaluation were clearly defined for each session (as detailed in the educational module- Annexure 3 in extended data39).\n\nThe educational resources were mainly of the following types (Annexure 4 in extended data39):\n\n• Educational materials include pamphlets, flowcharts, handouts, case scenarios, and cartoons addressing diabetes and its health consequences, focusing on diabetic foot issues, associated risks, and self-management.\n\n• Insights from leading experts in the field of diabetic foot care, emphasizing the advantages of sound foot care practices, presented as “What do the experts say?”\n\n• Informative videos on the correct methods for diabetic foot care.\n\n• Newspaper articles discussing diabetic foot care practices, authored and published in regional newspapers.\n\n• Group discussions involving the study participants centered around self-management of diabetic foot health.\n\nThe effectiveness of the entire module was evaluated using conversation analysis and in-depth interviews.\n\nA total of 11 experts validated the module. Out of them, five were internal experts, i.e., members of the IP team, and six were external validators. The average age of the validators was 44 years, ranging from 35 to 60 years. Their average professional experience duration was 19 years, spanning from 10 to 35 years.\n\nThe data matrix generated in this phase displayed significant means and standard deviations for every item assessed in the educational module and resources. On average, the scores for each item were 8.5 or higher. Furthermore, all items aimed to secure consensus among experts, with standard deviations remaining below 1.5 (as indicated in Tables 1 and 2).\n\nThe reviewers put forth the following thoughts and suggestions.\n\nFor the educational module:\n\n“As the topic is diabetic foot related better to focus on it from the first session. General discussion on diabetes and its impact on health can be restricted. Only normal sugar values and ideal control levels can be stressed. Stress that foot problems are neglected can affect the livelihood when everything else is normal” (Expert 1)\n\n“As the background educational level of the beneficiary is unknown, prepare the module applicable to illiterates also” (Expert 1)\n\n“Comprehensively covers all aspects of foot care in diabetes” (Expert 2)\n\nFor educational resources:\n\n“As this topic is new to the target audience, if possible, we can add illustrations/images of how the IP team can come out to take care of the individual at the tertiary level. (just a suggestion, as it had more text than images/illustrations)” (Expert 1)\n\n“This resource provides an overview of how an interprofessional team works toward managing diabetic foot. It is simple and clear for a layperson to understand” (Expert 6)\n\nThe suggestions were incorporated, and necessary changes were made to the module and the educational resources.\n\nSubsequently, the IPC educational module was tested on a group of 30 willing participants who consented to participate in the study. The module was of three months duration and was implemented during January to March 2022. An analysis of WhatsApp conversations conducted after the sessions concluded that the module had a substantial positive impact on the participants, enhancing their understanding and implementation of diabetic foot care practices.\n\n“The session was very informative and useful” (WhatsApp Conversation 1)\n\n“Highly educative series. Learnt a lot about foot care and started following the tips given therein. Thanks for the valuable guidance given by your team” (WhatsApp Conversation 2)\n\n“I sincerely THANK you people for providing excellent knowledge to us. The way you have given answers to the queries is adorable. I also look forward in other areas of health tips in future. God bless you!” (WhatsApp Conversation 3)\n\nAmong the 30 participants, seven agreed to a telephonic interview and shared valuable insights about the conduct of the IPC educational module. According to the interviewees, all sessions of the IPC educational module were beneficial. The sessions and shared information were highly relevant, appropriate, and easily understandable. As stated by the interviewees, it was a good learning experience that helped them follow and improve the proper foot care practices. Figure 2 depicts a Word Cloud created incorporating the participants’ keyed responses. The participants’ responses were subjected to thematic analysis, and themes were identified. The participants’ responses in the form of quotes and the themes derived are presented in Annexure 539 in the extended data.\n\nThe major themes identified were: beneficial, appropriate, important, informative, useful, understandable, and improvement.\n\nThe observations made are presented below under the respective domains.\n\nThe participants stated that the overall experience of participating in the study was useful. In their view, it was helpful and was a good learning experience. It helped them learn and understand the proper foot care practice for diabetes.\n\nThemes identified were: beneficial, informative, and wonderful knowledge.\n\n“I got many benefits because aaa….. I am not aware of certain things, that you informed me, ahhh.. so where the changes are required there I had made changes” (Participant 1)\n\n“Based on our situation it was good and our foot should be cleaned and seeing about diabetes and diabetic foot, ummmm we get frightened. We should aaaah … maintain diet and our health ummm.. should be maintained, regarding food also, etc, we got an experience. Yes, it was useful” (Participant 4)\n\n“It was wonderful, mmmm.. the three months program was really very helpful. I have gained lot of knowledge, which otherwise I was not knowing about diabetes” (Participant 5)\n\nThe sessions were highly educative and useful, as stated by the study participants. The sessions helped them learn the proper practices of foot care in one setting rather than referring to multiple other sources, such as newspapers which the participants used to refer to gain information previously.\n\nThemes identified were: supportive and useful.\n\nIt was very useful for me, ahhhh … like how we should maintain our health. Before we didn’t knew information regarding this, ummmm …..was reading through newspapers regarding diabetes. It had given us more information ummmm … like what should not be done. And it ummm … helped a lot. (Participant 4)\n\nThe type of learning materials that mainly evoked the participants’ interest in learning the proper foot care practices were mainly videos and pictorial representations, as indicated by most of the participants.\n\nThemes identified were: helpful, understandable, videos, and pictures.\n\n“Videos were very helpful and understandable.” (Participant 3)\n\n“Actually, I have seen all your content; ummmm … the photographs of diabetic foot shared, aaa … a fear complex develop, because so far we have neglecting about our foot. After seeing those photos and that, ummm ….actually a fear complex has developed, as a result we have now started taking extra care about our foot.” (Participant 5)\n\nThe WhatsApp mode of sharing the educational resources was useful and appropriate as stated by the study participants. The participants could easily access the resources at their own pace and during their free time.\n\nThemes identified were: beneficial, convenient, and accessible.\n\n“Yes it was very useful, ahhhh … as accessing whatsapp is easy and um um.. unlike other application, in whatsapp we could open the resources conveniently aaa … at any time we need, when we are free. In other application this is not possible.” (Participant 6)\n\nThe study duration, i.e., three months, and the frequency (i.e., twice a week on Mondays and Fridays) in which the educational resources were shared were also mentioned as appropriate by most participants. A few of them, however, found it longer and repetitive.\n\nThe themes identified were: appropriate, useful, adequate, and repetition.\n\n“Yes …. appropriate and adequate” (Participant 3)\n\n“Yes, giving little-little information at a time, um um.. rather than giving whole information, we could ah ah understand. and in our free time we could see the information” (Participant 4)\n\n“I think it is too long, ah ah … so you could have finished within one or one and half months. And sometimes ummm..the repetition of the same things, I have noticed that, same thing have been repeated in so many whatsapp messages. It is repetition.” (Participant 5)\n\nAccording to the participants, the educational module effectively enhanced their understanding and implementation of self-management practices for diabetic foot care.\n\nThe themes identified were: improvement.\n\n“Definitely, because I was not caring much about my foot but after that um um … I have ahhh..been experiencing some burning sensation in my foot, then uh uh I had that diabetic neuropathy also, I was taking medicine for that also. So my foot is actually a a..red and very thin, and most of the time I was not wearing footwear, I mean uh uh … chappals inside the house, because we are very orthodox people, generally ummm.. don’t wear chappals inside. I was hesitating whether to wear ah ah..chappal inside the house and then finally after reading all your communications aaaa..I felt it better to start using footwear inside the ah ah house also. And regarding that care should be taken about that the uh uh.. foot, I have been seriously following it now. I never used to use this ummm..lotion or ahh.. moisturizer for my foot, but now I have made it a point, aaa.. every night before going to bed, I, I.. will use someee moisturizer and someee lotion and uhhh..taking precautions. And regarding neuropathy, ahhh … actually my family doctor had prescribed ummm.. some medicine and I’m continuously taking it, so it has given me lot of relieve.” (Participant 5)\n\nMost interviewees liked the module’s conduct entirely and stated no limitations. A few interviewees, however, mentioned the lack of individualization as a limitation of the IPC module. They added that the module must be tailor-made to meet every individual’s requirement.\n\nThe themes identified were: lack of individualisation/personalisation.\n\n“Ummmm …. Individualization is very very important, not group, that is my suggestion. Each patient is aa having their own problems. But giving mmm same medicine to everybody, aaaa it won’t work. You have to see the patient individually.” (Participant 2)\n\nSome of the interviewees also provided suggestions for further improvement of the module. Participants wished to have video conferencing and frequent interactions with the doctors to clarify their concerns. Periodic reviews would be better rather than unnecessary lectures. Further sharing the resources frequently is also stated as helpful by some participants. The rest of them had no further suggestions, as the module in itself was adequate and appropriate.\n\nThe themes identified were: interaction, follow-up, and frequent.\n\n“There should be a video conference or ummm interaction and the questions should be ready, ah ah they should straight away ask you questions and a a you should straight away answer it. Or you can tell this session ahh ahh I cannot answer, I will answer in the next session. So that will be ahhh more effective.” (Participant 1)\n\n“There should be reviews in aaa.. between would be easy rather than ah ah unnecessary lectures, but some may read, I will read at least once, ummm but some will ignore these, aaa rather than these things, on my point of view, ummm.. face to face interactions would be more effective. And aaa..you should aaa… Be factual to the patients, we don’t want to hear your lectures, it should be direct like this aaa the fact, ummm.. what is your prescription or medicine or a a..what you advice. Yaa because we are not coming to hear stories no, it should be factual.” (Participant 1)\n\n“Yes it can be improved by sharing this information frequently. Ah ah … And very much thank you for all this information.” (Participant 4)\n\n\nDiscussion\n\nAn increasing realization highlights the importance of adopting an interdisciplinary, or IP, approach to ensure effective diabetic foot care, emphasizing the requirement for a well-prepared team.27 In response to this requirement, India has introduced a nationwide effort called the Diabetic Foot Education Program (DFEP). This initiative is geared towards enhancing physicians’ knowledge about preventing diabetic foot problems, managing such issues (including debridement and offloading), providing foot-care education, and implementing methods to elevate the quality of healthcare for diabetic foot patients.28\n\nThe importance of managing diabetic foot ulcers by an IP diabetic foot ulcer team has been previously mentioned.23,29 Engaging a multidisciplinary foot care team has demonstrated substantial improvements in reducing amputations and other complications related to DFUs.30–32\n\nThe present study further demonstrates the importance of IP approach to diabetic foot care. In addition to the routine foot care practices, the IP team was also involved in the development and validation of the educational module on diabetic foot self-management. This attempt was found to be useful by the study participants, i.e., individuals with diabetes.\n\nBeyond the management of the condition, if the IP team collaboratively engages in raising awareness about the significance of self-care for diabetic feet and advocating the correct techniques for self-managing diabetic foot health, as is observed in the current study, it has the potential to reduce the issues linked to diabetic foot complications significantly. It is believed that when different healthcare professionals, i.e., physicians, surgeons, physiotherapists, nurses, dieticians, podiatrists form a team and constantly reiterate and reinforce the benefits of foot care in diabetes, diabetic foot self-management can be effectively practiced by the individuals with diabetes in specific and the community in general.\n\nThe constant reinforcement of the knowledge of proper practices of foot care in diabetes as provided in the module led current study was well appreciated by the study participants. It had a substantial positive impact on the participants, enhancing their understanding and implementation of diabetic foot care practices.\n\nResearch has uncovered an apparent disparity between the understanding and implementing of foot care practices among people with diabetes.1,2,14–17 This gap needs to be addressed by developing comprehensive behavior change strategies. Implementing comprehensive risk assessments for diabetic foot complications and foot care based on prevention, education, and support at the community level has become extremely important.14 Awareness sessions on diabetic foot self-management that are readily available to the community can help address this issue.\n\nIn the present study, the awareness was created via the educational module through the most commonly accessed platform, i.e., WhatsApp. The WhatsApp mode of sharing the educational resources was useful and appropriate as stated by the study participants. The educational resources were mainly focused on Diabetes and its Health Implications, Diabetic Foot and Self-Management, and the importance of Interprofessional Education in Diabetic foot care. The participants could easily access the resources at their own pace and during their free time. This attempt made the accessibility easier. It also successfully changed the participants’ behavior toward proper foot care practices.\n\nThe American Diabetes Association advocates for the utilization of initiatives like “Diabetes Self-Management Education” (DSME) to enhance understanding, behavior, and self-care, particularly when it comes to foot care for individuals dealing with diabetes.33 These programs have the potential to avert and address complications associated with diabetes, enhance the quality of life for patients, and alleviate the economic impact.33,34 Similar observations were made in the current study.\n\nNumerous prior studies have centered on assessing the influence of educational interventions on enhancing the knowledge and attitudes of individuals with diabetes regarding diabetic foot care.\n\nA straightforward in-person education approach proved to be successful in elevating awareness about foot care, and it demonstrated the potential to enhance motivation and induce behavioral changes among individuals with type 2 diabetes.35 The present study has identified the same as its limitations. The participants preferred face-to-face interaction rather than receiving the resources online. This approach may, however, not be suitable while addressing a large cohort of participants and needs to be suitably managed.\n\nThe efficiency of a culturally customized self-management education (SME) program for foot care was examined. The program encompassed an engaging group discussion that employed a narrative video, a PowerPoint presentation, and a printed guide. Following the intervention, foot care practices had a noticeable enhancement, as indicated by the results.18\n\nThese sessions were, however, standalone sessions conducted at a single point in time, unlike the prolonged three-month-long educational module described in the current study.\n\nThe influence of an intensive diabetes foot education initiative aimed at veterans at elevated risk of foot ulcers was previously assessed. This education program enhanced the knowledge and practices related to foot care among high-risk patients. However, the study emphasized the need to explore methods to improve the accessibility of these educational sessions.36\n\nProviding caregivers with ongoing interdisciplinary education on foot care has bolstered the family support system for managing diabetic ulcers.37 The present study agrees with the same and adds that ongoing IP education (in the form of modules) on the proper practices of foot care can be more effective in causing a behavioural change among individuals with diabetes and their caregivers towards proper practices of foot care.\n\nWhile prior research has underscored the benefits of educational interventions for enhancing understanding and practices related to diabetic foot care, the potential of IP collaborations in diabetic foot self-management remains relatively underexplored. The present study has attempted to explore the same. An IP approach to diabetic foot education helps to address the components holistically. Individuals with diabetes are comprehensively provided with all the relevant information using an IP approach.\n\nAn extensive review of the available literature uncovered limited evidence supporting the efficacy of educational interventions for enhancing diabetic foot management practices within the unique context of India. India, known for its rich cultural, ethnic, and economic diversity, employs various approaches to managing diabetes and its related complications, including diabetic foot issues. The limited access to healthcare services due to financial constraints and geographical barriers exacerbates the problem of inadequate foot care practices among individuals with diabetes. Consequently, there is a pressing need to develop accessible awareness sessions or modules tailored for these underserved populations to enhance knowledge and promote better self-management practices for diabetic foot care.\n\nThe creation of an IPC educational module and the evaluation of its impact on enhancing knowledge and practices associated with diabetic foot self-management, even before diabetic foot ulcers develop, has been a rarely explored topic. Consequently, this current study seeks to address this gap. It demonstrates the effectiveness of the IP collaborative educational module in enhancing knowledge and practices related to foot care in individuals with diabetes. Extending the module’s duration, as in this case, to three months, along with ongoing follow-up, can significantly boost its efficacy in improving foot care knowledge and practices, thus helping prevent complications linked to diabetic foot issues. Easy accessibility to the educational program/module provided via WhatsApp was also deeply appreciated by the study participants.\n\nEquipping the patient with insights into potential complications and stressing the significance of proper medical care can reduce the likelihood of complications and enhance adherence to diabetic foot care treatment.38 The current study demonstrates that an IPC educational module can effectively address these aspects.\n\nAlthough the implementation of the educational module was well appreciated by the study participants, a few concerns were raised. Some participants favored the repetitive sharing of the information, stating that it aided in changing their attitude towards following proper foot care practices. On the contrary, a few others found the process tedious and the duration unnecessarily prolonged. Measures need to be taken to address these issues. Suggestions to customize the educational module based on the individual’s needs were also expressed. More face-to-face interactions and factual communications were also preferred. The module can be further improvised based on these suggestions before future implementation to enhance its effectiveness and acceptance.\n\nFurther, the current study was piloted on a small cohort of participants,30 and only seven participants consented to a telephonic interview. It calls for further refinement in the execution of the educational module that can be seamlessly accessible to a large group of participants, i.e., individuals with diabetes.\n\n\nConclusion\n\nThe IPC Educational Module proves highly effective in enhancing the knowledge and practices of self-managing diabetic foot care among individuals with Type II Diabetes mellitus. The study participants express that the module has value and exhibits effectiveness in improving their understanding and implementation of diabetic foot self-management. The method of delivery, as well as the learning materials shared, piqued their interest in acquiring knowledge about proper foot care practices. Leveraging WhatsApp to access educational resources was considered “beneficial” and highly “convenient”.\n\nFurthermore, by personalizing the module to cater to individual needs, this educational approach could enhance foot care knowledge and practices in individuals with diabetes. Consistent follow-ups and ongoing reminders regarding foot care can foster a shift in attitude, consequently leading to improved healthcare practices among individuals with diabetes. In the long term, this can decrease hospital admissions for diabetic foot-related complaints, a reduction in amputations and mortality rates among those with diabetic foot conditions, and an overall enhancement of the quality of life for both individuals and society.", "appendix": "Data availability\n\nFigshare: Development and Validation of an Interprofessional Collaborative Educational Module on the Self-Management of Foot for Individuals with Type II Diabetes Mellitus. https://doi.org/10.6084/m9.figshare.24947508. 39\n\nThe project contains the following underlying data:\n\n- Evaluation tool_educational module.xlsx\n\n- Evaluation tool_educational resources.xlsx\n\n- WhatsApp Chat with Diabetic foot care.txt\n\n- Interview transcript 1.docx\n\n- Interview transcript 2.docx\n\n- Interview transcript 3.docx\n\n- Interview transcript 4.docx\n\n- Interview transcript 5.docx\n\n- Interview transcript 6.docx\n\n- Interview transcript 7.docx\n\nFigshare: Development and Validation of an Interprofessional Collaborative Educational Module on the Self-Management of Foot for Individuals with Type II Diabetes Mellitus. https://doi.org/10.6084/m9.figshare.24947508. 39\n\nThe project contains the following extended data:\n\n- Annexure 1_Validation tool for the educational module & resources.docx.pdf\n\n- Annexure 2_Interview guide.pdf\n\n- Annexure 3_Educational module_self management of diabetic foot.pdf\n\n- Annexure 4_Educational Resources.pdf\n\n- Annexure 5_Participant responses & Themes.pdf\n\n- Annexures.zip\n\nCONSORT Checklist for ‘Development and validation of an interprofessional collaborative educational module on the self-management of foot for individuals with type II diabetes mellitus’ https://doi.org/10.6084/m9.figshare.24947508. 39\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nThe authors express their sincere gratitude to:\n\n• Members of the IP team, i.e., the HCPs who helped in the development and validation (internal) of the educational module\n\n• HCPs who functioned as external validators of the educational module\n\n• All the faculty and fellows of MAHE FAIMER Institute for Leadership in Interprofessional Education, Manipal Academy of Higher Education, for their extended support and encouragement.\n\n\nReferences\n\nMagbanua E, Lim-Alba R: Knowledge and Practice of Diabetic Foot Care in Patients with Diabetes at Chinese General Hospital and Medical Center. 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Publisher Full Text\n\nRastogi A, Bhansali A: Diabetic foot infection: An Indian scenario. J. Foot Ankle Surg. 2016; 3: 71–79.\n\nAsharani PV, Lau JH, Roystonn K, et al.: Health literacy and diabetes knowledge: A nationwide survey in a multi-ethnic population. Int. J. Environ. Res. Public Health. 2021; 18: 9316. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nViswanathan V: Epidemiology of diabetic foot and management of foot problems in India. Int. J. Low Extrem. Wounds. 2010; 9: 122–126. PubMed Abstract \| Publisher Full Text\n\nVerma M, Sharma N, Rashi AV, et al.: Diabetic foot care knowledge and practices in rural north India:Insights for preventive podiatry. J. Assoc. Physicians India. 2021; 69: 30–34. PubMed Abstract\n\nSolana YM, Kheirb HM, Mahfouzc MS, et al.: Diabetic Foot Care: Knowledge and Practice. Journal of Endocrinology and Metabolism. 2016; 6(6): 172–177. Publisher Full Text\n\nGeorge H, Rakesh P, Krishna M, et al.: Foot Care Knowledge and Practices and the Prevalence of Peripheral Neuropathy Among People with Diabetes Attending a Secondary Care Rural Hospital in Southern India. J. Family Med. Prim. Care. 2013; 2(1): 27–32. PubMed Abstract \| Publisher Full Text\n\nMustafa A, Iqbal M, Parvez MA: Assessment of Knowledge, Attitude and Practices of Diabetics Regarding Their Foot Care.2017; 11(1): 5.\n\nAdarmouch L, Elyacoubi A, Dahmash L, et al.: Short-term effectiveness of a culturally tailored educational intervention on foot self-care among type 2 diabetes patients in Morocco. J. Clin. Transl. Endocrinol. 2017 Mar 1; 7: 54–59. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBeiranvand S, Fayazi S, Asadizaker M: Effect of educational programs on the knowledge, attitude, and practice of foot care in patients with diabetes. Jundishapur J. Chronic Dis. Care. 2015 Apr 1; 4(2): e26540. Publisher Full Text\n\nRen M, Yang C, Lin DZ, et al.: Effect of intensive nursing education on the prevention of diabetic foot ulceration among patients with high-risk diabetic foot: a follow-up analysis. Diabetes Technol. Ther. 2014 Sep; 16(9): 576–581. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSaurabh S, Sarkar S, Selvaraj K, et al.: Effectiveness of foot care education among people with type 2 diabetes in rural Puducherry, India. Indian J. Endocrinol. Metab. 2014 Jan; 18(1): 106–110. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nDas A, Pendsey S, Abhyankar M, et al.: Management of Diabetic Foot in an Indian Clinical Setup: An Opinion Survey. Cureus. 2020 Jun 15; 12(6): e8636. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPrabhath S, Handady G, Herle G, et al.: Importance of interprofessional collaboration in teaching diabetic foot self-management: Perceptions of health care professionals. Med. J. Armed Forces India. 2023. Publisher Full Text\n\nSong K, Chambers AR: Diabetic Foot Care. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023 Jan 2022 Jul 25. PubMed Abstract\n\nHsu CC, Sandford BA: The Delphi technique: making sense of consensus. Pract. Assess. Res. Eval. 2007; 12(1): 10.\n\nRibeiro ZMT, Spadella MA: Content validation of educational material on healthy eating for children under two years of age. Rev. Paul. Pediatr. 2018 Apr-Jun; 36(2): 155–163. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nOgrin R, Houghton PE, Thompson GW: Effective management of patients with diabetes foot ulcers: outcomes of an Interprofessional Diabetes Foot Ulcer Team. Int. Wound J. 2015 Aug; 12(4): 377–386. Epub 2013 Jul 9. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nRiaz M, Miyan Z, Waris N, et al.: Impact of multidisciplinary foot care team on outcome of diabetic foot ulcer in term of lower extremity amputation at a tertiary care unit in Karachi, Pakistan. Int. Wound J. 2019 Jun; 16(3): 768–772. Epub 2019 Feb 15. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWang C, Mai L, Yang C, et al.: Reducing major lower extremity amputations after the introduction of a multidisciplinary team in patient with diabetes foot ulcer. BMC Endocr. Disord. 2016 Jul 7; 16(1): 38. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPeter-Riesch B, Czock A, Uçkay I: Interdisciplinary Expert Group on the Diabetic Foot. Swiss interdisciplinary guidance on good practices for acute and complicated diabetic foot syndromes. Swiss Med. Wkly. 2021 Nov 11; 151: w30045. PubMed Abstract \| Publisher Full Text\n\nAmerican Diabetes Association: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019; 1–193.\n\nPowers MA, Bardsley J, Cypress M, et al.: Diabetes self-management education and support in type 2 diabetes: a joint position statement of the American Diabetes Association, the American Association of Diabetes Educators, and the Academy of Nutrition and Dietetics. Diabetes Educ. 2017 Feb; 43(1): 40–53. Publisher Full Text\n\nVatankhah N, Khamseh ME, Noudeh YJ, et al.: The effectiveness of foot care education on people with type 2 diabetes in Tehran, Iran. Prim. Care Diabetes. 2009 May 1; 3(2): 73–77. PubMed Abstract \| Publisher Full Text\n\nWard A, Metz L, Oddone EZ, et al.: Foot education improves knowledge and satisfaction among patients at high risk for diabetic foot ulcer. Diabetes Educ. 1999 Jul; 25(4): 560–567. PubMed Abstract \| Publisher Full Text\n\nThe diabetic foot. Ahmad J. Diabetes Metab. Syndr. 2016; 10: 48–60. Publisher Full Text\n\nDas A, Pendsey S, Abhyankar M, et al.: Management of Diabetic Foot in an Indian Clinical Setup: An Opinion Survey. Cureus. 2020 Jun 15; 12(6): e8636. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWantonoro W, Komarudin K, Imania DR, et al.: The Influence of 6-Month Interdisciplinary Accompaniment on Family Caregivers’ Knowledge and Self-Efficacy Regarding Diabetic Wound Care. SAGE Open Nurs. 2023 Apr 6; 9: 23779608231167801. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nOliver TI, Mutluoglu M: Diabetic Foot Ulcer. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023 Aug 8 2023 Jan. PubMed Abstract\n\nPrabhath S, Prakash H, Kamath G, et al.: Development and Validation of an Interprofessional Collaborative Educational Module on the Self-Management of Foot for Individuals with Type II Diabetes Mellitus. [Dataset]. figshare. 2024. Publisher Full Text" }	[ { "id": "279959", "date": "24 May 2024", "name": "Suyog Sindhu", "expertise": [ "Reviewer Expertise medical education", "interprofessional education and clinical pharmacology" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nGeneral Overview: The presented study addresses a significant issue in diabetic care— the management of diabetic foot health through interprofessional collaboration. The paper details the development and validation of an educational module aimed at enhancing self-management practices among individuals with type 2 diabetes mellitus. The study employs a robust methodological framework and provides evidence supporting the efficacy of the educational intervention.\nDetailed Review: Clarity and Accuracy of Presentation and Literature Cited: The manuscript is clearly and accurately presented, with well-organized sections that facilitate understanding. The background section effectively highlights the importance of foot self-care in diabetes management and the need for an interprofessional approach. Relevant literature is cited appropriately, grounding the study within the context of existing research on diabetic foot care and interprofessional education. Study Design Appropriateness and Technical Soundness: The study design is appropriate for the research objectives. The use of the Delphi method for module validation ensures expert consensus, lending credibility to the educational content. The implementation of a three-month-long module with structured sessions is a well-thought-out approach, aligning with educational best practices. The use of diverse educational materials (pamphlets, flowcharts, handouts, case-based cartoons, and videos) caters to varied learning preferences and enhances engagement. Detailing of Methods and Analysis for Replication: The manuscript provides sufficient details regarding the development of the educational module, the Delphi validation process, and the subsequent testing phase. The description of the two-stage validation process, including the expert panel composition and criteria for consensus, is comprehensive. Details on the module's content delivery via Whatsapp and the types of educational resources shared are clearly articulated. The methods section enables replication by other researchers, ensuring the study's reproducibility. Statistical Analysis and Interpretation: The study utilizes qualitative analysis techniques, including conversation analysis and in-depth interviews, to evaluate the module's efficacy. The interpretation of the qualitative data is appropriate, highlighting the participants' improved knowledge and practices in diabetic foot care. While the study lacks quantitative analysis, the qualitative insights provide valuable evidence supporting the module's effectiveness. Availability of Source Data for Reproducibility:\nThe manuscript mentions that all participating experts consensually validated the module, indicating transparency in the validation process. Detailed raw data from the in-depth interviews and conversation analysis has been provided. Support of Conclusions by Results:\nThe conclusions drawn are well-supported by the results. The consensus validation by experts and the positive feedback from participants underscore the module's effectiveness. The study convincingly argues that the IPC educational module can improve adherence to proper diabetic foot care practices, potentially reducing foot ulcers and amputations. The findings align with the stated objectives and contribute valuable insights into the role of interprofessional education in diabetic care. Recommendations: Quantitative Evaluation: Consider incorporating quantitative measures, such as pre- and post-intervention assessments, to complement the qualitative findings and provide a more robust evaluation of the module's impact. Extended Follow-up: Conduct a longer follow-up period to assess the sustained impact of the educational module on participants' foot care practices and health outcomes. Conclusion: The study presents a well-designed and thoroughly validated educational module that demonstrates significant potential in improving diabetic foot care through interprofessional collaboration. The manuscript is technically sound, methodologically robust, and offers valuable contributions to the field of diabetic education and care.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "11996", "date": "06 Sep 2024", "name": "Sushma Prabhath", "role": "Author Response", "response": "Dear Reviewer (Dr. Suyog Sindhu) Many thanks for your supporting lines on reviewing comments to the manuscript. It was a pleasure to read through your insights. We value the positive and appreciative lines provided by you. About the recommendations provided by you, your suggestions are well taken and we are planning to scale up the current study to a larger population (in the near future) wherein the points provided shall be duly considered in our future steps: Recommendations: 1. Quantitative Evaluation: Consider incorporating quantitative measures, such as pre- and post-intervention assessments, to complement the qualitative findings and provide a more robust evaluation of the module's impact. Response to reviewer's comments: We value your suggestion and shall definitely consider incorporating quantitative measures in our future attempts (future-ongoing research) complementing the qualitative findings to provide a more robust evaluation of the module's impact. Based on the current study findings, we are also aiming to refine and redefine the module to meet the requirements of the diverse population (i.e., individuals with diabetes). 2. Extended Follow-up: Conduct a longer follow-up period to assess the sustained impact of the educational module on participants' foot care practices and health outcomes. Response to reviewer's comments: Your suggestion is well taken and we shall aim to follow the same in our future attempts." } ] }, { "id": "302217", "date": "09 Aug 2024", "name": "Joseph Ngmenesegre Suglo", "expertise": [ "Reviewer Expertise Diabetes care modules" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors presented a paper on an interesting and clinically relevant topic “Development and validation of an interprofessional collaborative educational module on the self-management of foot for individuals with type II diabetes mellitus” They developed and validated an interprofessional collaborative (IPC) educational program involving HCPs to efficiently as a way of promoting healthy footcare practices. The paper however will require major revisions before it is accepted for indexing.\nAbstract The writing style is difficult to read in places and I feel that the whole paper could do with a review by a copy editor. The author should be consistent in the use of Type II or type 2 diabetes. Use one throughout the manuscript. The first sentence within the methods section of the abstract not required. This first line should be used to state explicitly the study design used. Avoid repetitions, the study aim has been repeated in different forms. It is seen in the background and under methods again.\nIntroduction Many statements/paragraphs within the manuscript require references eg The worldwide “occurrence of DFUs varies between 5% and 7.5% among individuals with diabetic neuropathy” (REF required).\nDesign of the study: The reporting guidelines used should be stated and cited within the methods sections of the study. I have seen the CONSORT guidelines checklist for randomised trials completed and uploaded – I am not sure if this is the appropriate guideline for this study as the study contains more qualitative elements than a randomised trial. The authors may want to assess other reporting guidelines such as the CORECQ guidelines for their suitability. The study seems to use sequential multimethod to develop and evaluate the module. It is quite difficult to understand exact design used in this study. If possible, can the authors give a summary of the design/methods using a flow diagram or framework? Also be very coherent in presenting the various phases of the study, clearly indicating how each phase informed the next phase. How were members of the FGD identified and by who? What criteria was use in recruiting them? Similarly, persons who carried out the validation of the module? How, and who recruited them? Participants that were interviewed, what sampling approach was used? The educational resources shared on whatsapp, who shared this information? Was it sent to participants on their individual phones or they were in single whatsapp group to receive the information? How did the authors assess whether participants actually read or watched the resources shared on whatsapp? This relates to participants fidelity/adherence to the intervention? How about internet accessibility for whatsapp users? Did you provide internet data bundle or incentive to participants? “The educational resources were developed in English and the local language, i.e., Kannada” – Was it first developed in English and translated or the vise versa? what methods were used to ensure consistency and accuracy?\nDiscussion Thinking about creating health inequality – what happens to persons with diabetes who have no access to whatsapp supported devices? Is this mode of delivery scalable? Will the findings be generalizable? Discuss these as part of the study limitations. “A straightforward in-person education approach proved to be successful in elevating awareness about foot care, and it demonstrated the potential to enhance motivation and induce behavioral changes among individuals with type 2 diabetes.35 The present study has identified the same as its limitations. The participants preferred face-to-face interaction rather than receiving the resources online. This approach may, however, not be suitable while addressing a large cohort of participants and needs to be suitably managed.” - I am not sure the message being communicated here – Do you mean participants in your study preferred face-to-face to online? The paper will benefit from proof reading to correct avoidable mistakes eg improvised instead of improved as stated under discussion. – “The module can be further improvised based on these suggestions before future implementation to enhance its effectiveness and acceptance” Conclusion The authors stated that “The IPC Educational Module proves highly effective in enhancing the knowledge and practices of self-managing diabetic foot care among individuals with Type II Diabetes mellitus” – I wish they don’t have to use the word “effective” which carries a statistical connotation. However, inferential statistics were not part of this study to evaluate participants' knowledge and practices. This was rather done quantitatively.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "12304", "date": "06 Sep 2024", "name": "Sushma Prabhath", "role": "Author Response", "response": "Dear Reviewer, Many thanks for reviewing our manuscript and providing your positive insights towards its improvements. Your valuable suggestions have thoroughly supported us in refining the manuscript. Reviewer’s overview: The authors presented a paper on an interesting and clinically relevant topic “Development and validation of an interprofessional collaborative educational module on the self-management of foot for individuals with type II diabetes mellitus” They developed and validated an interprofessional collaborative (IPC) educational program involving HCPs to efficiently as a way of promoting healthy footcare practices. The paper however will require major revisions before it is accepted for indexing. Response to comment: We value your suggestions and have made all the necessary corrections and inclusions as advised. As stated, the manuscript is also language edited to enhance its readability. A point-to-point reply to the stated comments is mentioned below: Comments/ Suggestions Clarifications/Modifications 1. Abstract The writing style is difficult to read in places and I feel that the whole paper could do with a review by a copy editor. Response to comment: The manuscript has been subjected to language editing to enhance its readability 2. The author should be consistent in the use of Type II or type 2 diabetes. Use one throughout the manuscript. Response to comment: We have now maintained the consistency of using ‘Type II Diabetes Mellitus’ throughout the manuscript as advised. 3. The first sentence within the methods section of the abstract not required. This first line should be used to state explicitly the study design used. Avoid repetitions, the study aim has been repeated in different forms. It is seen in the background and under methods again. Response to comment: The necessary corrections are made as suggested. The first line under methods section in the abstract states about the development of the educational module followed by details of its validation. The objective of the module previously mentioned in the methods is now removed to avoid repetition (as previously mentioned as the aim of the study in the ‘Background’) 4. Introduction Many statements/paragraphs within the manuscript require references eg The worldwide “occurrence of DFUs varies between 5% and 7.5% among individuals with diabetic neuropathy” (REF required). Response to comment: The references are adequately provided as advised. The statements/paragraphs requiring referencing are suitable cited. Suitable changes are made in the reference list too. 5. Design of the study: The reporting guidelines used should be stated and cited within the methods sections of the study. I have seen the CONSORT guidelines checklist for randomised trials completed and uploaded – I am not sure if this is the appropriate guideline for this study as the study contains more qualitative elements than a randomised trial. The authors may want to assess other reporting guidelines such as the CORECQ guidelines for their suitability. Response to comment: The reporting guidelines are stated and cited appropriately within the methods section as advised. We have included the following (as found appropriate): TIDieR (Template for Intervention Description and Replication); COREQ (COnsolidated criteria for REporting Qualitative research) Checklist and CONSORT (Consolidated Standards of Reporting Trials). TIDieR checklist for reporting the description of the educational intervention and its replication COREQ checklist for reporting the qualitative research carried out CONSORT checklist for reporting the usefulness of the educational intervention carried out as a clinical trial on the study participants, i.e., individuals with diabetes. 6. The study seems to use sequential multimethod to develop and evaluate the module. It is quite difficult to understand the exact design used in this study. If possible, can the authors give a summary of the design/methods using a flow diagram or framework? Also be very coherent in presenting the various phases of the study, clearly indicating how each phase informed the next phase. Response to comment: A flowchart summarizing the methodology is now presented as figure 1. It clearly indicates how each phase leads to the next. Also a detailed explanation is provided under each phase/step of the methodology. 7. How were members of the FGD identified and by who? What criteria was use in recruiting them? Similarly, persons who carried out the validation of the module? How, and who recruited them? Response to comment: The principal investigator (first author of the study) identified and invited the following HCPs, i.e., general physician, an endocrinologist, a surgeon, a physiotherapist, a dietician, and a nursing professional to constitute an IP team. The IP team also included an anatomist experienced in health professions education. All the HCPs invited to form the IP team were involved in diabetic care of the patients in their respective workplace. They were the members who were involved in the group discussion that aimed at the development of the educational module. The individuals who carried out the validation of the educational module were a team of both external and internal experts. The internal experts were the same HCPs who constituted the IP team and were previously involved in the FGD leading to the development of the educational module. The external experts involved in the validation of the educational were other HCPs cum experts in the field of medical education not related to the study. They were not involved in the constitution of IP team and the development process of the educational module. The current study is a part of a larger project designed to develop an interprofessional educational module to educate individuals with diabetes about proper practices of diabetic foot care. Relevant reference indicating the same is already included (cited-reference number 24) in the manuscript under “Development of the educational module”. However, to provide better clarity the sentences have been reframed as per reviewer’s comment. Relevant statements of effect have been included in the manuscript wherever appropriate. 8. Participants that were interviewed, what sampling approach was used? Response to comment: Convenient sampling was used. At the end of the implementation of the education module, i.e., sharing of the educational resources in the WhatsApp group after three months, the Participants were asked to express their willingness related to attending a telephonic interview related to the usefulness of the session. The consenting participants were telephonically approached for the interview. Statements of this effect are included in the manuscript. 9. The educational resources shared on whatsapp, who shared this information? Was it sent to participants on their individual phones or they were in single whatsapp group to receive the information? How did the authors assess whether participants actually read or watched the resources shared on whatsapp? This relates to participants fidelity/adherence to the intervention? How about internet accessibility for whatsapp users? Did you provide internet data bundle or incentive to participants? Response to comment: The principal investigator created a WhatsApp group for the study participants and the educational resources were shared therein. The information regarding creating the WhatsApp group and sharing of educational resources was previously conveyed to the participants during the recruitment process. The participants were encouraged to regularly review the resources. To ensure whether participants read or watched the resources shared on WhatsApp, the number of views per entry was reviewed and tracked. No other measures were taken to ensure participants’ fidelity/adherence to the intervention. The users (participants) used their own internet data pack to access WhatsApp. No internet data bundle facilities or incentives were provided to the participants for the same by the researchers. Statements of this effect are included in the methodology section of the manuscript. Issues related to participants fidelity/adherence to the intervention are also mentioned in the study limitations. 10. “The educational resources were developed in English and the local language, i.e., Kannada” – Was it first developed in English and translated or the vise versa? what methods were used to ensure consistency and accuracy? Response to comment: Yes, the educational resources were first developed in English and later translated to the local language, i.e., Kannada. To ensure consistency and accuracy of translated content, the following measures were followed: Back-Translation: After translating the content from English to the local language, i.e., Kannada, we had a different translator (who was not involved in the initial translation) translate the content back into English. It ensured that the translated version’s accuracy and consistency reflected the original content. Bilingual Expert Review: We also invited bilingual experts (fluent in both English and Kannada) to review the translated content. The experts assessed the accuracy of the translation, ensuring that it captured both the technical and cultural nuances of the original material. Statements of this effect are included in the methodology section of the manuscript. 11. Discussion Thinking about creating health inequality – what happens to persons with diabetes who have no access to whatsapp supported devices? Is this mode of delivery scalable? Will the findings be generalizable? Discuss these as part of the study limitations. Response to comment: We value the reviewer’s suggestions. However, in the present study, the inclusion criteria for recruiting participants (individuals with diabetes) clearly states that “The participants comfortable in using the “ WhatsApp”, i.e. a social media tool were preferred” Considering the issues on creating health inequality, we totally agree that the mode of delivery of the educational module, i.e., online via WhatsApp is not scalable considering individuals who have no access to WhatsApp supported devices. Thus, the findings cannot be generalizable. One possible solution to address this issue could be involving the care givers, next to kin or family members of the individuals with diabetes who have access to WhatsApp supported devices to inform and educate them. Statements of this effect is included in the ‘study limitations’ of the manuscript to provide clarity as advised. 12. “A straightforward in-person education approach proved to be successful in elevating awareness about foot care, and it demonstrated the potential to enhance motivation and induce behavioral changes among individuals with type 2 diabetes.35 The present study has identified the same as its limitations. The participants preferred face-to-face interaction rather than receiving the resources online. This approach may, however, not be suitable while addressing a large cohort of participants and needs to be suitably managed.” - I am not sure the message being communicated here – Do you mean participants in your study preferred face-to-face to online? Response to comment: Yes, some of the participants in our study preferred face-to-face in comparison to online interactions. But this approach will be suitable during stand-alone sessions, i.e., a one-day workshop/session and not during the implementation of an educational module of longer duration, i.e., three-months in this case. Further, the face-to face approach may not be suitable while considering many participants, wherein the issues of lack of attendance or participation may surface as the module/program progresses. Therefore, online mode of interactions is preferable. Measures should be taken to make the online interactions more participatory to enhance participant satisfaction and learning. Statements of this effect is included in the discussion section of the manuscript to provide more clarity 13. The paper will benefit from proof reading to correct avoidable mistakes eg improvised instead of improved as stated under discussion. – “The module can be further improvised based on these suggestions before future implementation to enhance its effectiveness and acceptance” Response to comment: The necessary corrections are made as suggested. A thorough proof reading of the manuscript is carried out to correct the mistakes. Further, the manuscript is also language edited to enhance its readability. 14. Conclusion The authors stated that “The IPC Educational Module proves highly effective in enhancing the knowledge and practices of self-managing diabetic foot care among individuals with Type II Diabetes mellitus” – I wish they don’t have to use the word “effective” which carries a statistical connotation. However, inferential statistics were not part of this study to evaluate participants' knowledge and practices. This was rather done quantitatively. Response to comment: We value the reviewer’s suggestion. Since inferential statistics were not part of the study to evaluate the participants knowledge and practices and the usefulness of the module was assessed only qualitatively (using personal interviews with the study participants); we have therefore replaced the statement “proves highly effective…..”. It now reads as follows: The IPC Educational Module can be useful in enhancing the knowledge and practices of self-managing diabetic foot care among individuals with Type II Diabetes mellitus. The study participants express that the module has value and exhibits usefulness in improving their understanding and implementation of diabetic foot self-management." } ] } ]	1	https://f1000research.com/articles/13-386
https://f1000research.com/articles/13-777/v1	09 Jul 24	{ "type": "Research Article", "title": "Estimating the efficacy of Newborn-Communication, Health, Feeding and Swallowing Education Program (N-CHFSEP) for primiparous mothers", "authors": [ "Deepthi Ouseph", "Jayashree Kanthila", "Sunil Baliga", "Shraddha Shetty", "Sudhin Karuppali", "Deepthi Ouseph", "Jayashree Kanthila", "Sunil Baliga", "Shraddha Shetty" ], "abstract": "Background Primiparous mothers face diverse challenges during pregnancy and post-childbirth. There is a lack of comprehensive educational programs for primiparous mothers on maternal functioning and newborn care. This study aimed to explore the efficacy of a developed educational program on the attitude of primiparous mothers towards newborn communication, general health, feeding and swallowing. The objectives were (1) to develop an attitude questionnaire (AQ), a parent education program, and a feedback questionnaire (FQ); and (2) to estimate the efficacy of the education program pre- and post-delivery.\n\nMethods Ninety-eight primiparous mothers without any obstetric history, proficient in English or Kannada, and delivering healthy newborns were recruited for the study. Phase 1 involved the development and validation of AQ, the parent education program [Newborn Communication, Health, Feeding and Swallowing Education Program (N-CHFSEP)], and FQ; while Phase 2 comprised of administering them on the mothers. Both quantitative (descriptive statistics, paired t-test, and chi-square test) and qualitative analysis were done on the parameters of interest.\n\nResults The results of the study demonstrated a notable increase in the number of mothers (not all) reporting heightened confidence levels following receiving the N-CHFSEP (which was observed in all the domains). This observed change (pre and post) was statistically significant as per paired t-test analysis (p <0.05) indicating a significant increase in confidence levels post-N-CHFSEP intervention, as well as recognizing warning signs related to the same. Sociodemographic factors such as age, education, occupation, and family type were reported to have a significant effect (p <0.05) on maternal confidence levels before and after N-CHFSEP administration. Feedback from participants highlighted the effectiveness of the program in enhancing knowledge and awareness, while also suggesting areas for improvement.\n\nConclusions This study demonstrates the effectiveness of N-CHFSEP in enhancing primiparous mothers' confidence in newborn care, thereby improving maternal and infant health.", "keywords": [ "accessible education", "child health", "early childhood development", "health education", "mental health", "primiparous mothers" ], "content": "Introduction\n\nPregnancy and childbirth represent a significant milestone in a woman's life permanently altering a woman's identity and way of living in a continuous, and dynamic manner. This phase is marked by significant physical and psychological transformations exerting a particular influence on primiparous mothers (first-time mothers) as they undergo a wide range of emotions including joy, excitement, and anxiety, along with the presence of overwhelming and stressful experiences such as routine newborn care, breastfeeding difficulties, lack of sleep, and physically taxing household duties.1 Maternal confidence, knowledge, and attitudes play an important role during this critical period.2 Reduced levels of confidence in primiparous compared to multiparous mothers negatively impact their ability to provide infant care.3 The neonatal period becomes an important stage for brain development demanding a significant level of care from caregivers, facilitating the formation of new connections within the brain.4 Developmental milestones (cognitive, gross, and fine motor, language, and social-emotional and behavioural) are a set of predetermined indicators that mark a child's achievement as they progress in their growth and development. The ability of caregivers to effectively identify these milestones facilitates early interventions, improving overall health outcomes.5 Communicative skills are the best predictors in the development of school-age language, reading, and cognitive skills, helping in long-term development. Awareness of the development of early communication skills among primiparous mothers suggested the need for more reliable and approachable information about the development of communication skills.6 Feeding and swallowing skills are considered promoters of physical, mental, and psychological health, providing infants with adequate nutrition required for development, which when unmet, may cause changes in the brain structure leading to general health challenges, cognitive deficits, and other metabolic, and behavioural difficulties. WHO (2010) has recommended certain guidelines for newborn care that includes maintaining cleanliness, ensuring adequate thermal protection, initiating proper breathing, providing eye care, promoting exclusive breastfeeding, administering immunizations, effectively managing illness, and offering specialized care for infants with low birth weight. Monitoring developmental milestones assumes a critical role in recognizing deviations and facilitating prompt interventions.5\n\nMaternal health literacy influences a woman's motivation and capacity to seek, comprehend, and apply information to enhance the well-being of both mother and child.7 Such literacy programs provide newborn health indicators, especially useful for primiparous mothers as they encounter feelings of frustration and uncertainty, struggling to identify specific reasons for their infant’s issues. Consequently, most new postpartum mothers express a strong desire for professional guidance and support in both infant and self-care.1 Studies on the needs of primiparous mothers have indicated their efforts to fulfil their informational requirements regarding pregnancy, through attending educational sessions and utilizing online resources to gather the necessary information. Numerous studies on primiparous mothers have highlighted the importance of educational programs delivered by healthcare professionals assisting in newborn care and the implementation of proper procedures to promote infant health.8,9 A quasi-experimental study conducted on 72 primiparous mothers to understand the effect of the Maternal and Newborn Care Intervention (MNCI) program on maternal functioning revealed its efficacy in improving primiparous mothers functioning during the postpartum phase.10 Similarly, Gozali and colleagues conducted a quasi-randomized controlled trial on 84 primiparous mothers in New York to evaluate the impact of a Newborn Education and Discharge Class, and they found mothers who took the programme to significantly exhibit higher levels of knowledge than the control group.3 A pilot study conducted using a pre-/post-intervention design to assess the efficacy of the “HUG Your Baby” parent education and support program, indicated the parent education and support program fostered parent's general well-being, offering them the needed tools to ensure a seamless transition from the NICU to home, thereby providing them with confidence in their position as carers.11 Several other universally used maternal literacy programmes have been reported to be used (1) the “Learn the Signs. Act Early.” (LTSAE) programme of the U.S. Department of Health and Human Services and the Centers for Disease Control and Prevention,12 (2) the Mount Sinai Parenting Center (3), (3) the Internet Newborn-Care Education Programme (INCEP) developed in Taiwan,13 (4) the postnatal psychoeducation programme developed in Singapore,14 and (5) an educational support program developed in Iran.15\n\nThe Early Childhood Development (ECD), a UNICEF global programme in India included schemes such as (1) the Home-Based Care for the Young Child (HBYC) developed by the National Health Mission as an expansion of the Home-Based Newborn Care (HBNC) programme, (2) the HBNC+ (an extension of HBNC),16 (3) the Rashtriya Bal Swasthya Karyakram (RBSK), which is an initiative of the Government of India's Ministry of Health and Family Welfare, and (4) an updated version of the Mother and Child Protection (MCP) Card.17 A cross-sectional study carried out on the use of MCP cards among 200 mothers with 1–12-month-old infants, indicated 86% of mothers to have read and comprehended the program, revealing the effectiveness of MCP cards as a health education tool for counselling during antenatal care visits in villages.18 A systematic review and meta-analysis were carried out to understand the effectiveness of educational and support intervention program on breastfeeding rates among primiparous women at six months and up to two years of postpartum period. The results indicated that the rate of breastfeeding in the intervention group at six months was twice as high as in the control group when the intervention combined both antenatal and postnatal teaching and support.19 Although these initiatives have covered a range of aspects of mother and child development, there exists a lack of a holistic educational programme covering important areas of baby development, such as feeding and swallowing, communication, and newborn health. This emphasises the need for a comprehensive educational module addressing a range of important developmental aspects for mothers with their newborns. Access to such reliable sources of information empowers primiparous women to enhance their confidence and shape their mental expectations and ideals regarding pregnancy and childbirth. Additionally, such programs would enable them to feel more assured and better formulate mental expectations and principles concerning their pregnancy and childbirth experiences.20 There are only a handful of centres that mandatorily provides such information to primiparous mothers with a dearth of existing studies in India pertaining to the efficacy of using such education programs. With primiparous mothers showing reduced levels of maternal confidence than multiparous mothers towards providing infant care (3), the current study aimed to explore the efficacy of an educational program on the attitude of primi mothers towards milestones of early infant communication, feeding-swallowing and general health of their infants. The objectives of the study were (1) to develop and validate an attitude questionnaire, parent education program and feedback questionnaire; (2) and to estimate the efficacy of an education program pre and post-intervention delivery.\n\n\nMethods\n\nThe research was a single-arm pre-post study carried out between August 2023 and February 2024. A non-random convenience sampling method was adopted for the study. The study was approved by the Institutional Ethics Committee (IEC KMC MLR 03/2023/108) of Kasturba Medical College, Mangalore, Manipal Academy of Higher Education on 20.07.2023 and was registered under the Clinical Trials Registry of India (CTRI/2023/05/053109) on 25.05.2023. We used the CONSORT checklist when writing our report.21 The study has adhered to the principles of Declaration of Helsinki.\n\nThe sample size was calculated using the formula: n= [Z_(1-α/2)^2×pq]/d^2; where Z = 1.96, standard normal at 5% level of significance; p = 0.47%, q= 1-p, d=0.1.22 A total of 98 primiparous mothers [mean age (in years): 26.03 ±3.79] were recruited for the study. Seventy-six (77.6%) of them belonged to a joint family, while 22 (22.4%) were from a nuclear family. These mothers comprised homemakers (62%), homemakers after having resigned from their jobs due to pregnancy (11%), working in educational sectors (8%), and other private/government sectors (19%). The educational qualifications indicated mothers have completed their basic formal education (38%), higher secondary education (19%), diploma (35%), graduation (35%), and postgraduation (3%).\n\nThe inclusion criteria included (1) inpatient primiparous mothers without any prior obstetric history, (2) mothers having given birth to healthy newborns through various delivery methods [vaginal, assisted vaginal (including vacuum, forceps, or cesarean)], and (3) mothers proficient in English or Kannada (a South Indian language spoken in the state of Karnataka). The exclusion criteria included (1) primiparous mothers delivering twins/triplets with significant history of obstetric, medical, or psychological problems, and (2) mothers who were health professionals. Multiparous mothers were excluded due to their experience in caring for newborns. Mothers with obstetric complications were excluded as that may affect their ability to participate in the educational program or effectively express their attitudes. All participants were recruited from Government Lady Goschen Hospital (a government hospital exclusive for maternity care), and Kasturba Medical College Hospital (a multidisciplinary speciality centre) of the Mangalore taluk, Dakshina Kannada district.\n\nThe present study was conducted in 2 phases. Phase 1 included the development of an (a) attitude questionnaire, (b) parent education program, and (3) feedback questionnaire; while Phase 2 included the administration of the questionnaires and the education program on the participants, followed by data analysis of the retrieved data.\n\nPhase 1: Development of the tools.\n\na) Attitude questionnaire (AQ): The AQ was developed by reviewing relevant literature8,21–25 on primiparous mothers' attitudes towards infant communication, feeding-swallowing practices, and general health. The questionnaire was designed to encompass various domains (communication milestones, feeding schedules, warning signs during feeding-swallowing and milestones, newborn hygiene, bathing care, vitamin supplements, immunizations, developmental milestones, and general care). The final version of the questionnaire (Appendix-I) comprised 16 closed-ended statements, each designed to assess maternal confidence in the above-mentioned domains. Items 1, 2, 3, 5, 7 were pertaining to communication skills and represented as C1, C2, C3, C5, and C7 respectively. Items 4, 6, 8, 9 and 12 were related to feeding-swallowing skills indicated as F4, F6, F8, F9 and F12 respectively. Finally, items 10, 11, 13, 14, 15 and 16 focused on newborn health and were indicated as H10, H11, H13, H14, H15 and H16 respectively. Each item was to be rated using a 5-point Likert rating scale (ranging from 5 being extremely confident to 1 being extremely unconfident). Additionally, the questionnaire included three open-ended questions indicated as G17, G18 and G19 targeting the mother's attitudes, concerns and opinions on the importance of communication and the well-being of newborns.\n\nb) Parent Education Program: The parent education program [Newborn-Communication, Health, Feeding and Swallowing Education Program (N-CHFSEP)] was developed after reviewing the existing literature12 on the developmental milestones of newborns. This provided an initial framework for the education program which was further developed with discussions with experienced pediatricians and speech-language pathologists (SLPs). The program covered essential information incorporating a comprehensive set of monthly milestones (0-6 months) crucial for development. The N-CHFSEP featured a total of 120 statements, each appropriately categorized within the corresponding age range. The following table (Table 1) depicts the general framework of the N-CHFSEP used in the current study.\n\nc) Feedback questionnaire (FQ): The FQ was developed after reviewing the literature13,19,26,27 on first-time mother's feedback towards parent education on infant communication, feeding-swallowing and general health of infants. A conceptual framework was developed which was expanded based on discussions with experienced pediatricians and SLPs. This questionnaire (Appendix-II) contained five closed-ended statements following a 5-point Likert rating scale (ranging from 5 being strongly agree to 1 being strongly disagree). Additionally, there was one open-ended question, allowing mothers to share their suggestions regarding the N-CHFSEP.\n\nContent Validation\n\nThe AQ, FQ, and N-CHFSEP were subjected to content validation by an expert panel to evaluate their adherence to established scientific facts and the grammatical accuracy of the designed statements. The panel included three primiparous mothers who were professionally qualified speech-language pathologists (SLPs) and three primiparous mothers who were professionally qualified paediatricians, each of them having a minimum of five years of clinical experience. All experts received a copy of the developed questionnaires (AQ and FQ) and N-CHFSEP. Each expert reviewed the tools (item-wise) on a 3-point Likert rating scale (0 being inappropriate, 1 being modifications required, and 2 being appropriate). For the N-CHFSEP validation, the panel evaluated the suitability of the milestones to appear under the corresponding age (0-6 months). Following the content validation by SLPs and the pediatricians, the content validation index (CVI) was calculated at both the item and scale level for the AQ, N-CHFSEP, and FQ respectively. The Item level CVI (I-CVI) was computed by dividing the number of experts who rated the items as one or two by the total number of experts. Scale level CVI (S-CVI) was then calculated by averaging the I-CVI scores for AQ, and FQ. The resulting S-CVI scores were 0.95 for AQ, 0.90 for N-CHFSEP, and 1.0 for FQ. The I-CVI scores for the N-CHFSEP fell below the desired level (0.78), indicating insufficient agreement among experts and, hence demanding a revalidation. The same expert panel participated in this process to obtain an I-CVI score of 1.\n\nThe AQ, FQ and N-CHFSEP underwent grammatical modifications (e.g. ‘The child … ….’ to ‘My baby … ….’) to enhance their comprehensibility for mothers. Based on expert advice, the N-CHFSEP was revised to highlight potential warning signs using the checklist released by the Centers for Disease Control and Prevention (CDC),12 within each month and across the 6 months. Furthermore, the program was revised to incorporate recommendations for fostering the child's communication abilities and holistic growth. Specific suggestions were made to include illustrations of certain elements in the N-CHFSEP, to facilitate better comprehension of the presented content. The SLPs provided valuable input, including guidance on breastfeeding practices, as well as identifying red flags related to communication and feeding milestones. The pediatric experts suggested the reorganization of milestones by months and repeating specific items in their respective months. Additionally, it was recommended to develop a pamphlet on the N-CHFSEP which would serve as a carry-home resource for mothers. Following the incorporations of the modifications the final N-CHFSEP was ready for administration.\n\nTranslation\n\nThe AQ, N-CHFSEP, and FQ were translated into Kannada (one of the common regional languages spoken in the Mangalore taluk). The AQ, N-CHFSEP, and FQ underwent both forward and backward translations which were performed by a bilingual translator proficient in both Kannada and English, with expertise in the subject matter. Following the completion of both forward and backward translations, a final Kannada version of the AQ, N-CHFSEP, and FQ was ready for administration. A pilot study was conducted on two Kannada-speaking participants to assess the comprehensibility, clarity, and cultural relevance of the finalized translated AQ, N-CHFSEP, and FQ. This continuous process of forward and backward translation contributed significantly to the questionnaire's accuracy and cultural appropriateness.\n\nPhase 2: Administration of the tools and data analysis\n\nThe data collection took place in the postnatal ward through one-on-one interactions. Participants were recruited by reviewing their medical records based on the inclusion and exclusion criteria. The data was collected from each of the participants on the second day following their delivery due to the discomfort commonly experienced by the mothers on the first-day post-delivery. Safety and hygiene were strictly adhered to by following hand hygiene protocols and by wearing surgical masks (as per WHO guidelines) before approaching the participants at their bedside. Efforts were made to facilitate participants to be seated in a comfortable position, enhancing effective interaction. The researcher obtained written informed consent from the participants followed by their socio-demographic details. Each participant was oriented to the study goals and objectives and was provided with comprehensive information pertaining to the questionnaires and the education program they will be subjected to. They were actively encouraged to seek clarifications on any uncertainties pertaining to the items within the questionnaire. The study commenced by providing each participant with the AQ which required them to read the questions and mark their level of confidence across each item, followed by the presentation of the N-CHFSEP, during which the examiner verbally presented the participants with the program, further to which a printed version of the N-CHFSEP was provided, after which the AQ was re-administered. Subsequently, feedback regarding the N-CHFSEP was obtained from the participants using the FQ. All verbal responses from the mothers were recorded using a digital voice recorder (Sony ICD-UX560F Stereo IC recorder 4 GB). The total administration spanned a duration of 25-30 minutes.\n\nThe digital voice recordings of the primiparous mothers' responses towards the AQ and FQ administration were transcribed and subjected to quantitative analysis. All open-ended questions were subjected to qualitative analysis by categorizing the verbatim into comprehensive themes to examine the responses received. Descriptive statistics (quantitative data) were performed using SPSS version 25.0. The continuous variables were analyzed using mean and standard deviation while the discrete variables were analyzed using frequency and percentage. The efficacy of the N-CHFSEP was estimated by comparing the pre and post-AQ scores and analyzing the FQ responses. A paired sample t-test was performed to determine the confidence levels (before and after intervention) of primiparous mothers across domains of communication skills, feeding-swallowing skills and general newborn health. Chi-square tests were carried out to determine the relationship between the demographics of the primiparous mothers and their confidence levels under each domain (communication skills, feeding -swallowing skills and general newborn health).\n\n\nResults\n\nNinety-eight participants were involved in the study and underwent the N-CHFSEP. Figures 1, 2 and 3 represents the confidence levels (before and after administration of PEP) of primiparous mothers in judging the communication skills, feeding-swallowing skills, and general health concerns of their infants respectively.\n\nFigure 4 represents the before-after confidence levels of primiparous mothers in judging communication, feeding-swallowing, and health concerns of infants.\n\nTable 2 represents the results of a paired sample t-test conducted to compare the effect of N-CHFSEP on confidence levels of primiparous mothers.\n\nThe chi-square correlation values between age, education, family type, and occupation towards the total pre-post-test measures of communication skills, feeding-swallowing skills and general infant health are represented in Table 3.\n\n* Good level of significance (p < 0.05).\n\nFollowing the administration of the AQ (pre-test), a variety of responses were obtained from primiparous mothers through open-ended questions pertaining to concerns on newborn care and development as well as their perceived importance of communication with the newborn. Figure 5 represents the identified concerns of primiparous mothers about newborn development.\n\nA certain proportion of primiparous mothers (5%) reported that communication with their infants will (1) obtain better responses from the newborn, (2) facilitate in general and intellectual development of the newborn, (3) develop social skills, (4) encourage play behaviours in newborns, and (5) improve mother-child bonding. However, a few mothers (2%) reported that communication with their newborns may not necessarily be important in the early years but becomes crucial only when the child becomes older. Additionally, some mothers (3%) reported to be unaware of the importance of communication with the newborn.\n\nThe results of the FQ revealed 67%, 32% and 1% of primiparous mothers to strongly agree, agree, and neutrally agree respectively towards the effectiveness of the education program. Following the administration of the FQ, a variety of responses were gathered from the open-ended question (Item no. 6). Several mothers (50%) reported that N-CHFSEP benefitted them by (1) providing additional information on communication skills, (2) offering a comprehensive view on the timelines of the developmental process, (3) emphasizing the importance of hearing, (4) addressing feeding concerns, and (5) providing insights into the newborn health. In addition, the programme was effective in (6) establishing the common disbelief that typically male children may verbally communicate much later than female children, and (7) understanding the behaviours to be observed during their newborn development. Others expressed a need for specific details pertaining to (8) fever management, (9) troubleshooting lactation failure and its effect on the baby, (10) details on avoidance of the type of feeds for the infant, and (11) developmental aspects beyond 6 months were reported by 8%, 15%, 5%, and 5% of the mothers respectively.\n\n\nDiscussion\n\nThe result of the current study portrays the confidence levels of primiparous mothers before and after being subjected to the N-CHFSEP, and the possible influencing variables (age, education, family type, and occupation) on the same. The results are discussed below:\n\nA notable increase in the number of mothers (not all) reporting heightened confidence levels following receiving the N-CHFSEP was observed. This observed change (pre and post) was statistically significant as per paired t-test analysis (p <0.05) (as reported in Table 2). Considering the questions (in AQ) pertaining to communication skills, 89 (for Item 1) and 84 (for Item 2) primiparous mothers reported having a pre-existing understanding (pre-AQ administration) of these skills, attributing this to their exposure to a variety of informational sources (educational programs, books, social media platforms, etc.) which may have helped them prepare well in advance for judging their newborn communication skills. In an Australian study, the researchers reported variability in the knowledge of primiparous mothers on early communication development and found them to often rely on friends and social media for information, which was mostly deemed unreliable according to maternal reports.6 Catering to the perspectives of primiparous mothers towards the importance of communication skills in the current study, it was reported that communication with newborns helps them to obtain responses, facilitate in general and intellectual development of their newborn, develop social skills, encourage play behaviours in newborns, and improve mother-child bonding. However, a few mothers reported that communication with their newborns may not necessarily be important in the early years but becomes crucial only when the child becomes older. Additionally, some mothers reported to be unaware of the importance of communication with the newborn. As per the concerns obtained (AQ-Item 18) from the participants of the current study, certain mothers reported to incorrectly estimate the developmental milestones in newborns which was reported in several other studies.28 Additionally, several mothers reported a lack of communication between healthcare professionals regarding newborn language development.2 However, the evident increase in the confidence levels (p<0.05) of the primiparous mothers in identifying the newborn communication skills in the current study (AQ-Item 1 and 2), can be attributed to the increased awareness these primiparous mothers would have received by the N-CHFSEP. As per the N-CHFSEP, the domains specified pertaining to communication development tapped upon milestones including the presence of a social smile, recognition of the mother, patterns of vocalization and babbling and communicative behaviours. The provision of such information may have imparted new knowledge on their newborn communication behaviours leading to increased confidence levels (p <0.05) as reported in Table 2. A randomized control trial done to study the effectiveness of educating parents on infant language development using a TMV Newborn program, in conjugation with a newborn hearing screening program found parents to have significantly enhanced knowledge about early language environments and caregiver responsiveness in promoting infant cognitive and language development.2\n\nNinety-two mothers reported a heightened increase in the confidence levels in identifying their newborns hearing abilities (AQ-Item 3) prior to the education program. This could be attributed to their awareness of the existing policies and implementation of newborn hearing screening programs available in Indian hospitals29 (including the one in which the participants of the current study were admitted for delivery), resulting in mothers being aware of the risk factors for hearing loss. Following the N-CHFSEP delivery to the participants of the current study, an increase in their confidence levels (p <0.05) for Item 3 was observed. The N-CHFSEP items pertaining to this aspect (on hearing loss) were directed to the knowledge and understanding of the timeline when their baby would ‘appear to listen and pay attention to sounds’, ‘localization of the speaker’, and ‘recognizing and responding to their name call’. An increase in the early detection of hearing loss with a corresponding improvement in language skills, behaviours, and the quality of life of infants due to universal newborn hearing programs has been reported.30\n\nConsidering the mothers confidence levels in independently identifying the warning signs (AQ-Items 5 and 7) during the infant’s communication development, an increase in their levels was observed following the N-CHFSEP delivery. This may be attributed to the aspects of N-CHFSEP which included warning signs on ‘social smile’, ‘types of child response’, ‘attentional skills’, and ‘patterns of vocalizations’ along with the corresponding timelines, thereby helping them in identifying potential issues in newborn development. The program also provided mothers with strategies to be used at home to increase communication skills in newborns, thereby increasing their confidence levels. Previous studies have proclaimed a potential lack of awareness among caregivers on implementing communication strategies.31 There is a scarcity of studies focusing on the danger signs of newborn communication development skills in India. Hence, the provision of N-CHFSEP in the current study enhanced maternal confidence levels in identifying and responding to these skills.\n\nA notable increase in the number of mothers (not all) reporting heightened confidence levels in feeding-swallowing skills following receiving the N-CHFSEP was observed. This observed change (pre and post) was statistically significant as per paired t-test analysis (p <0.05) (as reported in Table 2). Considering the questions (in AQ) pertaining to feeding-swallowing skills, 89 (for Item 4) and 93 (for Item 12) primiparous mothers reported having a pre-existing understanding (pre-AQ administration) of these skills. This may be attributed to various factors such as (1) their personal experiences in observing feeding newborns within the family circle, (2) mothers prior to delivery may have self-educated themselves about feeding skills from other support networks, and (3) the availability of lactation counsellors in hospitals offering mothers with practical assistance and opportunity to discuss feeding related concerns during the hospital stay. This aligns with previous findings in India, which reported that 40% of the mothers received antenatal education on breastfeeding practices, while 61% were educated by family and friends.32 The study also reported that the majority of the mothers had good knowledge about breastfeeding and the nutritional advantages of the same, but only 45% of the mothers practised the knowledge they gained through these sources. As per the concerns obtained (AQ-Item 18) from the participants of the current study (as indicated in Figure 5), certain mothers reported concerns about breastfeeding knowledge and support. These included concerns towards deciding the feeding position, feeding duration, feeding schedule, feeding precautions, post-feeding management, aspiration management, and the type of feeds. The evident increase in the confidence levels (p <0.05) of the primiparous mothers (in the current study) in identifying newborn feeding schedules and understanding of exclusive breastfeeding for six months (AQ-Item 4 and 12), can be attributed to the adequate information provided in N-CHFSEP such as ‘exclusive breastfeeding’, ‘burping’, ‘feeding duration’ and ‘schedule’, and ‘awareness on the usage of formula feeds’. This provision of information likely complemented their existing knowledge of newborn feeding and swallowing skills. Moreover, practical demonstrations by lactation counsellors further reinforce their understanding, contributing to an increase in their confidence levels as reported in Table 2. This finding is consistent with the findings of a systematic review done on the effectiveness of educational programs related to breastfeeding and supportive programs for primiparous mothers. The studies reported the mothers to have increased breastfeeding knowledge and self-efficacy, thereby increasing the frequency of breastfeeding.33\n\nConsidering the questions (in AQ) pertaining to the warning signs (AQ-Items 8 and 9) in feeding-swallowing skills, there was a decrease in the number of mothers (77 and 81) reporting to be confident (before N-CHFSEP) compared to items 4 and 12 (89 and 93). This decrease may be attributed to various factors such as lack of previous experiences in newborn care, fear of misinterpretation of potential warning signals, increased stress levels during the early motherhood period, limited access to antenatal and postnatal services, and information overload during the post-pregnancy period. These factors may lead to a state of confusion in mothers, making it difficult to distinguish and retain essential information related to newborn care feeding skills. This contradicts to a previous study conducted in Punjab which reported that 49.6% of urban mothers have a good knowledge of newborn danger signs.34 Following the N-CHFSEP delivery to the participants of the current study, an increase in their confidence levels (p <0.05) for Items 5 and 7 was observed which could be attributed to the program. The mothers were provided with adequate information on the neonatal danger signs such as ‘struggling to swallow’, ‘feeds coming out of the baby's nose immediately after being fed’, ‘vomiting of a large amount of feeds’, ‘coughing immediately after feeds’, ‘baby appearing dull and unable to take feeds’, and ‘forehead sweating immediately after feeds’. This is in line with a previous study done in South India, which included newborn feeding and health danger signs.35 The study demonstrated the effectiveness of a structured teaching program in improving the knowledge of postnatal mothers on newborn danger signs including those related to feeding and newborn health.\n\nA notable increase in the number of mothers (not all) reporting heightened confidence levels in newborn health following receiving the N-CHFSEP was observed. This observed change (pre and post) was statistically significant as per paired t-test analysis (p <0.05) (as reported in Table 2). Considering the questions (in AQ) pertaining to newborn health (AQ-Items 10, 11, 13 and 14), primiparous mothers reported having a pre-existing understanding (pre-AQ administration) of these skills. This may be attributed to the information provided on newborn hygiene and health status by the health professionals during their follow-up visits during the post-pregnancy/natal period. These heightened confidence levels may also be attributed to the significant role played by caregivers demonstrating and providing practical training on newborn care skills and the availability of educational cards such as Mother Child Protection Cards helping mothers to track newborn development, immunization schedules, and its importance. These findings were reaffirmed in another study done in South India, where 99.5 % of first-time mothers were aware of the importance of immunization for their children from various sources.36 Some of the concerns expressed by the participants of the current study (AQ-Item 18), were regarding their child's future education, selection of high-quality products to ensure child safety, precautions towards general health, weight gain, and bathing care. Following the N-CHFSEP delivery to the participants of the current study, an increase in their confidence levels (p <0.05) for Items 10,11, 13 and 14 was pertaining to newborn health observed in the mothers. This could be attributed to the N-CHFSEP which included adequate information on identifying the appropriate vitamin supplements, newborn hygiene practices, and post-immunization effects. Though the mothers were confident and aware of these aspects for their newborns, the N-CHFSEP supplemented their knowledge by providing comprehensive information on the administration timeline and schedules on the same. This aligns with previous findings which indicated the effectiveness of flipchart-assisted maternal education in improving breastfeeding practices, hygiene skills, and temperature maintenance in newborns after the educational intervention.37 Considering the mothers confidence levels in independently identifying developmental milestones and precautions towards hypothermia (AQ-Items 15 and 16), there was an increase in the number of mothers (91 and 92 mothers respectively) exhibiting heightened confidence levels following the N-CHFSEP delivery, compared to AQ-Items 10, 11, 13 and 14. This increase in confidence levels could be attributed to the N-CHFSEP, which provided adequate information offered in the child-rearing practices such as monthly milestones, and suggestions to prevent hypothermia. In contrast to many educational programs that do not emphasize comprehensive monthly milestones, especially those that are not verbally presented to these mothers, the N-CHFSEP in the current study was provided via a one-to-one educational session, which was advocated by previous research as well.27 The findings of the current study were consistent with a previous study done in the USA, where the researchers found a higher score in newborn care knowledge and maternal confidence after providing a Newborn Class program on developmental milestones and medical topics such as infant feeding and nutrition, infant health, and hygiene and infant well-being.3\n\nApart from the earlier mentioned reasons, the overall increase in the confidence levels of primiparous mothers in the current study could be attributed to the timing of intervention (provided second day of post-delivery), the expertise and the training provided by the health care professionals (SLP and Paediatrician), and the structure in which the education program was provided (monthly milestones, suggestions and danger signs) could have significantly contributed to the mother’s knowledge and confidence on early newborn caring skills, which was reiterated in previous studies.37 The majority of the participants in the current study were recruited from Government Lady Goschen Hospital, Mangalore which is exclusive for maternity care, encompassing a team of health care professionals from various disciplines. Studies have emphasized the significance of healthcare professionals as the primary source of information when queried about the benefits of postpartum educational programs.3 In addition, the hospital (in the current study) offered several instructional resources in Kannada and English such as posters on early newborn care skills and Mother Child Protection cards which may have supplemented their confidence levels.\n\nAccording to the results of the chi-square analysis, age, education, occupation, and family type had a significant effect (p<0.05) on the confidence levels before and after the administration of the N-CHFSEP. The maternal age (18-25 and 26-35 years) presented an effect (p <0.05) on the confidence levels in communication skills, feeding-swallowing skills, and newborn health as reported in Table 3. The higher confidence levels observed among both young and older mothers could be attributed to their inclination to use social media and mobile applications,38 which are generally free and readily available sources of information about newborn care. Such applications enable mothers to get information on monthly milestones, paediatric weight gain, vaccination charts, reminders on health checkup days, etc. Access to such information could contribute to increased confidence levels in managing various domains of communication skills, feeding-swallowing skills, and newborn health. Research on the utilization and effects of the Baby Buddy App, among first-time mothers revealed that the application provided easily accessible and reliable pregnancy information aiding them in effectively communicating with healthcare professionals.39\n\nMaternal education levels presented a significant effect (p <0.05) on the confidence levels before and after the administration of the N-CHFSEP as reported in Table 3. The higher educational levels (Degree, <=10th Std, <=12th Std) were observed to have an effect (p <0.05) on the confidence levels of newborn communication skills and general health whereas the lower education level (<=10th standard) specifically presented a significant effect (p <0.05) on the confidence levels in feeding-swallowing skills. This could be attributed to a deeper understanding of newborn care among highly educated mothers because of their formal education and exposure to various informational resources. A study on maternal educational levels reported to be significantly associated with the knowledge, attitude, and practice in newborn care.40 They found mothers with no formal education to score less than those who had higher education, which was corroborated by others as well. Higher levels of education may cause an urge among these mothers to obtain evidence-based resources from reliable websites and scientific journals. This inclination may prompt them to seek clarification from qualified healthcare professionals when needed. For example, considering communication skills, mothers may look for strategies such as purchasing specialized toys to enhance newborn communication abilities. They may also critically evaluate the information for its validity and relevance before implementing it. Higher education levels may help them make decisions on newborn health resulting in higher confidence levels among these mothers.\n\nAccording to the results reported in Table 3, a significant effect (p <0.05) on maternal confidence levels on overall newborn care and development was observed among those who belonged to a joint family type. With a joint family structure generally comprising grandparents (experienced caregivers) or extended families, it becomes natural for first-time mothers to absorb traditional methods of newborn care along with practical demonstrations, thereby boosting their confidence levels. Regular interaction and discussions by these caregivers provide mothers with practical suggestions and solutions in various aspects of newborn care. The joint family type facilitates obtaining collective information on effective parenting strategies and decision-making during certain newborn practices such as feeding, hygiene practices, and newborn health practices, reassuring the first-time mothers in the process.\n\nPrimiparous mothers from nuclear families presented a significant effect (p <0.05) on confidence levels concerning general newborn health as reported in Table 3. This might be because of the greater responsibility mothers in nuclear families may experience towards newborn care, without the presence of the extended family members. To overcome such challenges, mothers trained themselves to become competent in newborn care practices. The provision of N-CHFSEP in the current study may have addressed these maternal concerns by equipping them with monthly milestones, newborn care suggestions, and monthly warning signs, thereby causing an effect on their confidence levels. Hence it is important to consider the family structure when developing interventions aimed at enhancing maternal confidence in newborn care.\n\nMaternal occupations such as homemakers and others (government and private officials) were found to have a significant effect (p<0.05) on the confidence levels concerning newborn communication skills, feeding-swallowing skills and newborn health as reported in Table 3. Homemakers generally get opportunities to engage in interactions with their newborns thereby fostering newborn language development and communication skills. Their consistent presence at home provides opportunities for monitoring newborn care and interventions when required causing increased confidence levels among mothers pertaining to these skills. As reported in Table 3, only homemakers when compared to other occupations showed a significant effect (p<0.05) on newborn feeding-swallowing skills. Although being a homemaker is highly advantageous, there do exist challenges such as feeling isolated, lacking professional advice, and feeling financial constraints, making them less confident in newborn practice in the process. Primiparous mothers with government and private jobs may face unique challenges in balancing work with their caregiving duties. Access to resources such as government-sponsored healthcare programs or childcare services, could positively impact their ability to prioritize feeding skills development. The provision of N-CHFSEP, which involved comprehensive information on newborn caregiving skills might have complemented and enhanced the caregiving practices of both homemakers and government officials. In contrary studies have found no significant association between mothers' occupation and newborn care.40,41\n\nIt becomes important to obtain feedback (FQ Item 6) from primiparous mothers for a comprehensive understanding of the strengths and weaknesses of the developed N-CHFSEP. As per the feedback obtained (FQ- Item 6) from the participants of the current study, the N-CHFSEP provided mothers with additional information in various aspects regarding communication skills, emphasized the importance of hearing, and corrected misconceptions. Studies have found that feedback of educational programs has positive outcomes such as encouraging mothers to interact and read with their infants in a responsive manner. These mothers reported being willing to recommend the education program to others and apply the knowledge with their newborns at home (2). As per the feedback obtained (FQ- Item 6) from the participants of the current study, concerning newborn general health, the N-CHFSEP provided insights into newborn health, offering a comprehensive view of developmental timelines, and understanding the behaviours to be observed during their newborn development. A study on the NewBorn Class program reported that it benefitted approximately 58% of the mothers by providing comprehensive knowledge for first-time mothers, and providing information on medical topics such as feeding, diaper rash, and developmental skills (3). The mothers of the current study also demanded for additional information on fever management, troubleshooting lactation failure and its effect on the baby, details on avoidance of the type of feeds for the infant, and developmental aspects beyond 6 months. Furthermore, some mothers highlighted the need for the practical application of the information provided. They also suggested supplementing the N-CHFSEP through practical demonstrations to enhance their confidence levels in providing neonatal care. This feedback emphasizes the importance of practical learning experiences, suggesting hands-on demonstrations to be useful additions to future educational programs.\n\nAlthough the developed N-CHFSEP showed a significant positive change (pre and post-administration) in the attitude levels of the mothers, having a control group (mothers without receiving the intervention program) and comparing them to an experimental group (mothers receiving the intervention program) would have increased the validity of the tool. Additionally, the effectiveness of N-CHFSEP was determined immediately after the administration, leaving uncertainty about information retention up to 6 months post-intervention, which could be controlled for in future studies. Moreover, the study did not assess whether participants practically applied the knowledge gained from the N-CHFSEP in their daily caregiving routines, potentially limiting the effectiveness of the intervention. The N-CHFSEP included information on neonatal care from only two disciplines (SLP and Paediatrics), suggesting the possible inclusion of additional members (such as fathers, grandparents, lactation counsellors, psychologists, ASHA workers, nurses, etc.) in future studies to provide a more comprehensive understanding of various aspects of newborn health and development. The effectiveness of the N-CHFSEP could be enhanced by incorporating practical demonstrations or hands-on training sessions during administration which were among the demands by the primiparous mothers of the current study.\n\nWith the implementation of the N-CHFSEP in the current study, the primiparous mothers received a comprehensive education on various aspects of newborn skill development. The observed increase in confidence levels following N-CHFSEP suggested the program to effectively complement the mother's knowledge and understanding, thereby contributing to improved confidence and awareness regarding newborn care. This understanding is crucial for the implementation of comprehensive educational interventions addressing the specific needs of primiparous mothers as it may lead to enhanced maternal and infant health outcomes.\n\n\nEthics and consent\n\nThe study was approved by the Institutional Ethics Committee (IEC KMC MLR 03/2023/108) of Kasturba Medical College, Mangalore, Manipal Academy of Higher Education on 20.07.2023 and was registered under the Clinical Trials Registry of India (CTRI/2023/05/053109) on 25.05.2023. The researcher obtained written informed consent from the participants followed by their socio-demographic details.", "appendix": "Data availability\n\nName of the repository: Mendeley Data\n\nProject title: Estimating the efficacy of Newborn-Communication, Health, Feeding and Swallowing Education Program (N-CHFSEP) for primiparous mothers. 42\n\nhttps://data.mendeley.com/datasets/7c75ws94vn/2\n\nThis project contains the following underlying data:\n\n• DATA ENTRY SHEET.xlsx (includes data on the patient demographics, responses from pretest Attitude Questionnaire, posttest Attitude Questionnaire, and Feedback Questionnaire)\n\n• Read Me.txt (description to understand the variables in data files)\n\n• completed_CONSORT_checklist.docx (includes the CONSORT checklist)\n\nLicense: Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nNan Y, Zhang J, Nisar A, et al.: Professional support during the postpartum period: primiparous mothers’ views on professional services and their expectations, and barriers to utilizing professional help. 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Publisher Full Text\n\nKaruppannan A, Ramamoorthy T, Rammamoorthi A, et al.: Mother’s Knowledge on Child’s Developmental Milestones and Parenting Skills in Kanchipuram District, Tamilnadu-A Descriptive Cross Sectional Study [Internet]. International Journal of Health Sciences and Research. 2020; 10. Reference Source\n\nÇinar IÖ, Öztürk A: The Effect of Planned Baby Care Education Given to Primiparous Mothers on Maternal Attachment and Self-Confidence Levels. Health Care Women Int. 2014; 35(3): 320–333. PubMed Abstract \| Publisher Full Text\n\nKhresheh R, Suhaimat A, Jalamdeh F, et al.: The effect of a postnatal education and support program on breastfeeding among primiparous women: A randomized controlled trial. Int. J. Nurs. Stud. 2011 Sep; 48(9): 1058–1065. PubMed Abstract \| Publisher Full Text\n\nHuang KY, O’Brien Caughy M, Genevro JL, et al.: Maternal knowledge of child development and quality of parenting among White, African-American and Hispanic mothers. J. Appl. Dev. 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PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWong MS, Mou H, Chien WT: Effectiveness of educational and supportive intervention for primiparous women on breastfeeding related outcomes and breastfeeding self-efficacy: A systematic review and meta-analysis. Int. J. Nurs. Stud. 2021 May; 117: 103874. PubMed Abstract \| Publisher Full Text\n\nSingh B, Chawla G, Kaur M, et al.: Knowledge about Danger Signs in Neonates and Health Seeking Behaviour amongst Mothers Attending Tertiary Healthcare Centre in Punjab, India. J. Clin. Diagn. Res. 2021. Publisher Full Text\n\nThomas AB, Devi LD: A Study to Assess the Effectiveness of Structured Teaching Programme on knowledge regarding selected Newborn Danger Signs among Post-natal mothers in Jayanagar General Hospital, Bangalore, Karnataka. International Journal of Advances in Nursing Management. 2020; 8(1): 63. Publisher Full Text\n\nKumar A: Awareness and Attitude Regarding Breastfeeding and Immunization Practices Among Primigravida Attending a Tertiary Care Hospital in Southern India. J. Clin. Diagn. Res. 2015; 9: LC01–LC05. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nEluri S, Baliga BS, Rao SS, et al.: Can Flip-Chart Assisted Maternal Education Improve Essential New Born Care Knowledge and Skills? A Randomized Controlled Trial. Matern. Child Health J. 2022 Sep 6; 26(9): 1891–1906. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBen-Sasson A, Jacobs K, Ben-Sasson E: The feasibility of a crowd-based early developmental milestone tracking application. PLoS One. 2022 May 26; 17(5): e0268548. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBailey E, Nightingale S, Thomas N, et al.: First-time Mothers’ Understanding and Use of a Pregnancy and Parenting Mobile App (The Baby Buddy App): Qualitative Study Using Appreciative Inquiry. JMIR Mhealth Uhealth. 2022 Nov 21; 10(11): e32757. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMemon J, Holakouie-Naieni K, Majdzadeh R, et al.: Knowledge, attitude, and practice among mothers about newborn care in Sindh, Pakistan. BMC Pregnancy Childbirth. 2019 Dec 6; 19(1): 329. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nOuseph D, Kanthila J, Baliga S, et al.: Estimating the efficacy of Newborn-Communication, Health, Feeding and Swallowing Education Program (N-CHFSEP) for primiparous mothers. Mendeley Data. V2. Publisher Full Text" }	[ { "id": "303850", "date": "29 Jul 2024", "name": "shaimaa Mohamed Amin", "expertise": [ "Reviewer Expertise community health nursing" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear [editor ], I hope this message finds you well. I wanted to extend my sincere gratitude to you for sending me the article for review. I truly appreciate the opportunity to contribute to the process and offer my insights. I've gone through the article and I have some constructive feedback that I believe could enhance the overall quality and impact of the piece.\nTitle: Your research title is clear and informative, but it can be made more concise and engaging. Here are a few suggestions to refine and enhance the title: Evaluating the Efficacy of the Newborn Communication, Health, Feeding, and Swallowing Education Program (N-CHFSEP) for First-Time Mothers\n\nAssessing the Impact of the N-CHFSEP on Newborn Care Among Primiparous Mothers Effectiveness of the N-CHFSEP in Enhancing Newborn Care Skills for Primiparous Mothers\n\nAbstract\n\nBackground: The background section effectively outlines the problem that primiparous mothers face challenges during pregnancy and post-childbirth. However, the statement \"There is a lack of comprehensive educational programs for primiparous mothers on maternal functioning and newborn care\" could benefit from citation of existing literature to support this claim. Additionally, specifying what aspects of \"maternal functioning\" are included could provide clarity. Objectives: The objectives are clearly stated and logically divided into two main goals: development of tools (attitude questionnaire, education program, feedback questionnaire) and evaluation of the program's efficacy. This separation is clear and helpful for readers to understand the study’s aims. Methods: The methods section is concise but detailed enough to understand the study design. However, it could be improved by specifying the inclusion criteria more precisely (e.g., \"primiparous mothers without any obstetric history\" could specify what kind of history excludes participants). Additionally, mentioning the duration of the study and the specific content covered in the N-CHFSEP could provide more context. Results: The results section effectively communicates the main findings, highlighting the statistically significant increase in maternal confidence levels post-intervention. The use of both quantitative and qualitative analysis is a strength. However, the phrase \"a notable increase in the number of mothers (not all)\" is vague and could be more precise. For example, specifying the percentage of mothers who reported increased confidence would provide more concrete data. Additionally, discussing the specific sociodemographic factors in more detail would enhance understanding of their impact. Conclusions: The conclusions succinctly summarize the study's implications, emphasizing the program's effectiveness in enhancing maternal confidence. However, it would be beneficial to briefly mention any limitations of the study or suggest directions for future research to provide a more balanced view. Keywords: The keywords are relevant and cover the main topics of the study. However, adding keywords like \"confidence,\" \"maternal education,\" and \"program evaluation\" might improve the searchability of the study.\n\nIntroduction: The introduction provides a comprehensive overview of the challenges faced by primiparous mothers and underscores the importance of educational programs to support them. Here are some suggestions to refine and strengthen the introduction:\n\nClarity and Focus:\nThe introduction covers a broad range of issues and studies, which can make it somewhat dense. Consider focusing more sharply on the main problem and the gap your study aims to fill. For example:\nHighlight the specific challenges primiparous mothers face and how these impact newborn care. Clearly state the need for a comprehensive educational program that addresses these challenges.\n\nStructure:\nFirst Paragraph: Introduce the general context of pregnancy and childbirth, emphasizing the unique challenges for primiparous mothers. Second Paragraph: Discuss the importance of maternal confidence, knowledge, and attitudes, and their impact on newborn care. Third Paragraph: Present the specific gaps in current educational programs, citing key studies that demonstrate the need for comprehensive support. Fourth Paragraph: Highlight existing educational programs and their limitations, particularly focusing on the need for a holistic approach. Fifth Paragraph: Conclude by summarizing the need for your study and its objectives.\n\nCitations and Evidence:\nEnsure all claims are supported by citations. For example, when discussing the impact of maternal confidence or the effectiveness of various programs, provide specific references. Use consistent and current references to strengthen the credibility of your argument.\n\nFlow and Readability:\nImprove readability by breaking long sentences into shorter, more concise ones. Use transition phrases to connect ideas and ensure a smooth flow from one paragraph to the next.\n\nSpecific Suggestions:\nOpening Sentence: \"Pregnancy and childbirth represent significant milestones in a woman's life, permanently altering her identity and way of living in a continuous and dynamic manner.\" Second Sentence: \"Primiparous mothers (first-time mothers) face a wide range of emotions including joy, excitement, and anxiety, alongside overwhelming and stressful experiences such as routine newborn care, breastfeeding difficulties, lack of sleep, and physically taxing household duties.\" Importance of Maternal Confidence: \"Reduced levels of confidence in primiparous mothers compared to multiparous mothers negatively impact their ability to provide infant care.\" Developmental Milestones: \"Effective identification of developmental milestones by caregivers facilitates early interventions, improving overall health outcomes.\" Educational Programs: \"Although numerous educational programs exist, there is a lack of a holistic approach that comprehensively addresses newborn communication, feeding, swallowing, and general health.\"\n\nConclusion of Introduction:\nSummarize Gaps and Objectives: \"Despite the availability of various educational initiatives, there is a noticeable gap in comprehensive programs that address all critical areas of newborn development. This study aims to develop and validate a comprehensive educational program and assess its efficacy in enhancing maternal confidence and knowledge among primiparous mothers.\"\n\nMethods\n\nStudy Design and Ethics:\nClarity: This section is clear and provides essential information about the study design and ethical approvals. Detail: Including the registration number and ethical approval details adds credibility. Mentioning the adherence to the CONSORT checklist and Declaration of Helsinki is crucial.\nParticipants:\nClarity: The paragraph provides detailed demographic data which is good for understanding the sample population. Structure: Breaking this into two paragraphs might enhance readability - one for sample size calculation and the other for demographic details. Detail: Including the sample size formula and demographic breakdown is thorough and helpful.\nInclusion and Exclusion Criteria:\nClarity: The criteria are clearly listed, which helps in understanding the participant selection process. Structure: The criteria are clearly separated into inclusion and exclusion, making it easy to follow. Detail: Including the proficiency in English or Kannada is important for understanding participant communication abilities.\nProcedure: The present study was conducted in 2 phases. Phase 1 included the development of an (a) attitude questionnaire, (b) parent education program, and (3) feedback questionnaire; while Phase 2 included the administration of the questionnaires and the education program on the participants, followed by data analysis of the retrieved data.\nClarity: The procedure is outlined, indicating a clear structure to the study. Detail: Describing the phases helps in understanding the study's flow.\nDevelopment of Tools: a) Attitude questionnaire (AQ):\nClarity: The development process of the AQ is well-explained, detailing the domains and types of questions. Detail: Including specific item numbers and their domains adds precision.\nb) Parent Education Program : Clarity: The development process of the N-CHFSEP is described in detail.\nDetail: Mentioning the consultation with experts adds credibility.\nc) Feedback Questionnaire (FQ): Clarity: The development process of the FQ is clear and detailed.\nDetail: Including the types of questions adds precision. Discussion\n\nThe discussion section of this study provides a comprehensive analysis of the impact of the Newborn Communication, Hearing, Feeding, and Swallowing Education Program (N-CHFSEP) on the confidence levels of primiparous mothers, emphasizing key areas such as communication, feeding-swallowing skills, and newborn health. While the study effectively highlights the statistical significance of increased confidence post-intervention and relates these findings to previous research, it could benefit from a more concise presentation. The detailed breakdown of influencing variables (age, education, family type, and occupation) is insightful, yet the narrative occasionally becomes repetitive, potentially diluting the focus. Additionally, the discussion extensively references existing literature to contextualize findings, which is commendable, but a more balanced approach with critical reflections on the study's limitations, such as the lack of a control group and the short-term assessment of the intervention's impact, would enhance the overall analysis. The feedback from mothers and the suggestion for practical demonstrations underscore the need for a hands-on approach in educational programs, a point that could be more prominently integrated into the discussion. Overall, while the discussion is thorough and well-supported by data, a more streamlined and critically reflective narrative would strengthen its impact\nPlease address conclusion, limitations & implications of the study\n\nOnce again, thank you for entrusting me with this task. I look forward to our continued collaboration and to seeing the final version of the article. Warm regards, Shaimaa Mohamed Amin\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? No", "responses": [] }, { "id": "318054", "date": "03 Sep 2024", "name": "Amogh Verma", "expertise": [ "Reviewer Expertise Internal Medicine", "Pediatrics", "Allergy and Immunology", "Surgery and Emergency Medicine." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study evaluates the effectiveness of a tailored educational program, the Newborn-Communication, Health, Feeding, and Swallowing Education Program (N-CHFSEP), in enhancing the confidence of primiparous mothers in newborn care. The research addresses a significant gap in maternal education, particularly in the context of first-time mothers who face unique challenges in caring for their newborns. Strengths:\nRelevance and Impact: The study addresses a highly relevant topic in maternal and child health. The focus on primiparous mothers and the development of a comprehensive educational program is commendable, particularly in regions where such resources may be limited. Methodological Rigor: The development and validation of the study tools (Attitude Questionnaire, Feedback Questionnaire, and N-CHFSEP) are well-detailed and supported by content validation from experts in pediatrics and speech-language pathology. Statistically Significant Findings: The study presents statistically significant improvements in maternal confidence levels across communication, feeding-swallowing, and general health domains, which suggests that the N-CHFSEP is an effective intervention. Practical Implications: The study provides valuable insights for healthcare providers and policymakers, highlighting the importance of structured educational programs for new mothers.\nWeaknesses:\nStudy Design: The absence of a control group limits the ability to attribute the observed improvements in confidence levels solely to the N-CHFSEP intervention. This is a significant limitation that should be addressed in future studies. The single-arm pre-post study design, while valid for exploratory research, does not provide the level of rigor necessary to establish causality. Generalizability: The sample is limited to primiparous mothers in a specific region, and the exclusion of multiparous mothers may limit the generalizability of the findings to the broader population. Expanding the sample to include a more diverse demographic would strengthen the study. Short-term Assessment: The study measures outcomes immediately post-intervention, leaving questions about the long-term retention of knowledge and skills. A follow-up assessment at 6 months or beyond would provide a more comprehensive understanding of the program's sustained impact. Limited Qualitative Data: While quantitative data is well-represented, the qualitative feedback from participants is not fully explored. Incorporating more qualitative insights could provide a richer context to the statistical findings and highlight areas for improvement in the program.\nRecommendations for Publication:\nRevisions: I recommend that the authors address the limitations in their discussion section by clearly acknowledging the absence of a control group and the implications for the study's findings. Additionally, suggestions for future research should be included, particularly regarding long-term follow-up and expanding the sample population. Potential for Improvement: The study would benefit from a more in-depth analysis of the qualitative data collected, as this could provide valuable insights into the participants' experiences and the practical application of the program. Additionally, including recommendations for enhancing the program, such as integrating practical demonstrations, would be beneficial. Suitability for Indexing: Despite its limitations, the study contributes valuable insights into maternal education and has practical implications for improving maternal and infant health. I believe the manuscript is suitable for indexing with revisions. However, the authors should emphasize that this is a preliminary study, laying the groundwork for more rigorous future research.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] } ]	1	https://f1000research.com/articles/13-777
https://f1000research.com/articles/13-915/v1	09 Aug 24	{ "type": "Research Article", "title": "Publisher preferences for a journal transparency tool: A modified three-round Delphi study", "authors": [ "Jeremy Y. Ng", "Henry Liu", "Mehvish Masood", "Rubaina Farin", "Mireille Messih", "Amaya Perez", "IJsbrand Jan Aalbersberg", "Juan Alperin", "Gregory L. Bryson", "Qiuxia Chen", "Alan Ehrlich", "Alfonso Iorio", "Wim J. N. Meester", "John Willinsky", "Agnes Grudniewicz", "Erik Cobo", "Imogen Cranston", "Phaedra Eve Cress", "Julia Gunn", "R. Brian Haynes", "Bibi Sumera Keenoo", "Ana Marušić", "Eleanor-Rose Papas", "Alan Purvis", "João de Deus Barreto Segundo", "Pathiyil Ravi Shankar", "Pavel Stoev", "Josephine Weisflog", "Margaret Winker", "Kelly D. Cobey", "David Moher", "Henry Liu", "Mehvish Masood", "Rubaina Farin", "Mireille Messih", "Amaya Perez", "IJsbrand Jan Aalbersberg", "Juan Alperin", "Gregory L. Bryson", "Qiuxia Chen", "Alan Ehrlich", "Alfonso Iorio", "Wim J. N. Meester", "John Willinsky", "Agnes Grudniewicz", "Erik Cobo", "Imogen Cranston", "Phaedra Eve Cress", "Julia Gunn", "R. Brian Haynes", "Bibi Sumera Keenoo", "Ana Marušić", "Eleanor-Rose Papas", "Alan Purvis", "João de Deus Barreto Segundo", "Pathiyil Ravi Shankar", "Pavel Stoev", "Josephine Weisflog", "Margaret Winker" ], "abstract": "Background We propose the creation of a journal transparency tool (JTT), which will allow users to obtain information about a given scholarly journal’s operations and policies. We are obtaining preferences from different stakeholders to inform the development of this tool. This study aimed to identify the publishing community’s preferences for the JTT.\n\nMethods We conducted a modified three-round Delphi survey. Representatives from publishing houses and journal publishers were recruited through purposeful and snowball sampling. The first two Delphi rounds involved an online survey with items about JTT metrics and user features. During the third round, participants discussed and voted on JTT metric items that did not reach consensus after round 2 within a virtual consensus meeting. We defined consensus as 80% agreement to include or exclude an item in the JTT.\n\nResults Eighty-six participants completed the round 1 survey, and 43 participants (50% of round 1) completed the round 2 survey. In both rounds, respondents voted on JTT user feature and JTT metric item preferences and answered open-ended survey questions regarding the JTT. In round 3, a total of 21 participants discussed and voted on JTT metric items that did not reach consensus after round 2 during an online consensus group meeting. Fifteen out of 30 JTT metric items and none of the four JTT user feature items reached the 80% consensus threshold after all rounds of voting. Analysis of the round 3 online consensus group transcript resulted in two themes: ‘factors impacting support for JTT metrics’ and ‘suggestions for user clarity.’\n\nConclusions Participants suggested that the publishing community’s primary concerns for a JTT are to ensure that the tool is relevant, user-friendly, accessible, and equitable. The outcomes of this research will contribute to developing and refining the tool in accordance with publishing preferences.", "keywords": [ "health literacy", "scholarly publishing", "periodicals as topic", "publications", "ethics in publishing", "journal transparency tool" ], "content": "Introduction\n\nPeer-reviewed scholarly journals play a critical role in disseminating biomedical research. Scientific publications must be reported and disseminated according to best-practice standards to be of use to clinicians, researchers, patients, and others. For example, published research should be properly indexed and archived so that it can be found and preserved over time. Several calls have been made for academic journals to become more transparent, including initiatives to open the peer-review process and to make study data publicly available. 1 , 2 This project is part of a program of research being conducted to establish user needs and preferences for a journal transparency tool (JTT) within the biomedical sciences. A JTT, as we envision it, could be an automated tool to provide users with information about a given journal’s transparency practices. This in turn could help users decide on the journal’s credibility and whether to interact with it (e.g., read and cite articles published in it, submit manuscripts to it). The tool is expected to add value by providing stakeholders with information about how a journal operates and which best practices it meets. The benefit of this tool may be most obvious for producers of research looking to publish, as well as readers of research looking to consume evidence to help inform healthcare-related decisions. Additionally, this tool may be of great value to new researchers that are being introduced to the research community and individuals in the profession of evaluating, publishing, and indexing research.\n\nWe have identified three types of stakeholders whose preferences would be important to consider when developing the JTT: (1) publishers; (2) researchers and clinicians 3 ; and (3) patients. 4 Here, we focus on the needs and preferences of group 1, namely those working in the publishing industry, including full-text publishers, discovery services (e.g., Web of Science, Scopus, PubMed), preprint servers, self-published journals, university-published journals, and reference managers. Publishers are intimately involved in the dissemination of research. Publishing houses have a duty to support the journals that operate under their umbrella. In contrast, editors have responsibility for manuscript evaluation, including peer review, revisions, selection of manuscripts for publication, and editorial content. For the purposes of this analysis, editors are included under the umbrella term of ‘publishers.’ The aim of this study was to identify preferences for a JTT within the international publisher community. This study is descriptive, and we had no a priori hypotheses.\n\nWe conducted a modified three-round Delphi survey with a synchronous online consensus exercise to determine publishing community preferences. The Delphi method is a means of structuring communication between experts around a complex issue to make a collective judgment on a given topic. It is a social science technique but has been applied in other settings, including healthcare environments (see Refs. 5, 6 for examples). The Delphi approach allows for effective communication by individual group members and the group as a whole. 7 It limits direct confrontation between individuals, fosters independent thought by the experts involved, and aims to achieve consensus within a group without the need for a leader. 8 By using the Delphi method, we established the international English-speaking publisher communities’ consensus view on what should be included in a JTT, which will contribute to meaningfully situating the tool within the scholarly landscape and help to ensure that the most relevant inputs are used to build the tool.\n\n\nMethods\n\nWe obtained research ethics board approval for the proposed study from the Ottawa Health Science Network Research Ethics Board (REB ID# 20220132) on April 06, 2022. The final protocol was registered on April 28, 2022, using the Open Science Framework (OSF) 9 at https://osf.io/fsmzc. Anonymized voting data and participant responses from rounds 1 and 2, along with the round 3 thematic analysis, were shared publicly using OSF at https://osf.io/8v63x/. We followed the ACcurate COnsensus Reporting Document (ACCORD) checklist in reporting our findings. 10\n\nWe conducted a modified three-round Delphi study, similar to the approach used in a previously published study. 11 Diamond et al. have proposed key methodologic criteria to report in publications of Delphi studies, 12 which were used to inform the present study. The first two rounds of the Delphi involved completing an online independent survey using SurveyLet. 13 The third round consisted of a virtual consensus group meeting with participants from earlier rounds.\n\nParticipants were recruited from a diverse group of academic publishing houses. Purposeful sampling based on this list of potential participants and snowball sampling were used to increase representation and target outreach/invitations. To be eligible, participants needed to be fluent in English. Representatives were invited from publishing houses to participate in our Delphi study using a study advertisement and standardized recruitment script (see https://osf.io/6r3np). Members of the public, patients, or carers were not invited for recruitment in any of the three rounds. Participants were not provided financial compensation for taking part in the study, but those who agreed to participate in the third round –that is, the virtual consensus group meeting– were invited to co-author the present research report.\n\nOur advertisement and recruitment script (see https://osf.io/6r3np) were disseminated (IJA, AM, MW) to the publisher community via two large publishing societies: the Open Access Scholarly Publishing Association (OASPA) 14 and the International Association of Scientific, Technical, and Medical Publishers (STM), 15 as well as the World Association of Medical Editors (WAME) (https://www.wame.org/). OASPA provides an international community for open-access publishing and seeks to advance open-access publishing solutions. STM is also global in reach, with more than 140 members, which publish nearly 66% of all journal articles and work to advance trusted research worldwide. WAME is an international, nonprofit voluntary association of editors of peer-reviewed medical journals that seeks to foster international cooperation among and the education of medical journal editors. OASPA, STM, and WAME assisted with recruitment by targeting and sharing the invitation via email with their members. In addition, a member of the research team (JYN) extracted all journals catalogued in Directory of Open Access Journals (DOAJ) and used the RAND function 16 on Microsoft Excel to select a random sample of 750 journals. Publishers of these selected journals, which were manually checked to ensure they met the eligibility criteria (RF, MMessih, AP), were also sent our advertisement and recruitment script for participation in the study. Individuals interested in participating were redirected from the invitation to an online survey where they were provided with more information about the study, including participant inclusion criteria, and asked to complete an online informed consent form prior to proceeding.\n\nRound 1\n\nParticipants were asked to complete an online survey (see https://osf.io/6r3np), which asked about their needs and preferences for a JTT. This survey was purpose-built for the study and included 30 items that addressed the following: (1) participant demographic characteristics (e.g., employment information, years working in the publishing industry, and areas of expertise); (2) JTT user features (i.e., how the JTT user interface should look, how data automation can facilitate the metrics the JTT reports, and how to disseminate a completed JTT to the community and track its uptake); and (3) JTT metrics (i.e., metrics that users will access about each individual journal on the JTT to make informed decisions regarding the use of that journal for clinical or research purposes). These survey items were informed and chosen by a team of experts in journalology (JYN, KDC, DM). Survey items regarding JTT metrics were posed in a question format, with responses provided on a 9-point Likert scale 17 with endpoints labeled ‘strongly agree’ and ‘strongly disagree.’ Participants were provided with a textbox to provide any comments on each item. Respondents also had the opportunity to suggest additional items for the JTT for participants to consider in round 2 of the survey. This survey was pilot tested by a group of researchers who were not part of the study prior to administration.\n\nParticipants were sent the survey on May 23, 2022, followed by two reminder emails, each spaced 1 week apart. Responses to the round 1 Delphi survey were collated, with all information presented in aggregate. For items assessing publishers’ needs and preferences for a JTT, we defined consensus on an item as 80% agreement to include or exclude an item. This cutoff was selected based on findings from a systematic review of Delphi studies. 12 In our design, all items with 80% of responses in the top third (7-9) or bottom third (1-3) of our 9-point scale were considered to have reached consensus for inclusion or exclusion. Once items met consensus, they were not included in subsequent rounds. Furthermore, open-ended survey responses from round 1 were analyzed to provide feedback and incorporate any new suggestions for round 2 participants.\n\nRound 2\n\nParticipants who completed round 1 of the survey were emailed an invitation and link to the complete round 2 of the Delphi survey. Members of the research team (JYN, HL, DM, KDC) created round 2 based on the responses obtained in round 1. It contained all survey items in round 1 that did not reach consensus, as well as any new items or clarifications required based on comments participants made in round 1. Comments provided by individual participants to explain responses to items from the round 1 survey were presented back to all participants for consideration as they re-voted on each item. Participants were also provided the opportunity to suggest new JTT items for respondents in Round 3 to vote on.\n\nParticipants were provided with the percentage of scores on each third of the scale for each item not in consensus from round 1, along with a collated and de-identified version of any comments made on each item. Participants were sent the survey on March 6, 2023, followed by two reminder emails, each spaced 1 week apart. We processed responses resulting from round 2 and defined consensus in the same way as in round 1.\n\nRound 3\n\nWe invited all respondents from round 1 to take part in an online consensus group meeting. If unavailable, an option was provided to participants to send another representative from their publishing organization to take part in round 3 in their place. Participants met virtually on Zoom on December 6, 2023, to establish consensus on any remaining JTT metric items from rounds 1 and 2 of the Delphi. The virtual consensus meeting was moderated by a steering committee with an expertise in journalology (JYN, JA, GLB, QC, WJNM, JW, KDC, DM) to ensure that participants could express their views on any outstanding items while ensuring that the focus of the meeting and goals of final consensus on items were met.\n\nWe provided all participants with a summary of the results obtained in round 2 approximately one week prior to the meeting. This summary listed all the JTT metrics that did and did not reach consensus. Items that did not reach consensus were presented with the number and percentage of round 2 participants that identified that specific JTT metric as ‘unimportant’ (1-3 points), ‘neutral’ (4-6 points), and ‘important’ (7-9 points) for inclusion on the tool on a 9-point scale. Participants voted through the anonymous polling feature on the Zoom platform, where they were provided three options to select from during the voting of each item: (1) support for inclusion on the JTT, (2) support for exclusion on the JTT, or (3) abstain from voting. The group’s voting results were presented to participants immediately following receipt of all responses. Members of the steering committee did not vote during round 3, and a separate research member (HL) took field notes during the session.\n\nWe report the number of participants that completed each round of the Delphi and their basic demographic characteristics using frequencies and percentages. Data for each round of the Delphi was analyzed successively and presented independently. Quantitative items are presented using frequencies and percentages. For each survey item assessing needs and preferences for the JTT, we indicated whether consensus was reached and, if so, at what round.\n\nOpen-question survey responses from rounds 1 and 2 were analyzed using a thematic content analysis. 18 Two members of the research team (JYN, HL) aggregated and independently coded responses. Themes were confirmed through multiple iterative meetings between research members (JYN, HL), with all items reaching consensus through discussion. Similarly, for the round 3 online consensus group, an automated Zoom transcript, which was reviewed for accuracy (MMasood), was used to conduct a thematic content analysis. 18 One member of the research team (MMasood) coded, combined, and uploaded online consensus group notes into Microsoft Excel and established themes based on the codes. Two members of the research team (JYN, MMasood) subsequently discussed the generated themes to confirm their accuracy and relevance.\n\n\nResults\n\nChallenges with gaining a sufficient participant sample size led to two deviations from the protocol. First, within round 1, additional participants were recruited from a random sample of 750 journals extracted from DOAJ. Similarly, to increase the sample size, participants in round 3 were recruited from all respondents from round 1, rather than from a random, stratified sample of respondents (see Table 1 for participant demographic characteristics).\n\nTime and resource constraints also resulted in additional changes to the round 3 online consensus group. First, round 3 was conducted within a single day as opposed to two half-days to accommodate participant availability. Second, JTT user features (i.e., preferences for a website or API interface, fee-for-usage, the use of automation, and registration for access on the tool; see Table 2) and JTT metric items (see Table 3) that did not reach consensus in round 2, along with novel JTT metrics suggested by round 2 participants, were originally intended to be discussed and voted in round 3. Instead, only JTT metrics items that did not reach consensus in round 2 (see Table 3 for items) were discussed and voted on within round 3.\n\na Round 1 and 2 items were scored on a 9-point scale, where 1 to 3 points were categorized as ‘unimportant,’ 4 to 7 points were categorized as ‘neutral,’ and 7 to 9 points were categorized as ‘important’ for inclusion within the tool.\n\nParticipants\n\nA total of 86 participants completed the round 1 survey (see Table 1 for participant demographic characteristics). Respondents voted on JTT user feature (Table 2) and JTT metric item (Table 3) preferences and answered open-ended survey questions regarding the JTT. Please view the following link for complete round 1 responses: https://osf.io/92zh8.\n\nParticipants had less than 1 year (n = 1, 1.2%), 1 to 3 years (n = 10, 11.6%), 4 to 10 years (n = 34, 39.5%), 11 to 20 years (n = 21, 24.4%), and over 20 years (n = 20, 23.3%) of experience working in the publishing industry, with most being involved as an editor and/or with completing editorial tasks (n = 47, 55.3%). Editorial processes/peer review (n = 72, 81.8%), the publication process (n = 68, 77.3%), and open access (n = 64, 72.7%) were the top three areas of expertise in publishing that respondents identified with. Participants worked with over 70 international publishers/publishing organizations at the time of the study (see https://osf.io/92zh8 for the complete, unedited list of institutions).\n\nJTT user features\n\nParticipants voted on four JTT user feature items in round 1 (Table 2). None of the JTT user feature items reached the 80% consensus threshold after both rounds of voting. Participants provided the most support for: hosting the JTT on a website over an application programming interface (API)/browser plugin interface (n = 51, 58.0%); not paying to use the tool (n = 52, 61.2%); and fully automating the JTT (n = 41, 48.2%). The use of registration to access the JTT platform was contentious, with roughly equal proportions of participants being in support (n = 33, 38.8%), neutral (n = 22, 25.9%), and opposed to its use (n = 30, 35.3%). Open-survey responses regarding the JTT user format suggested that participants were predominantly concerned with ensuring that the JTT will be user-friendly and accessible.\n\nJTT metrics\n\nOf the 17 JTT metric items that participants voted on within round 1, five reached consensus (Table 3). The following items were agreed upon as ‘important’ to include in the JTT on a 9-point scale: a metric that reports whether (1) the journal describes its approach to publication ethics or not; (2) the journal editors are listed or not; (3) the journal uses fake digital object identifiers (DOIs) or not; (4) the journal reports misleading scholarly metrics or not; and (5) there is verifiable contact information or not.\n\nParticipants suggested seven novel JTT metrics to vote on, including metrics that report: (1) whether the journal has any article submission or processing fees and information about the journal’s funding model; (2) the journal’s citation metrics; (3) the journal’s policies surrounding equity, diversity, and inclusion; (4) the journal’s policies on retractions/corrections; (5) the journal publisher’s size and how the JTT’s evaluation may negatively affect smaller publishers just by virtue of their size; (6) the journal’s policies regarding reporting ethics, funding, and conflicts of interest; and (7) the journal’s peer review model and metrics. All seven JTT metrics were added in for participants to vote for in round 2. Within open-ended survey responses, participants also raised concerns about how ‘transparency’ is defined by the tool and how metric scoring may negatively affect smaller publishers/journals.\n\nParticipants\n\nForty-three (50% of round 1) participants completed the round 2 survey. Respondents voted on JTT metric and user feature items that did not reach consensus in round 1, as well as any additional items suggested by participants in round 1 (see Table 3 notes for newly added items). Please view the following link for complete round 2 responses: https://osf.io/nh6cv.\n\nMost respondents had more than 4 years of experience working in the publishing industry (n = 39, 90.7%). Similar to round 1, most participants were involved as an editor and/or completed editorial tasks (n = 26, 60.5%), and the top three areas of expertise within publishing participants identified were editorial processes/peer review (n = 38, 88.4%), the publication process (n = 35, 81.4%), and open access (n = 34, 79.1%). At the time of the study, participants in this round worked for 30 international publishers/publishing organizations (see https://osf.io/nh6cv for the complete, unedited list of institutions).\n\nJTT user features\n\nIn round 2, participants voted on four JTT user features (Table 2). While none of the items reached the 80% consensus threshold, respondents displayed similar voting preferences to round 1. Most participants supported hosting the JTT on a website over an API/browser plugin interface (n = 33, 76.7%), not paying to use the tool (n = 32, 76.2%), and fully automating the JTT (n = 24, 55.8%). Furthermore, similar to round 1, the use of registration to access the JTT platform was contentious, with roughly equal proportions of participants being in support (n = 17, 39.5%), neutral (n = 10, 23.3%), and opposed to (n = 16, 37.2%) its use. Open-survey responses regarding the JTT user format suggested that participants were predominantly concerned with ensuring that the JTT would be user-friendly, easy to understand, and concise.\n\nJTT metrics\n\nIn round 2, participants voted on their preferences regarding 19 JTT metric items (12 metric items that did not reach consensus in round 1 and seven novel items added based on round 1 responses). Of these 19 items, four met the 80% consensus threshold. Participants found the inclusion of the following items to be ‘important’ on a 9-point scale: a metric reporting (1) the journal’s policies regarding reporting ethics, funding, and conflicts of interest; (2) the journal’s policies on retractions/corrections; (3) the journal’s peer review model and metrics; and (4) whether the journal uses DOIs or not (Table 3).\n\nIn open-ended survey responses, participants suggested eight novel JTT metrics to include for voting (see https://osf.io/nh6cv for the complete list). These new items were not voted on within round 3 due to time and resource constraints. Participants also suggested that the JTT metric scoring strategy should be openly shared to provide transparency and allow users to understand how metrics are evaluated in the tool’s assessment process. Furthermore, similar to round 1, participants raised concerns with how ‘transparency’ is defined. They added that the JTT should adopt a widely recognized definition of ‘transparency’ to ensure a clear understanding of the concept and its application within the tool.\n\nParticipants\n\nIn round 3, 21 participants discussed and voted on JTT metric items that did not reach consensus after round 2 (Table 3) within an online consensus group meeting. Specifically, round 3 participants included EC, IC, PEC, JG, RBH, BSK, AM, EP, AP, JDBS, PRS, PS, JW, MW, and seven other publishers. Demographic characteristics were not collected for round 3 participants.\n\nJTT user features\n\nIn round 3, JTT user feature items that did not meet consensus in round 2 were not discussed nor voted on due to time and resource constraints.\n\nJTT metrics\n\nDuring round 3, participants discussed and voted on the inclusion of JTT metrics within an online group meeting. There were 15 items that had not reached consensus in round 2. After discussing each item, two individual items were modified to be expanded into two items each, resulting in four items in total, and two novel items were added for voting (see notes on modifications made in Table 3). With these revisions, participants ultimately voted on 19 JTT metric items in round 3.\n\nOf the 19 JTT metric items voted on in round 3, six met the 80% consensus threshold. Participants supported the inclusion of four items: a metric (1) reporting whether the journal is a member of COPE or not; (2) reporting whether the journal has any article submission or processing fees; (3) reporting whether the journal uses ORCIDs or not; and (4) reporting whether the journal is listed in the DOAJ or not. Participants supported the exclusion of two items: (1) an option for the JTT to collect/share journal incidents; and (2) a metric reporting whether the written content presented on the website is clear or not. In total, 15 out of the 30 JTT metrics reached consensus after all three rounds of voting (see Table 4 for the complete list of consensus items).\n\na Round 1 and 2 items were scored on a 9-point scale, where 1 to 3 points were categorized as ‘unimportant,’ 4 to 7 points were categorized as ‘neutral,’ and 7 to 9 points were categorized as ‘important’ for inclusion within the tool.\n\nA thematic content analysis 18 of the online group meeting transcripts resulted in two themes (see https://osf.io/978vs for the thematic analysis and Table 5 for a summary of the themes). First, several factors influenced the support individuals had for JTT metrics. This included how relevant the metric was to transparency and open practices; if the information gathered by the metric was already captured within another one; and how challenging it would be to gain membership for that metric when applicable (e.g., to be indexed on DOAJ). Concerns were raised within multiple rounds regarding how certain metrics could be exclusionary towards journals (e.g., small publishers) based on selection criteria that are not related to adherence to transparency and open practices (e.g., language, costs, geographic location). For items that reached consensus for exclusion in round 3, the primary issue raised by participants was the inability to objectively define and evaluate the relevant metrics using a clear criterion on the JTT. Within the second theme, participants provided suggestions to increase user clarity. Respondents stated that, with each JTT metric, users should be provided clear descriptions of what the metric is, how it is measured on the JTT, and potential biases that may be associated with the metric. Further, participants suggested that the naming of the JTT and its components should be clear and accurate. Some respondents stated that the tool should be renamed (i.e., the tool should not be called the ‘Journal Transparency Tool’) to increase clarity, but alternative names were not proposed.\n\na P refers to participant ID.\n\n\nDiscussion\n\nThe aim of this three-round Delphi study was to determine the needs and preferences of the publishing community for a JTT. A total of 86 and 43 participants completed an online survey in rounds 1 and 2, respectively (see Table 1 for demographic information). In round 3, 21 participants discussed and voted on JTT items that did not reach consensus after round 2 within an online consensus group meeting. After all rounds of voting, none of the four JTT user feature item preferences obtained consensus (Table 2). However, 15 out of a total of 30 JTT metric items (Table 3) reached the 80% consensus threshold (see Table 4 for the full list of consensus items). An analysis of the round 3 online group transcript resulted in two themes: ‘factors impacting support for JTT metrics’ and ‘suggestions for user clarity’ (Table 5).\n\nEnsuring the tool will be accessible and easy-to-use appeared to be the primary priority for participants. Several suggestions were provided to ensure that the tool has these properties. First, participants suggested that JTT metrics should have clear descriptions of what the metric is and what it is intended to measure. Further, while none of the JTT user features reached consensus, respondents within open survey questions emphasized that user features (e.g., the tool’s browser interface, the use of registration to access the tool) should be accessible through a reliable and user-friendly platform and that information on the tool should be presented concisely in easily digestible formats. Finally, participants suggested that the naming of the tool itself and tool components should be clear and accurate. All these suggestions will be considered during the implementation of the tool.\n\nParticipants also appeared to be concerned about the tool’s adherence to transparency. Specifically, with there being multiple ways to conceptualize transparency and open practices within biomedical research, 19 – 21 participants raised concerns with how ‘transparency’ would be defined and implemented on the JTT. In addition, respondents suggested that the JTT scoring strategy should be shared openly to increase transparency and allow users to understand how metrics are weighted/evaluated in the tool’s assessment process. In response to this feedback, we will adopt a widely recognized definition of ‘transparency’ on the JTT to ensure a clear understanding of the concept and its application within the tool. Similarly, the JTT scoring system for metric evaluation will be readily available for users to access and understand on the tool itself.\n\nConcerns that the JTT may increase inequity within the international scientific community were also raised by several participants. Specifically, respondents in all rounds indicated that certain publishers (e.g., publishers from low-income countries, and non-English language journals) may not be able to obtain ‘high’ scores on JTT metrics due to barriers related to costs, language, and/or geographic location. These journals, which already face barriers to engagement, 22 , 23 may consequently be penalized due to the JTT scoring system and lose readership despite not engaging in suboptimal transparency and open practices. To respond to these concerns, we will actively work on mitigating biases associated with the tool. This may include, but is not limited to, translating sections of the JTT to reduce language barriers and/or adding informative descriptive labels to notify users about biases associated with JTT metrics. Community stakeholders will also be asked about potential biases associated with the JTT’s scoring system during iterative consultations throughout the timeline of the tool’s development.\n\nThis study allowed us to establish publishing community preferences for the JTT and represents one study of a three-part initiative to determine the needs and preferences of stakeholder groups (i.e., patients, 4 researchers/clinicians, 3 and publishers) for the JTT. Considering the needs of the publishing community in our design of the JTT will help to ensure the tool we develop resonates with the publisher community and fulfills needs that they identify. The next phase of development will require integrating preferences from all stakeholder groups and developing the tool for use. Ultimately, some items that reached consensus may not be possible to include depending on how preferences between different stakeholders correspond with each other and decisions the team will make regarding user features (e.g., if we fully automate the tool, some metrics may not lend well to automation). We anticipate iterative consultation with the community as we work to develop the JTT that best meets users’ needs.\n\nThis study has several strengths. First, the participant sample included a heterogeneous and diverse group of publishers that represented over 70 international institutions (see https://osf.io/nh6cv for the complete list of institutions). Further, the use of an open invitation to participate for all publishers allowed us to reduce the potential for bias that would come if we had approached individual publishers and/or used a single sampling approach. Another strength of this Delphi study is the use of a cross-sectional survey and an online consensus group to determine participant preferences. While the survey identified broad trends in journal preferences, the online consensus group allowed us to determine the specific motivations behind why participants provided support or opposition to survey items. Conversely, one weakness of the present analysis is that we only included participants fluent in the English language, so our findings may not be representative of individuals who do not publish in English. 24\n\n\nConclusion\n\nThis study aimed to identify the preferences of the publishing community for a JTT. We conducted a three-round modified Delphi with publishers that were recruited through purposeful and snowball sampling. The first two Delphi rounds involved an online survey, and the third round occurred through an online consensus group discussion. After all rounds of voting, fifteen out of 30 JTT metric items, but none of the four JTT user feature items reached consensus. Participants suggested that their primary concerns for a JTT are to ensure that it is relevant, user-friendly, accessible, and equitable. Results from this analysis will be used to inform the development of the JTT to help enable and sustain robust transparency and open practices within the scientific community.\n\n\nEthical considerations\n\nResearch ethics approval was obtained from the Ottawa Health Science Network Research Ethics Board (OSHN-REB#: 20220132-01H) on April 06, 2022. The final protocol was registered on the Open Science Framework (OSF) and can be found at https://osf.io/ur67d. Participants provided implied consent to participate during three rounds of the study, as approved by the aforementioned REB with this study being deemed as having minimal risk. This study was conducted in adherence with the Declaration of Helsinki.", "appendix": "Data availability\n\nOpen Science Framework: Publisher Preferences for a Journal Transparency Tool: A Delphi Study, https://doi.org/10.17605/OSF.IO/8V63X. 25\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nWe followed the ACcurate COnsensus Reporting Document (ACCORD) checklist in reporting our findings.\n\n\nAcknowledgements\n\nWe acknowledge Claire Redhead and Jose Florencio Lapena Jr. for their assistance in recruiting participants from OASPA and WAME, respectively. We acknowledge Elisa De Ranieri, Joan Marsh, and Frontiers Media for their aid and participation in the online consensus group meeting.\n\n\nReferences\n\nLee CJ, Moher D: Promote scientific integrity via journal peer review data. Science. 2017; 357: 256–257. PubMed Abstract \| Publisher Full Text\n\nPrager EM, Chambers KE, Plotkin JL, et al.: Improving transparency and scientific rigor in academic publishing. J. Neurosci. Res. 2019; 97: 377–390. PubMed Abstract \| Publisher Full Text\n\nNg JY, Moher D, Ehrlich A, et al.: Researcher and Clinician Preferences for a Journal Transparency Tool: A Mixed-Methods Survey and Focus Group Study.2023. Publisher Full Text\n\nRicketts A, Lalu MM, Proulx L, et al.: Establishing Patient Perceptions and Preferences for a Journal Authenticator Tool To Support Health Literacy: A Mixed-Methods Survey and Focus Group Study. In Review.2021. Publisher Full Text\n\nPenciner R, Langhan T, Lee R, et al.: Using a Delphi process to establish consensus on emergency medicine clerkship competencies. Med. Teach. 2011; 33: e333–e339. PubMed Abstract \| Publisher Full Text\n\nFleuren M, Wiefferink K, Paulussen T: Determinants of innovation within health care organizations: Literature review and Delphi study. Int. J. Qual. Health Care. 2004; 16: 107–123. Publisher Full Text\n\nLinstone HA, Turoff M: Delphi: A brief look backward and forward. Technol. Forecast. Soc. Change. 2011; 78: 1712–1719. Publisher Full Text\n\nDalkey N, Helmer O: An Experimental Application of the DELPHI Method to the Use of Experts. Manag. Sci. 1963; 9: 458–467. Publisher Full Text\n\nOpen Science Framework (OSF). Reference Source\n\nGattrell WT, Logullo P, van Zuuren EJ , et al.: ACCORD (ACcurate COnsensus Reporting Document): A reporting guideline for consensus methods in biomedicine developed via a modified Delphi. PLoS Med. 2024; 21: e1004326. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCukier S, Lalu M, Bryson GL, et al.: Defining predatory journals and responding to the threat they pose: a modified Delphi consensus process. BMJ Open. 2020; 10: e035561. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nDiamond IR, Grant RC, Feldman BM, et al.: Defining consensus: A systematic review recommends methodologic criteria for reporting of Delphi studies. J. Clin. Epidemiol. 2014; 67: 401–409. PubMed Abstract \| Publisher Full Text\n\nSurveyLet. Reference Source\n\nOpen Access Scholarly Publishers Association (OASPA): Reference Source\n\nSTM: (accessed February 4, 2024). Reference Source\n\nRAND function: Microsoft.Reference Source\n\nJebb AT, Ng V, Tay L: A Review of Key Likert Scale Development Advances: 1995–2019. Front. Psychol. 2021; 12: 12. Publisher Full Text\n\nJoffe H, Yardley L: Research Methods for Clinical and Health Psychology. Content Themat. Anal. 2003; 56–68.\n\nCambridge Core: Transparency and Openness. (accessed March 13, 2024). Reference Source\n\nThe University of Manchester: Research transparency. (accessed March 13, 2024). Reference Source\n\nMcVay MA, Conroy DE: Transparency and openness in behavioral medicine research. Transl. Behav. Med. 2019; 11: 287–290. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKhelifa R, Amano T, Nuñez MA: A solution for breaking the language barrier. Trends Ecol. Evol. 2022; 37: 109–112. PubMed Abstract \| Publisher Full Text\n\nShumba CS, Lusambili AM: Not enough traction: Barriers that aspiring researchers from low- and middle-income countries face in global health research. J. Glob. Health Econ. Policy. 2021; 1. Publisher Full Text\n\nKhanna S, Ball J, Alperin JP, et al.: Recalibrating the scope of scholarly publishing: A modest step in a vast decolonization process. Quant. Sci. Stud. 2022; 3: 912–930. Publisher Full Text\n\nNg JY, Moher D, Aalbersberg IJ, et al.: Publisher Preferences for a Journal Transparency Tool: A Delphi Study. OSF. 2024. Publisher Full Text" }	[ { "id": "313617", "date": "27 Aug 2024", "name": "Andreas Nishikawa-Pacher", "expertise": [ "Reviewer Expertise meta-science" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for inviting me to review this document. It reports about a survey of publishers' wishes regarding what a 'journal transparency tool' should entail. The document describes the three-round Delphi survey in minute detail; it all seems plausible and honest, and the whole project seems to aim for a platform that will be useful for many scholars, including meta-scientists. (I personally would be delighted if there was a reliable, up-to-date platform that would tell me which journals publish registered reports!)\nThere is not much to criticize. the one thing that seemed missing was the availability of machine-readable, structured data of the survey results (e.g., in a CSV or Excel format), given that one of the pre-formulated questions of this peer review report is whether \"all the source data underlying the results available to ensure full reproducibility\". In addition, I think the abstract's \"Results\" section would be more interesting if it was not mainly about numbers, but rather about the contents of the survey outcome. Finally, in the final section, announcing a definition of 'transparency' that the authors plan to use would have been interesting as well (rather than simply to state that some kind of agreeable definition will be used).\nOther than that, there is only one aspect that I would raise. Namely, the whole report seems to mainly revolve around the authors' very own project. I would have expected, especially in the Introduction and the Discussion, a much more broader 'horizontal' view with regards to similar efforts that may be or may have been underway.\n\nFor instance, there used to be the \"Journal Observatory\" from a mainly Dutch team at https://www.journalobservatory.org/prototype/ -- or the \"Platform for Responsible Editorial Policies\" (PREP [2]) and related initiatives (in fact, the latter's website has a \"related initiatives\" section at https://www.responsiblejournals.org/relatedinitiatives). What are the project's similarities and differences with regards to that? There are also less comprehensive and more granular, single-issue-focused efforts of analyzing scholarly journals which may merit a discussion. They may address something highly specific, such as a call for journals to harmonize reporting standards of radiation dosimetry [1], or they may be more general, such as my dataset on journals' Twitter accounts [3] . Is it intended to do a survey of such all-discipline-encompassing journal-level initiatives to see which of them can be integrated into such a JTT tool?\nSpeaking of which -- by \"which\" I refer only partly to my self-citation (though another will come soon), instead I rather mean the \"bottom-up\" data collection undertaken by researchers external to the publishing industry -- the fact that this project may seem to operate automatically makes me wonder to what extent it is possible to enact such an automation with regards to many of the indicators, such as the use of fake DOIs, the misleading metrics, the open peer reviews, the availability of verifiable contact information, or the information about the journals' funding model. Is not the majority of the indicators listed in Table 3 impossible to fetch with full automation? This observation does prompt me to ask whether the project expects publishers themselves to provide the data to the JTT, or whether the information are to be scraped in a different way (and this is what leads me to the next self-citation that the beginning of this paragraph anticipated, namely my \"Open Editors\" project which used webscraping to collect data about editors from thousands of journals [4]). Can one reasonably expect publishers themselves to provide data in a standardized way? With my Open Editors project, I thought that the answer may be no... at least for now. It's too much of a huge coordination issue. With 20+ indicators other than the listing of editors, the problem is even multiplied. And if one believes that publishers themselves will be so observant & virtuous to provide all the data that will be asked from them, then what would be the additional costs imposed upon the companies to do that on a regular basis, and who would ultimately pay for that?\nThese are just some practical aspects that I would think of which merits some discussion, I believe. They are not central to the actual Delphi survey, but they would 'frame' the report by differentiating itself from relevant other projects, by showing what similar initiatives exist, and by weighing the pros and cons in a more in-depth manner.\nOther than that, I believe the project offers a laudable goal, and it will be interesting to witness its further steps.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "12724", "date": "31 Jan 2025", "name": "Jeremy Ng", "role": "Author Response", "response": "We kindly thank the reviewer for providing their feedback on our manuscript. The results section of the abstract principally focused on percentages of items that reached consensus due to this Delphi study’s purpose and design, which aimed to determine publisher preferences on the Journal Transparency Tool (JTT). As with most survey questions being quantitative in nature, we believe these numerical findings to be the most relevant study results. With regards to declaring a definition of ‘transparency’, it was noted within the results that participants had raised concerns over how transparency would be defined, and we acknowledge that transparency in research can encompass different dimensions of research practices. As the studies identifying preferences for the development of the JTT involves three stakeholder groups of publishers, researchers and clinicians, and patients, we believe there is merit in determining a definition of transparency for the JTT on a later date, based on findings of all stakeholder groups. Consequently, a definition of transparency will not be included in this report. With regards to the survey results in a machine-readable form, we have now re-posted the publicly available results on OSF in an Excel format: https://osf.io/z546q However, the full underlying source data unfortunately cannot be shared due to REB restrictions. On the initiatives described by the reviewer, we have mentioned the Platform for Responsible Editorial Policies (PREP) and of the “Journal Observatory” to the Discussion section, “As a whole, similar to other initiatives [24,25], we believe that this tool will be beneficial in responding to calls for academic journals to become more transparent [1,2].” It was, however, not possible to contrast similarities and differences between these tools, as the JTT does not exist yet. Further, the present paper is focused on the preferences of journal publishers as a stakeholder for the planned JTT. We are not planning to conduct a survey into all journal-level initiatives. Further on the point of implementation, we acknowledge that there may be difficulties in implementing all participants’ preferences with regards to automation, as noted in the Discussion section (e.g., how some metrics may not lend well to automation, how the majority of participants would not pay for a tool). All three stakeholders’ preferences inform the creation of the JTT, but not all aspects may ultimately be feasibly implemented. However, this study lays the groundwork for the JTT’s future development. Response to Reviewers Summary We thank both reviewers for their feedback. In response to comments provided by Andreas Nishikawa-Pacher, machine-readable survey results have been uploaded to Open Science Framework (OSF), and references to similar initiatives (e.g., the Journal Observatory) were added to the manuscript. Further, concerns raised by this reviewer regarding defining 'transparency' and difficulties with feasibly enacting all participant preferences are acknowledged and appreciated. In response, we note that the Journal Transparency Tool (JTT) is currently within preliminary stages, and defining such items will require the collation of data from multiple stakeholders, leading to the limited information being provided regarding such elements within the present report. Further, we appreciate the comment that the abstract’s results may be more interesting if it focused on the contents of the survey outcome rather than numerical data. However, we believe that the present focus aptly represents this report’s findings due to the ‘numeric’ nature of the data provided by the present study design (i.e., a modified Delphi). Alternatively, we appreciate the concerns raised by Bahar Memarian regarding the tool's contribution and design, along with the purpose of the present research study. In response, we clarify that the JTT aims to help users identify journals that adhere to transparent research practices and highlight how this addresses a known gap within the literature. Further, the goal of this research study was to use a modified Delphi approach to capture publisher preferences for the JTT. The sections of the manuscript highlighting such information have been provided within our response for further clarity." } ] }, { "id": "320276", "date": "13 Sep 2024", "name": "Bahar Memarian", "expertise": [ "Reviewer Expertise The role of AI in higher education research", "higher education research", "engineering education research", "human factors engineering" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for your work. Please find suggestions on areas of improvement below:\n\nIt is unclear what the tool has to offer beside curating and collecting information that is available off the web The research questions and goal is missing and the work presented is more of an organizational effort as opposed to a research (e.g., review or empirical paper with clear gap, purpose and methodology) The selection and rationale for survey design is not clear The outcomes of the study does not add to new knowledge formation Overall the study needs to be revisited and a clear research goal and study design needs to be considered. Given the large number of authors, the contribution and relevance of their work to this topic is also unjustified\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "12725", "date": "31 Jan 2025", "name": "Jeremy Ng", "role": "Author Response", "response": "We kindly thank the reviewer for providing their feedback on our manuscript. Regarding the research goals, we envision the JTT as a tool that allows stakeholders to more easily determine a journal’s operations and transparency practices, which will include publicly available information. This could especially be helpful for prospective tool users that are unfamiliar with what constitutes less transparent practices and are unsure where online to look for such information. For instance, a survey of medical oncologists found that 45.2% of participants indicated a lack of knowledge in identifying journals with predatory backgrounds [1]. Other work on researchers publishing in presumed predatory journals had found 28.3% of participants being previously unaware of the potentially predatory nature of the journal they had published in [2]. We have described the prospective value of the tool in the Introduction: “A JTT, as we envision it, could be an automated tool to provide users with information about a given journal’s transparency practices. This in turn could help users decide on the journal’s credibility and whether to interact with it (e.g., read and cite articles published in it, submit manuscripts to it). The tool is expected to add value by providing stakeholders with information about how a journal operates and which best practices it meets. The benefit of this tool may be most obvious for producers of research looking to publish, as well as readers of research looking to consume evidence to help inform healthcare-related decisions. Additionally, this tool may be of great value to new researchers that are being introduced to the research community and individuals in the profession of evaluating, publishing, and indexing research.” In terms of the survey design, this research is one of a three-part initiative to obtain preferences for a journal transparency tool from stakeholders of patients, researchers and clinicians, and publishers. A modified Delphi methodology was conducted to obtain publishers’ preferences in particular, which we believe is beneficial in understanding how to serve the needs of the greater scientific community. The last paragraph of the introduction describes and elaborates on our decision to utilize this methodology: “The Delphi method is a means of structuring communication between experts around a complex issue to make a collective judgment on a given topic. It is a social science technique but has been applied in other settings, including healthcare environments (see for example: [5,6]). The Delphi approach allows for effective communication by individual group members and the group as a whole [7]. It limits direct confrontation between individuals, fosters independent thought by the experts involved, and aims to achieve consensus within a group without the need for a leader [8]. By using the Delphi method, we established the international English-speaking publisher communities’ consensus view on what should be included in a JTT, which will contribute to meaningfully situating the tool within the scholarly landscape and help to ensure that the most relevant inputs are used to build the tool.” The contributions of each author have been enumerated in the author details, in accordance with CRediT (Contributor Role Taxonomy) roles. The contributions of each author have been significant and relevant to this work and justify authorship. Richtig G, Richtig E, Böhm A, Oing C, Bozorgmehr F, Kruger S, Kiesewetter B, Zielinski C, Berghoff AS. Awareness of predatory journals and open access among medical oncologists: results of an online survey. ESMO open. 2019 Jan 1;4(6):e000580. Cobey KD, Grudniewicz A, Lalu MM, Rice DB, Raffoul H, Moher D. Knowledge and motivations of researchers publishing in presumed predatory journals: a survey. BMJ open. 2019 Mar 1;9(3):e026516. Response to Reviewers Summary We thank both reviewers for their feedback. In response to comments provided by Andreas Nishikawa-Pacher, machine-readable survey results have been uploaded to Open Science Framework (OSF), and references to similar initiatives (e.g., the Journal Observatory) were added to the manuscript. Further, concerns raised by this reviewer regarding defining 'transparency' and difficulties with feasibly enacting all participant preferences are acknowledged and appreciated. In response, we note that the Journal Transparency Tool (JTT) is currently within preliminary stages, and defining such items will require the collation of data from multiple stakeholders, leading to the limited information being provided regarding such elements within the present report. Further, we appreciate the comment that the abstract’s results may be more interesting if it focused on the contents of the survey outcome rather than numerical data. However, we believe that the present focus aptly represents this report’s findings due to the ‘numeric’ nature of the data provided by the present study design (i.e., a modified Delphi). Alternatively, we appreciate the concerns raised by Bahar Memarian regarding the tool's contribution and design, along with the purpose of the present research study. In response, we clarify that the JTT aims to help users identify journals that adhere to transparent research practices and highlight how this addresses a known gap within the literature. Further, the goal of this research study was to use a modified Delphi approach to capture publisher preferences for the JTT. The sections of the manuscript highlighting such information have been provided within our response for further clarity." } ] } ]	1	https://f1000research.com/articles/13-915
https://f1000research.com/articles/13-1258/v1	21 Oct 24	{ "type": "Research Article", "title": "The Gelatin-Chitosan-Tetraethyl Orthosilicate Calcium Hydroxide Composite as a Potential Dental Pulp Medicament (Study on Expression of COX-2, PGP 9.5, TNF-α and Neutrophils number)", "authors": [ "Al-qatta Ghadah Abdulrahman", "Endytiastuti Endytiastuti", "Retno Ardhani", "Iwa Sutardjo Rus Sudarso", "Bidhari Pidhatika", "Mh Busra Fauzi", "Heni Susilowati", "Yulita Kristanti", "Juni Handajani", "Al-qatta Ghadah Abdulrahman", "Endytiastuti Endytiastuti", "Retno Ardhani", "Iwa Sutardjo Rus Sudarso", "Bidhari Pidhatika", "Mh Busra Fauzi", "Heni Susilowati", "Yulita Kristanti" ], "abstract": "Introduction Calcium hydroxide (Ca(OH)2) is the material of choice for pulp therapy. However, Ca(OH)2 has drawbacks such as toxicity, poor sealing, and tunnel defect formation. Alternative materials have been developed to provide more biocompatible materials with better dentin formation ability. The objective of this study was to evaluate the effect of composites containing gelatin (G), chitosan (CH), tetraethyl orthosilicate (TEOS), and Ca(OH)2, namely G-CH-TEOS-Ca(OH)2 (Extended data) on inflammation of the dental pulp (expression of COX-2, PGP 9.5, TNF-α, and neutrophil number).\n\nMaterials and methods A total of 16 Wistar rat models of acute pulp injury were prepared and divided into two groups, treatment and control, 8 with each. In the treatment group, we applied a pulp-capping material using G-CH-TEOS-Ca(OH)2 and Ca(OH)2. On the 1st and 3rd days, rats were sacrificed. Tissue samples from 4 rats in each group were processed for histological preparation. COX-2, PGP 9.5, and TNF-α were observed using immunohistochemical (IHC) staining, and neutrophil numbers were observed using hematoxylin-eosin staining. Image analysis of COX-2, PGP 9.5, and TNF-α expression was performed using ImageJ software.\n\nResults The results showed a decrease in COX-2 expression, but not significantly while PGP 9.5 and TNF-α expression were significantly higher than those in the control group. Neutrophil numbers were lower in the treatment group than in the control group, but the difference was not statistically significant.\n\nConclusion The G-CH-TEOS-Ca(OH)2 composite material may have potential as an exposed pulp medicament by reducing inflammation (COX-2 expression and number of neutrophils) and increasing the regeneration factor (TNF-α expression) and nerve (PGP 9.5 expression).", "keywords": [ "Calcium Hydroxide (Ca(OH)2)", "Gelatin-Chitosan-Tetraethyl Orthosilicate-Calcium Hydroxide (G-CH-TEOS-Ca(OH)2) Composite", "capping material", "COX-2", "PGP 9.5", "TNF-α", "neutrophils" ], "content": "Introduction\n\nDental caries are one of the most common chronic illnesses worldwide. Tooth decay is a complex illness involving tooth structure, oral bacteria, and dietary carbohydrates. It dissolves the mineral content of the teeth and is mostly dependent on several important contributing factors. 1 Small surface roughness or subsurface demineralization is the first symptom, followed by cavitation, pulp involvement, swelling, abscesses, and systemic symptoms. 2\n\nSevere toothache can be incapacitating, and infection and sepsis resulting from caries spreading to the dental pulp can sometimes cause major systemic consequences (e.g., spreading local infection and, very rarely, treatment-related death due to anesthesia-related complications) in addition to tooth loss. 3 An inflammatory reaction in the pulp is called pulpitis. 4 occurs primarily due to cariogenic causes and less frequently as a result of trauma, dental abnormalities, and restorative procedures. Pulp hyperemia occurs when inciting conditions are present. Pulp diseases, including acute pulpitis, chronic pulpitis, pulp degeneration, and pulp necrosis, are dental disorders that originate in pulp tissue. Dental caries that are not treated appropriately may later evolve into pulp disease. 5\n\nAn important evolutionary enzyme that is involved in a variety of physiological and pathological processes is COX-2. It controls the expression levels of numerous serum proteins and plays a crucial role in viral infection. This enzyme significantly affects proinflammatory cytokines, and its inhibition or lack by itself does not impair the immune system’s ability to fight illness. 6\n\nProtein gene product 9.5 (PGP 9.5) is a neuronal protein with a specific biological purpose. It is expressed in axons and is used to map individuals with neurodegenerative diseases. It functions as a carboxyl-terminal hydrolase and ligase. Significantly, while PGP 9.5, a highly neuron-specific protein that is frequently employed as a generic neuronal marker, has also been utilized to quantify the neural protein recovered from pulpal tissue 7 and to detect nerve fibers in the dental pulp. It has been shown to be helpful in identifying the A-delta and C fibers of dental pulp. 8 It has been hypothesized that processes leading to nerve degeneration are connected to the early loss or lack of expression of this protein. The nerve structures of the dental pulp were assessed using PGP 9.5. A potential diagnostic marker for identifying nerve fibers in inflamed tooth pulp is PGP 9.5 expression. 7\n\nIn response to bacterial endotoxins, such as lipopolysaccharide (LPS), macrophages preferentially release tumor necrosis factor α (TNF-α). 8 Numerous lines of evidence suggest that TNF-α is responsible for maintaining chemotaxis in fibroblasts and inflammatory cells. 9 Inflammatory cytokines, such as TNF-α and interleukins, play a crucial role in the first 48 h of normal pulp tissue healing. They not only attract inflammatory cells and stem/progenitor cells but also trigger a series of events that lead to tissue regeneration, reparative dentin formation, or both. 10\n\nTraditionally, calcium hydroxide has been the preferred material for vital pulp therapy. At pH 12, calcium hydroxide (Ca(OH)2) is an alkaline substance that has been shown to have bactericidal effects and the capacity to stimulate the growth of hard tissue in human teeth. Ca(OH)2 is widely used in vital pulp treatment. Nevertheless, Ca(OH)2 has a number of drawbacks, such as superficial necrosis of the pulp and surrounding tissues, poor sealing and adherence to dentin, unpredictable dentinal bridge formation, and tunnel defects in these bridges that could serve as possible entry points for bacteria. Because of this weakness, scientists are searching for substitute materials with antimicrobial properties that can be mixed with calcium hydroxide. 11,12\n\nNeutrophils are the most abundant white blood cell in humans. Neutrophils are immunological cells with unique biological characteristics that exhibit strong antibacterial activity. These cells are highly effective in phagocytosing prokaryotic and eukaryotic species, leading to their death. Their role as first responders to acute inflammation, aiding in the healing of injured tissues and removal of pathogens, is well established. Crucially, the antimicrobial activity of neutrophils is not limited to their capacity to combat bacteria within a restricted intracellular space. Neutrophils also release effectors into the extracellular space where their killing apparatus can survive and continue to operate long after death. 13,14\n\nIn the past two years, Tetraethyl Orthosilicate (TEOS), Carbonated Hydroxyapatite (CHA), chitosan (CH), and gelatin (G) have been used to create composite materials. A silane-based crosslinker that can establish bonds with both inorganic and organic materials is called TEOS. The inorganic mineral Ca(OH)2 found in this study’s composite material, gelatin, chitosan, TEOS, and Ca(OH)2, bonds to polymer chains in a naturally occurring organic polymer matrix (gelatin and chitosan) by the action of TEOS, a crosslinker. Silicon (Si) found in TEOS binds as siloxane to form a silica core that can prevent the spontaneous release of Ca(OH)2. This substance can be used for medication delivery with good stability. 15\n\nThis study aimed to determine the effect of composite materials with gelatin (G), chitosan (CH), Tetraethyl Orthosilicate (TEOS), and Ca(OH)2 on inflamed dental pulp. Evaluation was carried out on the expression of inflammatory factors, such as COX-2 expression and number of neutrophils, pulp vitality (PGP 9.5 expression), and pulp repair process (TNF-α expression).\n\n\nMethods\n\nThe Ethics Commission of the Faculty of Dentistry at Universitas Gadjah Mada approved the study procedure through the issuance of ethical clearance number No. 58/UN1/KEP/FKG-RSGM/EC/2023 on May 9, 2023. The Integrated Research and Testing Laboratory (LPPT) Unit IV, Universitas Gadjah Mada, provided experimental animals. At the Integrated Research Laboratory, Faculty of Dentistry, Universitas Gadjah Mada, the gelatin-chitosan-TEOS-Ca(OH)2 composite material was prepared in accordance with our earlier study. 16\n\nSixteen male Wistar rats (Extended data) were used in the experiment and were divided into two groups. Eight rats in each group were divided into four groups on the first and third observation days following treatment. Before treatment and termination to Wistar rats, all rats were anesthetized using Ketamine HCl (0.1 ml/100 g body weight) (Ketamil, CV. Karebet Karya Persada, Indonesia, catalog No. 2960000999-2HH-100335784) to reduce animal suffering. 38 Ketamine HCl (0.1 ml/100 g body weight) was used intramuscularly to anesthetize the experimental animals, and cavities were then prepared. The maxillary first molars were prepared on the occlusal surface to pulp depth using a diamond round bur No. 010 driven by a micromotor that rotated at 35,000 rpm. The treatment group was treated with Gelatin, Chitosan, TEOS, and Ca(OH)2 composite, 37 , 38 whereas the control group was treated with Ca(OH)2 (Brazilian Biodinamica brand powder). The application was performed on the base of the cavity before temporary filling was used to fill it (Figure 1). 36\n\nThe rats were administered ketamine HCl (0.1) and xylene ml/100-gram body weight) intramuscularly on the thigh to induce anesthesia on the first and third days following treatment. The jaws were fixed for four weeks at 4°C in 10% buffered formalin and decalcified with 10% EDTA (pH 7.4) (Extended data). The next step involved tissue cutting, histological preparation, and the creation of paraffin blocks. Using a microtome (Accu-Cut® SRMTM Rotary Microtome, Sakura Finetechnical Co., Ltd, Japan), paraffin blocks were sliced into 4 μm thick pieces for hematoxylin-eosin and immunohistochemistry (IHC) staining.\n\nThe paraffin sections were dewaxed three times for five minutes apiece using xylol, and the rehydration process was then carried out using 100% alcohol for five minutes, and 95%, 90%, 80%, and 70% for three minutes each. An immunohistochemistry kit (Elabscience, USA) was used for IHC staining. To remove endogenous peroxidase activity, samples were incubated with 3% H2O2 for 10 min. The samples were then washed thrice in PBS for two minutes. After adding Normal Goat Blocking Buffer, the samples were incubated for 30 min at 37°C (Extended data). The samples were shaken to remove excess liquid. Primary antibodies against COX-2 (Rabbit Polyclonal antibody COX-2, NB100-689, Novusbio, USA), TNF-α (Rabbit Polyclonal Antibody TNF-α, bs2081R, Bioss Antibody, USA), and PGP 9.5, (Monoclonal Mouse Antibody PGP 9.5, MAB60072, R&D Systems, USA) were added at a proper dilution ratio of 1:100 in PBS. Overnight Incubation was performed at 4°C. The next day, the cells were washed three times with PBS washes for two minutes. Polyperoxidase-anti-Mouse/rabbit IgG was added to the samples, which were then incubated for 20 min at room temperature. PBS was used for washing three times for two minutes. After adding 3,3′-diaminobenzidine (DAB) to the samples, the DAB coloring process was closely monitored until the color of the samples turned brownish yellow, indicating a positive result. The chromogenic reaction was stopped by washing the sections in deionized water, after which hematoxylin was used for counterstaining.\n\nUsing a light microscope at 200× magnification, COX-2 expression, PGP 9.5, and TNF-α were identified as varying degrees of yellowish to brown staining, primarily found in the cytoplasm and nuclear membrane of the positive cells. Three fields were observed in the prepared cavities (Figure 1). 36 ImageJ software (National Institutes of Health) free access, version 154, was used for the image analysis. Method of Counting: Three distinct ocular fields were used to count neutrophil cells in the cavity preparation area. Data were analyzed using post hoc LSD and ANOVA.\n\n\nResults\n\nThe results showed that COX-2 expression on all observation days 1st and 3rd was lower in the treatment group than in the control group (Table 1). The results of immunohistochemical staining using anti-COX-2 antibodies showed a brown color in the extracellular matrix of the dental pulp with varying intensities, indicating positive COX-2 expression. The stronger the color intensity, the stronger is the COX-2 expression. Histological observations (Figures 2 and 6) 36 on the 1st day of both groups showed that there was COX-2 expression by the extracellular matrix in the area under the injury. The treatment group showed lighter color intensity than the control group. On the 3rd day, there was a significant decrease in COX-2 expression (Table 1) in both groups, with the color intensity in the control group being stronger than that in the treatment group (Figure 2). On the observation day, there was no significant difference in COX-2 expression between the control and treatment groups (Table 1). 36\n\n* Significance (< 0.05).\n\nD = dentin, PD = Predentin, = area of injury.\n\n(Magnification ×200).\n\n(Magnification x200).\n\nInflammation decreased with increasing observation time. = area of injury, = neutrophils.\n\nThe results for PGP 9.5 showed brown nerve pulp after administration of gelatin-chitosan-TEOS-Ca(OH)2 composite compared to controls (Figure 3), 36 and the expression in the treatment group was significantly higher compared to controls on both observation days 1st and 3rd (Table 1). The highest expression of PGP 9.5 was observed in the treatment group on 3rd day of treatment (Table 1).\n\nTNF-α expression appeared brown in the odontoblasts after administration of the gelatin-chitosan-TEOS-Ca(OH)2 composite and controls on the 1st and 3rd days (Figure 4). 36 The expression of TNF-α in the control group was weaker than that in the control group on 3rd (Figure 6). On the 1st and 3rd days of observation, there was no significant difference between the control group; however, TNF-α expression increased significantly between the control and treatment groups based on the day of observation (Table 1). The highest TNF-α expression appeared on the 3rd day of treatment (Figure 6). 36\n\nThe results of histological observations (Figures 5 and 7) 36 showed that on 1st day in the group administered Ca(OH)2 (control), the number of neutrophils was higher than that in the treatment group. Results of the mean neutrophil number calculation. The mean number of neutrophils in both the groups decreased significantly on the 3rd days of observation (Table 1).\n\n\nDiscussion\n\nThe results of this study showed that the use of a composite gelatin-chitosan-TEOS-Ca(OH)2 medicament as pulp capping leads to increased COX-2 expression on the 1st day then decreases significantly on the 3rd day (Figures 2 and 6). 36 These results were in line with the number of neutrophils which decreased in 3rd day of observation (Figure 5). These findings suggest that the gelatin-chitosan-TEOS-Ca(OH)2 composite material induces a lower inflammatory response.\n\nIn this study, the cavity was prepared using a low-speed rotary instrument. Every rotary cutting instrument generates heat and vibrations that may damage the tooth pulp. If heat is delivered to the pulp, it may cause histopathological alterations can occur. Excessive heat transmission may also cause pulp inflammation and irritation. 17 Chronic inflammation without any clinical symptoms may also develop over time as a result of the cumulative effect of irritating stimuli, leading to more severe permanent pulpal damage. The pulp’s reaction to irritation is determined by its condition, degree of tissue damage, and activity of inflammatory mediators. 18\n\nInflammation of the dental pulp is a complicated process that is controlled by several molecular mediators, and the mechanism is the same as that of inflammation in other connective tissues. The primary role of these inflammatory mediators is to shield tissues from external irritants such as chemicals, mechanical forces, and germs. 19–21 Through the stimulation of the pulp’s innate and adaptive immunological responses, as well as a variety of molecular mediators, these irritants have the potential to negatively impact and harm the dental pulp. Injuries that result from the preparation of deep cavities can trigger the production of TNF-alpha and IL-1 by tissue-resident macrophages and fibroblasts, which can increase COX-2 expression in the injured area. 22\n\nThe findings demonstrated that COX-2 expression was discernible in the extracellular matrix, neutrophils, macrophages, lymphocytes, and fibroblasts in the region of injury. Tissue damage, such as that caused by surgery or conditions such as pulpitis or periodontitis, causes the creation of COX-2, which in turn causes the synthesis of prostaglandins that sensitize pain fibers and encourage inflammation. 23 PGE2 and prostacyclin are products of COX-2 activity and are implicated in various physiological and pathological processes, including inflammation and pain. 24\n\nThe dental pulp can be impacted and harmed by exogenous irritants, such as mechanical, chemical, and bacterial agents, because they can activate the pulp’s innate and adaptive immune responses in addition to a variety of molecular mediators. Damage resulting from prepared deep holes has the potential to activate tissue-resident macrophages and fibroblasts, causing them to release TNF-α and IL-1, which in turn can elevate COX-2 expression in injured areas. 25\n\nThere was a significant difference between the 1st and 3rd day of treatment as well as between the 1st and 3rd day of control, and the COX-2 color intensity in the treatment groups was lower on the first and third days compared to the control group. According to Jiang et al., 26 this outcome is assumed to be caused by the antibacterial and anti-inflammatory qualities of chitosan, which can reduce the bacterial load and reduce the initial inflammatory insult. The regulated release of Ca(OH)2 is facilitated by the matrix offered by gelatin. This minimizes the risk of excessive initial burst release, limits the entry of pathogens, and reduces the requirement for acute inflammatory cell infiltration. Both gelatin and Ca(OH)2 exhibit anti-inflammatory properties. 27,28 The composite gelatin-chitosan-TEOS-Ca(OH)2 provides an environment that limits post-treatment inflammation in the pulp tissue, as seen by the lowered levels of these proinflammatory cytokines and mediators. (Extendd data).\n\nThe evaluation conducted on the first day post-treatment aided in determining the immediate reaction of COX-2 expression to the therapy, and we observed a non-significant decrease in COX-2 expression in the treatment group when compared to the control. The evaluation on the third day aided in tracking any short-term variations and possible trends in COX-2 expression after the first reaction, where the mean expression was much lower than on the first day.\n\nAfter taking these factors into consideration, the composite gelatin-chitosan-TEOS-Ca(OH)2 material seems to help the pulp by reducing the initial inflammatory insult and, due to the synergistic effects of its bioactive components, fostering a more favorable healing environment. As the number of observation days increased, we saw a drop in the pattern of COX-2 expression. The overall pattern was reduced on the third day when compared to the first, with a significant decrease between the control and treatment groups (Table 1). On the 3rd day, a comparison of COX-2 expression and neutrophil counts between the treatment and control groups revealed no discernible differences. This suggests that the reduction in acute inflammation caused by the gelatin-chitosan-TEOS-Ca(OH)2 material is equivalent to that of Ca(OH)2. It is crucial to remember that further investigation and assessment are required to validate the long-term results and clinical effectiveness of this composite material. Specifically, the ratios of gelatin and chitosan within the material need to be changed to enhance their anti-inflammatory properties and maximize their efficacy.\n\nThe presence of chitosan may be the reason for the notable increase in PGP 9.5 expression on the first and third days after injection, which is consistent with other research showing the regeneration potential of chitosan-based composites. Chitosan, a natural copolymer of glucosamine and N-acetylglucosamine, is used in gene therapy, tissue engineering (TE), and other biomedical fields because of its biocompatibility, stability, sterilizability, biodegradability, antimicrobial activity, and immunostimulatory activity. 29\n\nChitosan also offers a biomimetic microenvironment that promotes cell growth owing to its similarity to glycosaminoglycans (GAGs) found in naturally occurring extracellular matrix (ECM) materials. Furthermore, its osteoconductive properties can support osteogenic differentiation and biomineralization of stem/progenitor cells. 29 The shortcomings of chitosan in terms of mechanical strength and early cell attachment can be effectively addressed by blending it with other biomaterials, such as gelatin. 29 A protein fragment known as gelatin is produced when collagen fibers partially break down. Its numerous benefits, such as low antigenicity, biodegradability, hydrogel qualities, and affordability, have made it widely available in TE. Additionally, the Arg–Gly–Asp (RGD) integrin recognition motif supports the first cell attachment. Blends of chitosan and gelatin, or CS/Gel, have been suggested as scaffolding materials for bone regeneration and other tissues, including skin, cartilage, and peripheral nerves. 29 These blends can potentially combine these features.\n\nThe incorporation of calcium hydroxide (Ca(OH)2) and tetraethyl orthosilicate (TEOS) into the composite may increase its effectiveness by promoting cellular adhesion, proliferation, and extracellular matrix formation. It is probable that the composite material triggered an early neurogenic response by triggering signalling pathways linked to cell differentiation and proliferation. Therefore, the persistent increase in PGP 9.5 expression may be a sign of continued axonal development and growth, which would ultimately aid in functional recovery. 29 The study findings confirmed that the treatment group receiving gelatin, chitosan, TEOS, and Ca(OH)2 had the highest levels of PGP 9.5 expression.\n\nTwo distinct receptors attach to TNF-α and initiate signal transduction pathways. These pathways trigger numerous biological responses such as cell survival, differentiation, and proliferation. 30 After administering the gelatin-chitosan-TEOS-Ca(OH)2 composite and Ca(OH)2 to the control group, odontoblasts were shown to express TNF-α, indicating that both materials triggered an inflammatory response. The brown coloration observed indicates an upregulation of TNF-α production, which is a key proinflammatory cytokine involved in various cellular processes, including tissue repair and inflammation. On the 1st and 3rd days, there was a similar expression of TNF-α in the treatment and control groups, indicating that the level of inflammatory response caused by both materials in tooth pulp was equivalent. This result is consistent with other research showing that Ca(OH)2 has strong immunomodulatory effects in dental pulp tissues, which upregulates TNF-α expression. 30\n\nOn the third day, the control group showed lower TNF-α expression than the treatment group, which was remarkable. This disparity could point to variations in the TNF-α expression kinetics between the gelatin-chitosan-TEOS-Ca(OH)2 composite and pure Ca(OH)2. Compared with pure Ca(OH)2, the composite material might have produced a stronger inflammatory response or maintained TNF-α expression for a longer period of time. Further research is necessary to clarify the underlying mechanisms causing this variation in TNF-α expression between the two groups.\n\nOn the 1st day, infiltration of inflammatory cells, especially neutrophils, was observed in both groups. Neutrophils are leukocytes that first migrate to tissue/injury locations. These cells are dominant within 24-36 hours after injury and function to eliminate irritants and damaged tissue through phagocytosis. 31,32 Changes in the endothelium surface caused by the activation of inflammatory mediators, such as histamine, cysteinyl-leukotrienes, and cytokines generated by tissue-resident leukocytes during damage can trigger the recruitment of neutrophils to the injured area. 31 On the first and third days, the mean neutrophil count of the treatment group was lower than that of the control group. These results are in line with earlier research showing the inherent anti-inflammatory properties of the constituent parts of our composite, such as chitosan, 33 gelatin, 28 and Ca(OH)2. 29 Post-treatment inflammation of the pulp tissue was inhibited by the composite gelatin-chitosan-TEOS-Ca(OH)2, as evidenced by the decreased levels of proinflammatory cytokines and mediators. This suggests that pulp-capping methods result in better pulp healing and regeneration rather than necrosis or infection, which could compromise the effectiveness of vital pulp therapies. 34 Reductions in these indicators have been linked to improved clinical results in comparable studies. This suggests that pulp-capping treatments result in better pulp healing and regeneration rather than necrosis or infection, which compromises the effectiveness of vital pulp therapy procedures. 35\n\nThe gelatin-chitosan-TEOS-Ca(OH)2 composite may facilitate a rapid resolution of inflammation and stabilization of the pulp capping wound site by restricting early neutrophil infiltration. Based on the results obtained, we conclude that the gelatin-chitosan-TEOS-Ca(OH)2 composite and Ca(OH)2 evoke similar biological responses in terms of neutrophil number, with no significant difference observed between the treatment group and the control group every day of observation. The results also showed that the gelatin-chitosan-TEOS-Ca(OH)2 composites can stimulate the pulp repair process and pulp vitality. To completely understand the therapeutic effectiveness and underlying mechanisms of action of gelatin-chitosan-TEOS-Ca(OH)2 in endodontic applications, more research is required.\n\n\nConclusion\n\nThe gelatin-chitosan-TEOS-Ca(OH)2 composite material has potential as an anti-inflammatory agent in the exposed pulp by reducing COX-2 expression and the number of neutrophils. These findings suggest a potential regenerative effect of the gelatin-chitosan-TEOS-Ca(OH)2 composite by increasing TNF-α expression and PGP 9.5, making it a promising candidate for further exploration in dental pulp therapy.\n\nThe Ethics Commission of the Faculty of Dentistry at Universitas Gadjah Mada approved the study procedure through the issuance of ethical clearance number No. 58/UN1/KEP/FKG-RSGM/EC/2023 on May 9, 2023.\n\n\nData availability\n\nFigshare: Data final assignment recognition program (RTA)-2024. https://doi.org/10.6084/m9.figshare.26819887 36\n\nThis project contains the following:\n\n• Raw data\n\n• Figure files\n\n• Table\n\nThe data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nFigshare: Data final assignment recognition program (RTA)-2024. https://doi.org/10.6084/m9.figshare.27021160.v1 37\n\nThis project contains the following:\n\n• Figure files\n\nThe data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nFigshare: Data final assignment recognition program (RTA)-2024. https://doi.org/10.6084/m9.figshare.27020713.v2 38\n\nThis project contains the following:\n\n• Arrive checklist\n\nThe data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).", "appendix": "References\n\nQuock RL: Dental caries: a current understanding and implications. 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Publisher Full Text\n\nAlipour M, Pouya B, Aghazadeh Z, et al.: The antimicrobial, antioxidative, and anti-inflammatory effects of polycaprolactone/gelatin scaffolds containing chrysin for regenerative endodontic purposes. Stem Cells Int. 2021; 2021(1): 3828777. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nReyes-Carmona JF, Santos AR, Figueiredo CP, et al.: In vivo host interactions with mineral trioxide aggregate and calcium hydroxide: inflammatory molecular signaling assessment. J. Endod. 2011 Sep 1; 37(9): 1225–1235. PubMed Abstract \| Publisher Full Text\n\nBakopoulou A, Georgopoulou Α, Grivas I, et al.: Dental pulp stem cells in chitosan/gelatin scaffolds for enhanced orofacial bone regeneration. Dent. Mater. 2019 Feb 1; 35(2): 310–327. PubMed Abstract \| Publisher Full Text\n\nKolaczkowska E, Kubes P: Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 2013 Mar; 13(3): 159–175. Publisher Full Text\n\nPittman K, Kubes P: Damage-associated molecular patterns control neutrophil recruitment. J. Innate Immun. 2013 Mar 7; 5(4): 315–323. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nChang SH, Lin YY, Wu GJ, et al.: Effect of chitosan molecular weight on anti-inflammatory activity in the RAW 264.7 macrophage model. Int. J. Biol. Macromol. 2019 Jun 15; 131: 167–175. PubMed Abstract \| Publisher Full Text\n\nLi JY, Wang SN, Dong YM: The effect of topical application of meloxicam on inflamed dental pulp. J. Dent. Sci. 2021 Jul 1; 16(3): 915–921. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAleksandrowicz P, Brzezińska-Błaszczyk E, Kozłowska E, et al.: Analysis of IL-1β, CXCL8, and TNF-α levels in the crevicular fluid of patients with periodontitis or healthy implants. BMC Oral Health. 2021 Dec; 21: 120–129. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAl-qatta GA, Endytiastuti, Ardhani R, et al.: Data final assignment recognition program (RTA)-2024. Dataset. figshare. Publisher Full Text\n\nHandajani J: Extended data-Composite with Gelatin (G), Chitosan (CH), Tetraethyl Orthosilicate (TEOS) and Ca(OH)2. figshare. Figure. 2024. Publisher Full Text\n\nHandajani J: ARRIVE-Juni Handajani. Dataset. figshare. 2024. Publisher Full Text" }	[ { "id": "341881", "date": "19 Dec 2024", "name": "Angela Quispe-Salcedo", "expertise": [ "Reviewer Expertise Dental pulp biology" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors of this study aimed to evaluate the effect of a calcium hydroxide gelatin-chitosan-tetraethyl orthosilicate composite material on pulp inflammation in rats. This is a descriptive morphological study, in which results were collected on days 1 and 3 after surgery. Although this is an interesting idea, the usefulness of this material needs further research and analysis. This manuscript contains several errors that the author needs to improve before considering for indexing.\n1. Title: Please remove the parentheses and write a brief title that summarizes the purpose of your research\n2. The introduction is too long and the paragraphs are too short. Please pay attention to the content and combine paragraphs 1 and 2, and 6 and 8. The information in paragraph 7 should be linked back to paragraphs 1 and 2, for example , In paragraph 9, I suggest adding the information that the research was done outside on mice (line 2 of paragraph 9).\n3. Method: Why did the author use a micromotor instead of a handpiece under refrigeration? In this way, pulp damage is greater, is this done intentionally under high temperature conditions? Why did the author choose days 1 and 3? The initial repair phase, takes place from day 5. Days 1 and 3 are for observation of inflammatory reactions. There is no morphological assessment of pulp tissue. H-E staining is required. Did the author mean Xylene instead of Xylol? Please explain. The authors did not adequately explain how they quantified the IHC results and how they performed the neutrophil quantification. The description of “yellowish to brownish color grades” is unacceptable. Brand and company name information is missing from the descriptions of some reagents. Information about statistical software is also missing.\n4. Results: The results of this study were not convincing, nor were they properly presented in the manuscript. To name just a few of the main concerns, what the authors claimed were positive antibody responses, in fact appeared to be nonspecific responses distributed throughout the pulp tissue. The images were not standardized, and it was difficult to observe the immune response at this magnification. In Fig. 3, PGP-9.5 should be located in the nerve fibers of the pulp tissue, but there is no evidence of nerve fibers. Figure 4 is very poor, the image is very dark and there is nothing to compare. Figure 5 is related to the presence of neutrophils but we cannot assess them at this magnification and the samples show different locations so the images cannot be compared or read. The graph in Figure 6 must be split into three independent graphs for each marker and finally linked to Figure 7, there is no measurement or unit of analysis for the number of neutrophils on the Y axis. We, the readers, do not understand how the author calculated it.\n5. Discussion Unnecessary long, the paragraphs are not connected. Please summarize and discuss in detail your results compared to previous studies. This section needs to be completely rewritten.\n6. Conclusion Unfortunately, in its current form, the results of this manuscript cannot support the conclusions drawn by the authors.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No", "responses": [ { "c_id": "13182", "date": "30 Jan 2025", "name": "Juni Handajani", "role": "Author Response", "response": "Dear Reviewer, Thank you for the very valuable input to improve our manuscript. We have made revision according to the reviewer's suggestion, including: 1. Revision of the research title 2. Rewritten of the introduction 3. Addition of explanations on research methods and observations 4. Revision of research results and Figures 1, 6 and 7, and descriptions 5. Addition of research discussion and references 6. Revision of the conclusion Thank you" } ] }, { "id": "354056", "date": "16 Jan 2025", "name": "Euis Reni Yuslianti", "expertise": [ "Reviewer Expertise Oral biology", "biomedical", "oral biochemistry", "herbal medicine in dentistry" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript is clear and logically organized, but please more recent references and a deeper discussion of alternative pulp-capping materials. The methodology is mostly sufficient, please more details on composite preparation and ethical handling of animals. The discussion could benefit from clearer emphasis on the clinical relevance of the findings. Please explicitly stating how the composite material could be superior to traditional Ca(OH)2-based treatments in vital pulp therapy. The explanation of TNF-α expression kinetics, could include additional references to ensure claims are fully substantiated. Please deep discussion how the observed inflammatory responses might affect long-term outcomes (e.g., pulp vitality, dentin bridge formation).\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13183", "date": "30 Jan 2025", "name": "Juni Handajani", "role": "Author Response", "response": "Dear Reviewer, Thank you for your valuable sugggestion to improve our manuscript. We have revised the discussion by adding previous research findings that support the results of this study. Thank you." } ] } ]	1	https://f1000research.com/articles/13-1258
https://f1000research.com/articles/13-132/v1	22 Feb 24	{ "type": "Review", "title": "Unveiling the Group A Streptococcus Vaccine-Based L-Rhamnose from Backbone of Group A Carbohydrate: Current Insight Against Acute Rheumatic Fever to Reduce the Global Burden of Rheumatic Heart Disease", "authors": [ "Ade Meidian Ambari", "Dwita Rian Desandri", "Bambang Dwiputra", "Basuni Radi", "Faqrizal Ria Qhabibi", "Pirel Aulia Baravia", "Indira Kalyana Makes", "Dwita Rian Desandri", "Bambang Dwiputra", "Basuni Radi", "Faqrizal Ria Qhabibi", "Pirel Aulia Baravia", "Indira Kalyana Makes" ], "abstract": "Group A Streptococcus (GAS) is a widely distributed bacterium that is Gram-positive and serves as the primary cause of acute rheumatic fever (ARF) episodes. Rheumatic heart disease (RHD) is a sequela resulting from repeated ARF attacks which are also caused by repeated GAS infections. ARF/RHD morbidity and mortality rates are incredibly high in low- and middle-income countries. This is closely related to poor levels of sanitation which causes the enhanced incidence of GAS infections. Management of carditis in RHD cases is quite challenging, particularly in developing countries, considering that medical treatment is only palliative, while definitive treatment often requires more invasive procedures with the high costs. Preventive action through vaccination against GAS infection is one of the most effective steps as a solution in reducing RHD morbidity and mortality due to curative treatments are expensive. Various developments of M-protein-based GAS vaccines have been carried out over the last few decades and have recently begun to enter the clinical stage. Nevertheless, this vaccination generates cross-reactive antibodies that might trigger ARF assaults as a result of the resemblance between the M-protein structure and proteins found in many human tissues. Consequently, the development of a vaccine utilizing L-Rhamnose derived from the poly-rhamnose backbone of Group A Carbohydrate (GAC) commenced. The L-Rhamnose-based vaccine was chosen due to the absence of the Rhamnose biosynthesis pathway in mammalian cells including humans thus this molecule is not found in any body tissue. Recent pre-clinical studies reveal that L-Rhamnose-based vaccines provide a protective effect by increasing IgG antibody titers without causing cross-reactive antibodies in test animal tissue. These findings demonstrate that the L-Rhamnose-based vaccine possesses strong immunogenicity, which effectively protects against GAS infection while maintaining a significantly higher degree of safety.", "keywords": [ "Acute rheumatic fever", "Group A Carbohydrate", "Group A Streptococcus", "rhamnose", "vaccine" ], "content": "Introduction\n\nGroup A Streptococcus (GAS) is a cosmopolitan bacterium that has become the etiology of various human diseases, from mild illnesses such as tonsilitis and impetigo, to severe ones such as scarlet fever, toxic shock, and necrotizing fasciitis. Acute rheumatic fever (ARF) is an inflammatory reaction triggered by Group A Streptococcus infection which usually occurs approximately two to three weeks following a sore throat illness.1,2 ARF is characterized by several clinical symptoms consisting of polyarthritis migrant (35-88%) and carditis (50-78%) which usually cause mitral or aortic valve regurgitation. Besides that, other signs that usually accompany ARF include abnormal involuntary movement or Sydenham chorea (2-19%), erythema marginatum (<6%), subcutaneous nodule (1-13%), and increased laboratory values such as erythrocyte sedimentation rate, neutrophils, and CRP.2–5 These clinical symptoms are used in establishing the diagnosis of ARF which is concluded in Jones criteria which was first proposed in 1944 and has undergone several revisions until the American Heart Association (AHA) issued the latest revision in 2015 which divides these clinical syndromes into major and minor criteria and dividing the population based on where they live whether they are classified into low, medium, or high-risk areas.3,6 Various clinical manifestations that appear during ARF are the result of autoantibodies against tissues found in the joints, brain, and heart due to the similarity of the molecular structure of protein found in body tissues with the molecular structure of M-protein antigen found in GAS.7,8 The structural similarity between α-helical coiled M-protein antigens in GAS and various body proteins that cause autoantibodies is referred to as molecular mimicry (Figure 1). Molecular mimicry between Streptococcus and the heart reveals a cross-reactive antibody that recognizes several types of epitopes found on Streptococcus M-protein and protein found on heart valves.8,9 In the latest development, the concept of “neo-antigen” theory emerged and explains that GAS gained access to the sub-endothelial collagen matrix, where the peptide associated with rheumatic fever (PARF) M-protein domain binds to type IV in the CB3 region thereby creating a neo-antigen that can induce an autoimmune response against collagen.10,11 Both molecular mimicry and neo-antigen theories are still being further researched, however repeated ARF will cause tissue scarring as a result of response to pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-12, and tumor necrosis factor-α (TNF-α) which increased when ARF occurs and ultimately causing tissue fibrosis.12,13 Fibrosis in heart valves, including the mitral valve, causes valve regurgitation, which progresses to stenosis. Mitral regurgitation (MR) to mitral stenosis (MS) conversion is a pathognomonic sign of rheumatic heart disease (RHD).12,14,15\n\nMHC = Major Hiscompatibility Complex, TCR = T-cell Receptor, IL = Interleukin, VCAM1 = Vascular Cell Adhesion Molecule-1.\n\nRheumatic heart disease (RHD) is a myocardial pan-carditis and the cardiac sequela of ARF. Although ARF is self-limiting, inflammation in heart valves caused by a single or repeated episode of ARF can lead to scarring and chronic valve dysfunction.16,17 Chronic rheumatic heart disease (RHD) is clinically identified by the occurrence of fibrinous pericarditis and interstitial granulomas or Aschoff’s nodules. These nodules consist of clusters of loose granulomas with necrosis of central fibrinoids, macrophages, B cells, and multinucleated giant cells in the myocardium. The myocardial damage caused by RHD can improve without leaving any lasting harm, however, if it is associated with valvulitis, it leads to permanent damage.18,19 The diagnosis of carditis due to RHD based on the finding of diastolic murmur sound through auscultation at the apex of the heart is categorized as clinical carditis. Meanwhile, the establishment of carditis through echocardiography examination due to normal findings during physical examination is referred to as subclinical carditis.20,21 Heart valve-related RHD is the most serious clinical manifestation and has been the focus of numerous studies for the last several decades.9,22–24 In symptomatic severe valvular cases, ideally, treatment for RHD requires surgery or catheter-based treatment. Medication using drugs is usually only used to treat heart failure or atrial fibrillation (AF) which is the further result of valve regurgitation or stenosis due to RHD.21 For patient with severe symptomatic mitral stenosis, percutaneous mitral balloon commissurotomy (PBMC) is the main treatment of choice.21,25,26 PBMC treatment is a main option, especially in low and middle-income countries because the cost is not as expensive as valve surgery with a success rate of more than 95%.27 However, there are several contraindications such as left atrial clots or extensive calcium deposits which make PBMC prohibited and the only way is to carry out a valve surgery procedure which is much more expensive.21,26 The high cost of curative treatment for RHD is due to the absence of pharmacological treatment that can treat valve problems so expensive invasive treatment is the only way. Therefore, preventive measures have a vital role in efforts to reduce the global burden of RHD. RHD prevention and control is broadly divided into three parts, including primordial prevention, primary prevention, and secondary prevention.21,28,29 Vaccination is a means of preventing ARF and RHD due to the specific protection against GAS infection.30 Therefore, vaccine development is very promising as a big step to reduce the incidence of ARF and RHD, especially in low- and middle-income countries which have worse sanitation and socioeconomic levels than high-income countries, which ultimately affects the rate of GAS infection.\n\n\nDiscussion: Current Global Epidemiology of GAS, ARF, and RHD\n\nGAS is one of the top ten causes of infection-related death worldwide. GAS infections predominantly occur in low and middle-income (developing) nations, where factors such as overcrowding, inadequate nutrition, unsatisfactory sanitation, and substandard living conditions are believed to contribute to the widespread occurrence of GAS disease.31,32 GAS is responsible for approximately 700 million cases of pharyngitis per year globally. An estimated minimum of 517,000 deaths occur annually due to severe GAS infections, with a minimum prevalence of 18.1 million cases and an annual increase of 1.78 million new cases. Meanwhile, the burden of invasive GAS (iGAS) cases is very high, with 600,000-663,000 new cases reported every year with a mortality rate of 25% or around 163,000 deaths per year.32–35 Streptococcal pharyngitis is a very common infection in children. Streptococcus in susceptible hosts can trigger an abnormal inflammatory immune response due to the cross-reactivity of Streptococcal antibodies to myocardial, synovial, and basal ganglia tissue, thus becoming the main etiology of ARF. ARF which is a sequela of GAS infection mainly occurs in children and adolescents. The peak incidence of ARF is between 5 to 15 years and is very rare at 30 years. Epidemiologically, ARF occurs in all parts of the world.8,36 In every single year, approximately 500,000 new cases of ARF are reported worldwide.2,37 A study conducted by the World Health Organization (WHO) reveals that the total global burden of acute rheumatic fever (ARF) cases amounts to 471,000 cases annually. Among children aged 5 to 15 years old, the incidence of ARF is 10 cases per 100,000 in industrialized countries and 374 cases per 100,000 in Pacific countries.32 From an economic standpoint, the economic costs of ARF are quite expensive, for example in the USA it has been estimated that the country has to pay for ARF 224-539 million USD per year.4\n\nAround 60% of individuals residing in endemic populations who have ARF will ultimately develop RHD. RHD is a serious consequence of inappropriate GAS infection management resulting in recurrent ARF attacks. According to the IMHE Global Burden of Disease report, the global prevalence of RHD exceeds 40 million cases, primarily concentrated in low- and middle-income nations.38 Rheumatic heart disease (RHD) has a substantial impact on the morbidity and mortality rates in low- and middle-income countries, resulting in over 300,000 deaths annually and more than 10 million disability-adjusted life years.39 According to data released in 2013, the prevalence of RHD cases is 33 million, with an annual death rate of 275,000, dominated by low- and middle-income countries. Furthermore, the prevalence of RHD increases with age, and the survival rate is determined by the availability of access and adherence to secondary prophylaxis to prevent ARF recurrence, the severity of the valve, and access to specialists and surgery.32,39,40 The epidemiology of RHD varies in each region, the prevalence is quite high in the Pacific41 and Africa,42,43 but high burden in Latin American country,44 the Middle East,45 and Asia.32 Meanwhile, in industrialized countries such as the USA, the incidence of RHD is very rare (0.04 cases per 1000 children).46 An estimate shows that 40% of people with RHD are never aware of an ARF episode, in other words they never know they have had an ARF attack. Consequently, RHD is only detected when individuals show cardiac symptoms that appear late in the disease.15,47 If we draw a common thread from the high prevalence, morbidity, and mortality rates of RHD, it cannot be separated from the presence of GAS infection as the main etiology of ARF. Worldwide, Group A Streptococcus (GAS) continues to exhibit sensitivity to penicillin, despite evidence indicating that penicillin has not been successful in completely eliminating GAS-related pharyngitis and tonsillitis. In addition, GAS remains susceptible to other beta-lactam antibiotics such as amoxicillin and cephalosporins.48,49 Recent research has shown an uncommon mutation in penicillin-binding protein (PBP) 2B in two strains of GAS, which decreases their vulnerability to beta-lactam antibiotics.50 This is an alarm indicating that GAS is on the road to becoming resistant to frequently prescribed antibiotics, including penicillin and amoxicillin. Therefore, the most promising approach in the future in fighting antibiotic resistance in GAS, which is the main etiology of ARF that can develop into RHD, is the development and use of a GAS vaccine.\n\n\nGAS Vaccine Development for ARF/RHD\n\nA vaccine for GAS would theoretically be the most cost-effective intervention in an ARF/RHD endemic country. An economic assessment carried out in the USA showed that the implementation of the vaccination program would reduce the GAS infection rate by up to 20% in all age groups, thereby saving costs of approximately 1 billion USD.51 Furthermore, the development of an effective GAS vaccine will provide several potential benefits including protection from infection and a reduction in the rate of antibiotic use thereby reducing the rate of microbial resistance.52,53 However, nowadays there is still no licensed GAS vaccine and it is still in the development stage. In 2018, WHO issued a roadmap from the development of the first GAS vaccine.54 The primary obstacle in developing a successful and secure GAS vaccine has been constant in recent decades, which is the production of universally applicable vaccine candidates capable of safeguarding against both existing and future strains of GAS.55 The result of GAS genome sequencing shows two major issues in vaccine development, namely (i) extensive genome heterogenicity of gas isolates which is the result of frequent genetic recombination events such as gene exchange and single nucleotide polymorphism (SNP), and (ii) variations in protein sequences.56,57 A recent extensive genomic study showed that there are 13 candidate antigenic proteins that are conserved in more than 99% of GAS isolates found globally.1,58 Several candidates are still in the safety and immunogenicity testing stage in rodents or experimental mice and rabbits, while others are beginning to enter clinical trial development on human subjects. Antigenic protein candidates are broadly classified into two groups: (i) M-protein-based candidates and (ii) non-M-protein candidates.1,59–61\n\nM-protein is an immunodominant GAS protein encoded by the emm gene. The M-protein structure comprises a coiled-coil structure that extends 600 nm and is anchored in the bacterial cell wall.59,60,62,63 M-protein has been widely studied and is believed to have a role in adhering to host cells and blocking phagocytosis thereby helping GAS colonization.63,64 M-protein is a versatile protein in terms of both structure and function. M-protein can bind to fibrinogen, fibronectin, and host plasminogen, apart from that it also plays a role in interfering with complement protein deposits through binding to the Fc domain with IgG and complement regulators namely C4BP protein and factor H so that M-protein has a big role in virulence factors because can resist opsonophagocytosis.65–67 Recent investigations have shown a potential GAS vaccine candidate resulting from the development of vaccines containing the N-terminal or C-terminal domains of the M protein or a combination of the two that have protective efficacy against GAS infections.1 To date, there have been three GAS vaccine candidates recorded on globaldata.com that have been tested in the clinical trials phase or are scheduled for clinical trial phase I.1,33 In 2020, a phase I clinical trial was carried out using StreptAnova targeting M-protein. StreptAnova is a 30-valent vaccine candidate designed using the N-terminal peptide from 30 M-protein.1,68,69 Individuals who received StrepAnova developed functional (opsonophagocytic) antibodies, although protection from this vaccine has not been conclusively proven in animal challenge models.70 Meanwhile, other M-protein based vaccines such as StrepInCor contain a peptide consisting of 55 amino acids from the C-peptide region of the M protein. This region is the most conserved part among the GAS serotypes.71 StrepInCor vaccination in phase I clinical trials will begin in late 2023.33 One of the most promising clinical trial approaches currently is the use of a combination of two synthetic peptides, namely two M-protein epitopes (modified p*17 and J8) which have been paired with an epitope of the streptococcal anti-neutrophil factor, Spy-CEP (K4S2).1,33 Test results on pre-clinical models showed no cardiac or neurological pathologies so it was initiated into clinical trials in 2022. However, the main problem in developing an M-protein-based GAS vaccine is cross-reactivity with human organs, especially the myosin protein in heart muscle cells.64,72,73 The first evidence showing the existence of cross-reactivity between anti-streptococcal antibodies and human heart tissue was found in experimental mice that had been immunized with GAS components. In fact, cross-reactivity has become one of the main hypothesized mechanisms causing the emergence of ARF attacks several weeks after the onset of manifestations of GAS infection such as sore throat infection or impetigo due to autoimmunity which recognizes the M-protein GAS along with the proteins found in the heart valves, synovial tissue, and basal ganglia due to the similarity of protein structures which is referred to as molecular mimicry.8,74–77\n\nThe growing interest in developing GAS vaccines based on non-M protein antigens stems from a desire to avoid GAS vaccine targets that may cause autoimmunity. The development of non-M protein vaccines began in the 1990s using C5a peptidase (Streptococcal C5a protease, SCPA).78 Apart from SCPA, other non-M protein GAS vaccine candidates include Streptolysin O (SLO), Streptococcal Pyrogenic Exotoxins, and multi-component vaccines.33 All of these vaccine candidates are still in the pre-clinical trial testing phase. The main challenge in developing non-M protein-based vaccines is low coverage against all GAS strains globally. In addition, to achieve optimal protection against all GAS isolates, the various protein components in the vaccine must be present in all GAS isolates or strains.\n\n\nDevelopment of GAC Vaccine based on Poly-rhamnose Backbone from Group A Carbohydrate (GAC)\n\nThe surface polysaccharide known as Group A Carbohydrate (GAC) is present in all identified serotypes and is completely conserved. It is composed of repeating trisaccharide units with the main chain formed by α-1,2- and α-1,3-linked l-rhamnose (Rha) residue and a β-1,3-linked N-acetyl-d-glucosamine (GlcNAc) residue as a side chain embedded into the 3-O-position of the latter Rhamnose residue.56,79–81 The GAC component is very abundant and essential in GAS cells because it forms approximately 40-60% of the mass of the cell wall which has a function in structural support as a barrier against the environment and maintaining cell morphology.79 GAC forms covalent bonds with N-acetylmuramic acid (MurNAc) which is the main component of peptidoglycan. As previously mentioned, the GAC component is 100% conserved because all GAS serotypes express GAC which consists of a poly-rhamnose backbone with an N-acetylglucosamine (GlcNAc) side chain with repeating trisaccharide units [3) α-l-Rhap (1➔2) [β-d-GlcpNAc(1➔3) α-l-Rhap(1➔3)]n. The backbone of GAC consists of l-rhamnose repeat units linked by α-1,3-α-1,2 glycosidic (Figure 2).82–84 The average molecular mass of GAC has been reported to be 8.9 ± 1 kDa, which is responsible for the 18-unit repetition.56\n\nA molecular study shows the biosynthetic mechanism of GAC where the rhamnan (Rha) polymer is arranged on the cytoplasmic side of the plasma membrane and then translocated to the cell surface by the ABC transporter protein and modified by GlcNAc on the outside of the cell membrane. A lipid carrier, namely GlcNAc-P-P-Und, acts as an acceptor for the initiation of rhamnan backbone biosynthesis.85,86 Recent studies show that there are 12 gene clusters that play a role in expressing various enzymes and functional proteins that play a role in the GAC biosynthesis process. A series of steps in the rhamnan biosynthesis process involve the action of glycotransferases encoded by the GacB, GacC, GacG, and GacF genes so that the rhamnan polymer that forms the backbone will become a structure commonly known as poly-rhamnose.86–88 GacA is the first gene of the GAC gene cluster, but the GacA gene encodes an essential enzyme that has a function in catalyzing the last step of the four steps of the dTDP-l-Rhamnose biosynthesis pathway during the production of poly-rhamnose GAC cores. Meanwhile, the GacD and GacE genes encode transporter proteins that play a role in translocation of rhamnan polymer from the cytoplasmic side of the membrane to the outer surface of the cell membrane.81,87 Biosynthesis of rhamnan backbone as a component of GAC is very essential because it plays a role in GAS viability. Anchoring of GlcNAc to the poly-rhamnose chain to form the GAC structure involves a protein encoded by the GacL gene. GlcNAc is tethered to the 2-hydroxyl of the rhamnose residue so that GlcNAc presentation leads out of the rhamnose helix.56 Approximately 20 – 30% of the GlcNAc residues in GAC polymers contain modified components from glycerol phosphate.56,84 These modifications are mainly found in the C6-hydroxyl group. The location of the GAC polymer is located on the outer surface of the GAS cell wall and is highly conserved among GAS strains which makes GAC interesting polysaccharide component of glycoconjugate vaccines.79,88\n\nA known mutant group A streptococcus without the presence of GlcNAc has susceptibility to leukocytes, including neutrophils that show much greater binding ability to bacteria. This is caused by cathelicidin, which is a human peptide defense, which has a higher affinity for mutant polysaccharides.83,89 Furthermore, the absence of GlcNAc has a major influence because GlcNAc has a function in reducing the binding of cationic bactericidal enzyme human Group IIA.84,87,90 Therefore, the GlcNAc side chain is the most important virulence determinant in GAS. The polysaccharide branch consisting of rhamnose and GlcNAc side chains has shown immunogenic capabilities that have been demonstrated through rabbit and human antisera, NMR techniques demonstrating the interaction of GAC with mAb and computer simulations.82 The GlcNAc side chain is predicted to have a key role in the evasion of the human immune system. The GlcNAc side chain of GAC contributes to resistance to innate immunity and the virulence phenotype of globally distributed GAS strains. In GAS serotype M1, the absence of GlcNAc results in significantly reduced survival in the blood of humans and animals modeled for infection.91 Meanwhile, in GAS serotype M3, the GlcNAc side chain is required to increase survival in human blood through platelet releasate.83 The characteristics of resistance to neutrophil killing in GAS are more conserved in GAS strains M1, M2, M3, and M4 with the GlcNAc side chain of GAC.48,83,91\n\nA study conducted by Sabharwal et al. demonstrated that GAC is immunogenic and protective against GAS infection. In addition, antibodies against the presence of GAC in human serum are highly opsonic against various M-protein serotypes of GAS and are not cross-reactive against human tissues.92,93 Another study conducted by Pinto et al. also showed that the size and orientation of the antigenic epitope of GAC are crucial parameters for recognition by both monoclonal and polyclonal antibodies so that antibodies induced by GAC-based vaccines will effectively recognize epitopes on the surface of GAS cell walls.94 Both Pinto and Kabanova et al. simultaneously demonstrated that the repeat unit of GAC is an optimum epitope when used as a vaccine component to elicit an adequate immune response against GAS infection.94,95 Meanwhile, Wang and colleagues showed that three repeat units in the GAC structure conjugated to the inactive form of group A streptococcal C5a peptidase (ScpA193) showed efficient and feasible results if developed as a vaccine against GAS infection.93 However, several studies in pre-clinical studies show evidence that antibodies formed from pure GlcNAc-based GAC vaccines have autoimmunity capabilities due to cross-reaction with cardiac myosin protein.96–99 The study conducted by Galvin et al. found that monoclonal antibodies derived from patients with rheumatic carditis and arthritis were cross-reacted to GlcNAc from GAC residues.100,101 Antibodies that recognize GlcNAc from GAC residues are the main cause of major clinical neuronal disorders from acute rheumatic fever such as Sydenham chorea. This is confirmed by an in-vivo study conducted by Brimberg et al. used a mouse model that demonstrated the presence of streptococcal antibodies deposited in the frontal cortex, striatum, and thalamus.102 Therefore, the utilization of the GlcNAc component from GAC residues in vaccine development will face the same challenges as developing an M-protein-based GAS vaccine, namely the presence of cross-reactivity that can arise against human body tissue.\n\nl-Rhamnose (Rha) is a deoxy sugar because the hydroxyl group on one of the carbon atoms of the sugar carbon chain is replaced with a hydrogen atom.80,103 Rhamnose is very common in bacteria and plants. Rhamnose is an essential monomer for pathogenic bacteria because it is the main component of cell walls and capsules which has a vital role in virulence and bacterial survival.83,104 l-Rhamnose is synthesized by bacteria from glucose-1-phosphate (Glu-1-P) which acts as a precursor through the enzyme glucose-1-phosphate thymidylyltransferase (RmlA) which catalyzes the transfer process of thymidyl monophosphate nucleotide to Glu-1-P.86 Afterward, the enzyme dTDP-d-glucose 4,6-dehydratase (RmlB) catalyzes the deoxidation process of the hydroxyl group on C4 of the sugar ring followed by dehydration (release of H2O). The third enzyme, namely dTDP-6-deoxy-d-xylo-4-hexulose 3,5-epimerase (RmlC), catalyzes the double epimerization reaction at the C3 and C3 positions of the sugar ring. Next, the final step, namely the enzyme dTDP-6-deoxy-d-xylo-4-hexulose reductase (RmlD) reduces the keto function on C4 to form the final product, namely dTDP-l-Rhamnose or what is usually called rhamnose (Rha).86,104,105 Entire multiple steps of rhamnose biosynthesis are absent in mammalian cells. To date, neither rhamnose nor the genes responsible for biosynthesis have been found in mammals, especially humans.106,107 Rhamnose, which is the main component forming the GAC backbone of GAS in the form of poly-rhamnose, whose absence in mammalian cells is a very attractive candidate for the development of a universal GAS vaccine. Considering that the rhamnose biosynthesis pathway is very widespread and conserved in both Gram-positive and Gram-negative bacteria, as well as its absence in mammalian cells, rhamnose or poly-rhamnose-based GAS vaccines will have high protection coverage against various GAS serotypes without causing cross-reactivity in human body tissues.\n\nA study conducted by van Sorge et al. who injected poly-rhamnose (GlcNAc-deficient GAC) showed a significant reduction in binding to human monoclonal antibodies obtained from patients with rheumatic carditis. Furthermore, extensive pre-clinical studies by van Sorge et al. using mouse and rabbit models of GAS infection showed that poly-rhamnose backbone injection increased GAC antibodies which promoted opsonophagocytic killing in multiple GAS serotypes (Figure 3).91\n\nIgG antibodies formed against poly-rhamnose are able to provide passive protection of the murine system against various GAS strains and induce opsonophagocytic activity against the M1 strain as well as eight other strains.81,91 Recently, a glycoconjugate vaccine has been further developed which grafts synthetic tetra- and hexa-rhamnoside from the GAC backbone onto gold nanoparticles as a vaccine delivery platform.108 Through the vaccine delivery platform, effectiveness and efficacy will increase significantly. Therefore, the rhamnose component is very promising in the development of a safe and effective GAS vaccine. Research conducted by Sowmya et al. used recombinant poly-rhamnose backbone (pRha) carried using a carrier in the form of outer membrane vesicles (OMVs) from Escherichia coli bacteria to investigate immunogenicity and efficacy in animal models. The results of this study showed that pRha-OMVs induced specific antibodies that could recognize GAC from Streptococcus pyogens and Streptococcus dysgalactiae subsp. Equisimilis.109 An increase in IgG antibody titer correlates with increased bactericidal killing in the hypervirulent GAS strain M89. Aside from that, the increase in IL-17a in the study’s results indicated that long-term memory immune cells were stimulated after administration of the pRha-OMVs vaccine.109 Furthermore, regarding the safety level of the vaccine, in this study, there was no mention of any cross-reactivity to animal tissue which has been a challenge in the development of GAS vaccines. Over the last few decades, several studies have been conducted to further identify the effectiveness and safety level of rhamnose or poly-rhamnose-based vaccines from GAC (Table 1).\n\n\nConclusion\n\nThe Group A Streptococcus (GAS) vaccine based on l-Rhamnose obtained from the poly-rhamnose backbone Group A Carbohydrate (GAC) has shown a protective effect against GAS infection which has been proven through pre-clinical studies which show an increase in IgG antibody titers facilitating and improving opsonophagocytic ability against various GAS strains. In addition, various recent studies have shown that the use of Rhamnose-based vaccines does not show any cross-reactivity in test animal tissue thus the vaccine is able to provide protection against GAS infection without causing ARF attacks due to the absence of cross-reactive antibodies. These findings demonstrate that the l-Rhamnose-based vaccine possesses strong immunogenicity, which effectively protects against GAS infection while maintaining a significantly higher degree of safety. Prevention of GAS infection through effective vaccination will provide protection against ARF attacks and its sequelae, namely RHD, which has become a global burden both in terms of epidemiology and management costs, especially in low- and middle-income countries.", "appendix": "Data availability statement\n\nNo data are associated with this article\n\n\nReferences\n\nAjay Castro S, Dorfmueller HC: Update on the development of Group A Streptococcus vaccines. NPJ Vaccines. 2023; 8: 135. Nature Research. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWebb RH, Grant C, Harnden A: Acute rheumatic fever. BMJ. 2015; 351. BMJ Publishing Group. 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Publisher Full Text\n\nHenningham A, Davies MR, Uchiyama S, et al.: Virulence role of the glcnac side chain of the lancefield cell wall carbohydrate antigen in non-m1-serotype group a streptococcus. MBio. 2018 Jan 1; 9(1) PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nEdgar RJ, van Hensbergen VP , Ruda A, et al.: Discovery of glycerol phosphate modification on streptococcal rhamnose polysaccharides. Nat. Chem. Biol. 2019 May 1; 15(5): 463–471. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nZorzoli A, Meyer BH, Adair E, et al.: Group A, B, C, and G Streptococcus Lancefield antigen biosynthesis is initiated by a conserved α-D-GlcNAc-β-1,4-L-rhamnosyltransferase. J. Biol. Chem. 2019 Oct 18; 294(42): 15237–15256. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMistou MY, Sutcliffe IC, Van Sorge NM: Bacterial glycobiology: Rhamnose-containing cell wall polysaccharides in gram-positive bacteria. FEMS Microbiol. Rev. 2016; 40: 464–479. 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MBio. 2016; 7(3). PubMed Abstract \| Publisher Full Text \| Free Full Text" }	[ { "id": "330060", "date": "10 Oct 2024", "name": "Arif Nur Muhammad Ansori", "expertise": [ "Reviewer Expertise Molecular Biology and Bioinformatics" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nFirst of all, this manuscript is good and well-written. However, I may require some comments on the following issues. Basically, this manuscript is acceptable. However, in order to improve the readability of the paper by an English editing service as various sentences are mistyped. Title: The title is easy to follow and no mistakes. Abstract: This section was well-written and easy to understand. In addition, the study's objective and the state of the art of the study is clear. Furthermore, the keywords should represent the study. Discussion: The discussion of the study is lack of information about the important topics. To develop a systematic discussion, the authors should mention the limitation(s) of the study. Conclusion: In this part of the paper, the authors have established the conclusion of this study. References: Many references are out of guidelines. Please kindly check the references again, do not include the old references, and check the abbreviation of the journals/proceedings. Please mention many high-quality related publications in 2023-2024.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? No\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes", "responses": [ { "c_id": "12665", "date": "28 Oct 2024", "name": "Ade Meidian Ambari", "role": "Author Response", "response": "The authors convey their appreciation and gratitude to the reviewers for their constructive assessments and evaluations. The reviewers' suggestion has been optimally implemented, and these enhancements are evident in the latest version of this paper. Furthermore, we have enhanced the quality of grammar and English use by using editing services and utilizing grammar and paraphrasing tools to augment the paper's readability. Title: The title is easy to follow and no mistakes. Response: Thank you for the provided assessment. Abstract: This section was well-written and easy to understand. In addition, the study's objective and the state of the art of the study is clear. Furthermore, the keywords should represent the study. Response: Thank you for your insightful evaluation and feedback. The author modified the keywords to more accurately reflect the study. Discussion: The discussion of the study is lack of information about the important topics. To develop a systematic discussion, the authors should mention the limitation(s) of the study. Response: Thank you for the feedback. The authors enhance the quality of the Discussion section by including and expanding on different prior research findings, particularly those concerning the efficacy and safety of the Rhamnose-based GAS Vaccine, which is key to this study topic. In addition, the authors have included the study's limitations in the final paragraph of the discussion section. The authors faced challenges in incorporating relevant research data published in the past two years, which pertains to the study's shortcomings. The search was extended to encompass a minimum of the past decade. Conclusion: In this part of the paper, the authors have established the conclusion of this study. Response: Thank you for the provided assessment. References: Many references are out of guidelines. Please kindly check the references again, do not include the old references, and check the abbreviation of the journals/proceedings. Please mention many high-quality related publications in 2023-2024. Response: I appreciate your constructive criticism. The authors have assessed and amended all references cited in the manuscript according to metadata from the reference management software (Mendeley). Furthermore, we have eliminated several outdated references deemed non-essential (material remains accessible in other publications) (e.g., Giraud MF, Naismith JH. The rhamnose pathway. Curr Opin Struct Biol. 2000 Dec;10(6):687–96.), and the authors have incorporated recent studies published in 2023." } ] } ]	1	https://f1000research.com/articles/13-132
https://f1000research.com/articles/13-1390/v1	19 Nov 24	{ "type": "Systematic Review", "title": "Biological properties of Moringa oleifera: A systematic review of the last decade", "authors": [ "Javier Andrés Soto", "Andrea Catalina Gómez", "Maryeli Vásquez", "Andrea Natalia Barreto", "Karen Shirley Molina", "C. A. Zuniga-Gonzalez", "Andrea Catalina Gómez", "Maryeli Vásquez", "Andrea Natalia Barreto", "Karen Shirley Molina", "C. A. Zuniga-Gonzalez" ], "abstract": "Background The growing incidence of chronic diseases such as cancer and the emergence of drug-resistant microorganisms constitute one of the greatest health challenges of the 21st century. Therefore, it is critical to search for new therapeutic alternatives. Moringa oleifera is a plant well known for the properties of its phytocomponents and its role has been analyzed in a variety of fields, from medicine to biotechnology.\n\nMethods In this work, the biological activity of Moringa oleifera in human health was explored through a review of 129 original articles published between 2010 and 2021 related to antitumor activity and its potential uses against chronic and infectious diseases.\n\nResults\nMoringa oleifera extracts showed antioxidant, hypoglycemic, antihypertensive and cytoprotective properties at neuronal, hepatic, renal and cardiac levels. Besides, cytotoxic effects, apoptotic and antiploriferative activity against several cancer cell lines has been demonstrated. On the other hand, the antimicrobial potential of M. oleifera was also evidenced, especially against multidrug-resistant strains.\n\nConclusions Hence, it is supported that there is a wide range of clinical entities in which Moringa oleifera exhibits significant biological activity that could contribute to counteracting metabolic, infectious and chronic diseases in a similar or improved way to the drugs traditionally used.", "keywords": [ "Biological activity", "cancer", "chronic diseases", "infectious diseases", "Moringa oleifera", "phytochemical components." ], "content": "1. Introduction\n\nNatural resources such as plants have been used since ancient times to treat various diseases with positive results. Recently, the use of medicinal plants has gained interest in low-and middle-income countries, with Moringa oleifera being a plant with a high potential for health and industry due to the properties of its components.1\n\nMoringa oleifera (MO) is worldwide-distributed Indian native tree whose different structures (bark, leaf, root, seeds, pod, fruits and flowers) are consumed as therapeutic alternative to treat different ailments. Also, this plant shows a high nutritional power, especially its leaves,2 since these exhibit a high content of vitamins (A, C and E). Vitamin A plays a key role in vision, immunity, cell growth, differentiation and reproduction while vitamins C and E participate in the protection against free radicals acting as a good source of antioxidants. The leaves are also rich in essential amino acids and minerals such as iron, phosphorus, potassium and calcium, the latter being necessary for blood coagulation, the nervous system and the genesis and maintenance of bones and teeth, as well as to delay the onset of osteoporosis. In addition, MO has a high content of terpenoids, anthraquinones and glycosides.1–3\n\nThis plant also exhibits a low fat content (4.03-9.51%) where the presence of polyunsaturated fatty acids is higher than that of saturated fatty acids, hence the consumption of this plant could establish a relation with the prevention of coronary heart disease (3). In addition, it has been observed that MO is rich in fiber, a factor that contributes to the cleansing of the gastrointestinal tract. On the other hand, this plant’s presence of isothiocyanates confers to antibacterial activity.4\n\nSeveral authors have described MO as a plant that provides natural and medicinal supplements for human health, which is why scientific evidence has been found about its benefits. However, most of the studies have been based on in vitro analyses and there is very little in vivo evidence; this is because there is uncertainty about the cytotoxic effects that it could have.1\n\nOn the other hand, according to scientific studies that have been published in recent years indicate that one of the components with the greatest biological potential is the leaf, since it contains a series of vitamins and amino acids. In addition, it has a great capacity for water purification and for its great nutritional value.4 However, according to re-search carried out by Sultana in 2020, he showed that although there are works described in the literature that indicate that the leaves of MO have a high level of protein, in his study it was found the opposite. However, he makes the clarification that there may be environmental factors (geographical area) that affect this component.3\n\nThe data analysis represented in this review reflects the most relevant findings and the connection with the plant properties regarding various clinical conditions. This work revels new potential treatment options in the context of nature-based alternatives aiming to overcome the disadvantages associated with the implementation of conventional therapies, such as side effects and the lack of specificity and efficacy of current treatments.\n\nMoringa oleifera is a tree belonging to the Moringaceae family, native to the sub-Himalayan area of India, Pakistan, Bangladesh and Afghanistan whose genus has 13 species distributed from tropical to subtropical regions.5 MO is a plant widely studied worldwide for its components since these confer it particularities of interest in areas such as health, aesthetics, and nutrition, among others.\n\nThe most studied part is its leaves since these have been attributed different biological properties including antimicrobial, hypotensive, antiulcer, hypocholesterolemic, antispasmodic, antioxidant, anti-inflammatory and antitumor agent potential.6 In relation to its chemopreventive role, Sreelatha et al.7 evaluated the antitumor effect of Moringa oleifera leaf alcoholic extract (rich in phenolic compounds, such as quercetin and kaempferol) on glandular cervical cancer cells, revealing a potential in the inhibition of cell viability through the induction of apoptosis and oxidative stress through the generation of reactive oxygen species (ROS) and an antiproliferative effect, thus revealing a promising outlook as an antitumor alternative.7\n\nMO is one of the most cultivated and important medicinal plants in India and is considered as a staple food in various parts of the world since its valuable nutritional potential4 due to the high content of minerals and vitamins such as iron, potassium, copper, zinc, magnesium, manganese, vitamin C, vitamin E, beta-carotene, among others. Different studies have been described associated with the leaf, seed, fruit, bark and flower of Moringa oleifera in several types of cancer, which have revealed the biological antitumor activity both in vitro and in vivo. One of these works was performed by Hussein et al.8 in which they determined the components of Moringa oleifera seed essential oil in vitro that act as antioxidants, and showed the cytotoxic potential over tumor cell lines like human breast adenocarcinoma (MCF-7), colon carcinoma (HCT-116), human hepatocarcinoma (HepG2) and HELA cells (8).\n\nThis plant has been considered of great curative relevance in relation to the presence of significant phytochemicals9 also known as secondary metabolites such as polyphenols, tannins, sterols, terpenoids, flavonoids, saponins, anthraquinones, alkaloids and some reducing sugars mentioned along with anticancer elements, including glucosinolates, isothiocyanates, glycoside compounds and glycerol-1-9-octadecanoate.10 Phenolic acid derivatives are elements with similarity to flavonoids, which have been related to plant protection against UV rays and also with other defensive mechanisms. One type of phenolic acid, chlorogenic acids, are known for protecting against diseases caused by oxidative stress.11 Some of the main flavonoids found by Sultana and Anwar (2008) present in Moringa oleifera leaves are myricycin, quercetin and kaempferol, at concentrations of 5.8, 0.207 and 7.57 mg/g, respectively.12 Moreover, Vergara-Jiménez et al.13 point out that quercetin is found in MO dried leaves in concentrations of 100 mg/100 g. This phytochemical acts as a strong antioxidant and exhibits hypolipidemic, hypotensive and antidiabetic potential, which has been demonstrated in vivo with rats suffering from metabolic syndrome and rabbits with hyperlipidemia.13\n\nConcerning the biological activity of MO against microorganisms, Padla et al.14 highlight that isothiocyanates isolated from Moringa oleifera seeds showed inhibitory activity at the lowest concentration of 1 mg/ml towards all Gram-positive bacteria tested (Staphylococcus aureus, Staphylococcus epidermidis and Bacillus subtilis) and against the dermatophyte fungi Epidermophyton floccosum and Trichophyton rubrum ( Figure 1).14\n\nSeveral elements of this plant have been used traditionally in India as a preventive and treatment approach for pathologies such as asthma, gout, rheumatism, and infections.15 Same scenario occurs in Africa where this MO is used to combat arthritis, joint pain, headaches, abdominal pain, otitis, and dental pain and it has also been used as a cardiac and circulatory stimulant, in individuals with asthenia, intestinal parasites, febrile periods, renal and hepatic complications, epilepsy, anemia, ulcers, delirium, and trauma caused by snakes.\n\nMoringa oleifera has been used to treat respiratory diseases such as influenza and asthma, and even SARS-CoV-2, which caused the last pandemic,16 gastritis, headaches and flatulence17; thus demonstrating its wide range of uses for a variety of clinical entities. It should be remembered that millions of people in the world do not have access to modern medicine, having to resort to the alternatives provided by ancestral medicine.18\n\nThe relevance of the antioxidant activities of components that make up the Moringa oleifera plant, such as polyphenols, alkaloids, saponins, carotene, minerals, amino acids, and sterols, has been demonstrated. Such antioxidant features has been identified through several approaches, including colorimetric methods such as DPPHH (2,2-diphenyl-1-picrylhydrazyl), ABTS [2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid)], LPO (lipid peroxidation), FRAP (ferric reducing antioxidant power), among others, in order to obtain evidence related to the redox potential of the plant.19\n\nPolyphenols are phytochemicals found in large quantities especially in Moringa oleifera and are considered natural antioxidants. These are plant compounds that are attributed with the property of indirectly reducing oxidative damage in tissues by strengthening cells or eliminating free radicals.20 It has been demonstrated that consumption of polyphenols protects against chronic pathologies related to oxidative stress, including cardiovascular diseases and cancer.13 The presence of polyphenols in high concentrations in this plant leaves opens the door for their use in the aforementioned diseases. It is worth noting that to achieve the greater potential of antioxidants against damage caused by free radicals, the synergistic work of several antioxidants is necessary. A combination of effective antioxidants n the leaves of Moringa oleifera has been found21 among then, polyphenols, mostly flavonoids (myricetin, quercetin, and kaempferol), together with phenolic acids (chlorogenic acid, caffeic acid, and gallic acid).22\n\nMoringa oleifera extracts exhibit strong antioxidant activity and radical scavenging in vivo, protecting animals against oxidative stress-induced diseases. Consumption of leaf and seed extracts has shown significant therapeutic properties against diabetes and hypertension due to the phyto-components, exhibiting mitochondrial redox potential, increasing heme oxygenase-1 and reducing reactive oxygen species (ROS) induction as well as lipid peroxidation, thus conferring protective effects against negative effects associated with obesity.23,24 It is even suggested that its antioxidant capacity is so promising that the role of Moringa oleífera derivatives should be explored in the treatment of wastewater and as a future source of important nutraceuticals.21\n\nThe potential of Moringa oleifera as an anticancer agent has been elucidated through the role of ethanolic extracts obtained from the leaves and bark which have effectively inhibited the growth of cancer cells in breast, pancreas, and colorectal tissue. It is believed that the plant’s antitumor capacity is due to the presence of isothiocyanates, glucosinolates, glycosylated compounds, and glycerol 1-9-octadecanoate.25 It has also been proved that Moringa oleifera pods act as a chemo preventive agents in vivo This protective effect has also been identified by Shaban et al., 26 who observed an in-crease in antioxidant levels and a reduction in the formation of free radicals against several cancer cell lines (lung, liver, colon, and neuroblastoma) treated with the plant.26\n\nRegarding the extract of Moringa oleifera seed, this has shown specific growth inhibitory effects reflected in a 95% inhibitory activity on neuroblastoma cell line.27 In some cases, tumors treated with methanol extracts from fruits and leaves have grown slowly, indicating effective cell degradation. Likewise, it has been found that the extract is more effective in terms of volume, since at a concentration of 500 mg/kg, the doubling time and growth delay indicate tumor-suppressing properties.27\n\n\n2. Methods\n\nThis compilation is of a qualitative, descriptive and documentary nature and its development required the collection of original scientific articles obtained from databases such as PubMed, ScienceDirect, EBSCO Host, Scopus, and Google Scholar. The number of records identified through the database search was 2700 publications initially. Subsequently, these raw results were processed using filters such as keywords including Moringa oleifera, chronic diseases, infectious diseases, biological activity, human cancer, antitumor biological activity, in vivo and in vitro activity and anticancer properties, aiming to identify and select relevant information for the analysis of biological activity against human diseases, thus reducing the number of potential publications to 410.\n\nFrom the articles found in the above-mentioned databases, an exclusion and inclusion process was carried out. Once the data was obtained, this information was housed in a categorization matrix that specified different items such as access link, title, authors, journal, year, methodology, results, conclusions, and discussions aiming to synthesize the information and making it more accessible for a selective and exclusive analysis. This screening and analysis process allowed to obtain a total of 112 definitive publications. It is important to highlight that not only the articles described in the results section were used, this means that there is a greater number of articles mentioned and analyzed since other bibliographic sources were added in the rest of the body of the document.\n\nA systematic literature review was conducted using academic databases such as PubMed, Scopus, and Google Scholar. Original articles published between 2010 and 2021 that investigated the biological activity of Moringa oleifera in relation to its antitumor activity and potential uses against chronic and infectious diseases were included.\n\nInclusion criteria included studies that:\n\na) Addressed the biological activity of Moringa oleifera.\n\nb) Presented empirical results regarding its antitumor properties or effects on chronic and infectious diseases.\n\nc) Were original articles peer-reviewed.\n\nd) Exclusion criteria comprised reviews, editorials, and articles not published in English or Spanish.\n\nA search was performed using keywords such as “Moringa oleifera,” “antitumor,” “chronic diseases,” and “infectious diseases.” Following the initial search, titles and abstracts were screened to filter relevant articles. A full reading of the selected articles was then conducted to extract data on biological activity and proposed mechanisms.\n\nThe findings from the selected articles were synthesized, highlighting the most relevant biological properties and methodologies employed in each study. A descriptive approach was used to summarize results and discuss the implications of the findings for human health.\n\n\n3. Results and discussion\n\nChronic diseases are characterized by a long course and slow progression, and include cardiovascular diseases, cancer, chronic kidney and liver diseases, rheumatic disease, and diabetes. According to the World Health Organization (WHO), chronic diseases are the leading cause of mortality worldwide, causing approximately 41 million deaths each year, equivalent to 71% of deaths globally.28 These pathologies can be prevented by modifying common behavioral risk factors, such as smoking, alcohol consumption, unhealthy diet, and physical inactivity, which contribute to the development of metabolic changes that usually manifest themselves as hypertension, obesity, hyperglycemia, and hyperlipidemia.29\n\nSpecific genetic events and external agents such as physical carcinogens such as ultraviolet (UV) and ionizing radiation, chemical carcinogens such as asbestos, aflatoxins, arsenic, and biological carcinogens (Helicobacter pylori, viruses, and parasites) increase disease morbidity.30 However, cardiovascular diseases are positioned before cancer, as they are the leading cause of death among chronic diseases (approximately 18 million deaths per year), followed by cancer (9 million deaths per year) and diabetes (1.6 million deaths per year).28 These three pathologies are responsible for more than 80% of premature deaths, that is, fatal events occurring between the ages of 30-69 years.29\n\nConcerning infectious diseases, which are basically foodborne illnesses (FBIs), sexually transmitted infections (STIs) such as HIV/AIDS, acute respiratory infections (ARIs) including the common flu and the current novel coronavirus (COVID-19), and other parasitic and bacterial diseases; a global increase in drug resistance rates has been identified, indicating a loss of effectiveness in usual treatments. Regarding antiviral resistance, there is an increasing concern, mainly for immunocompromised patients, as well as for the emergence of drug-resistant parasites, which constitute one of the greatest threats to malaria control. In the case of drug-resistant fungal infections, the therapeutic situation is already difficult se because patients currently experience treatment problems, such as toxicity, especially in individuals with other underlying infections.31 Some infections can be prevented by vaccination; however, the increasing resistance to antimicrobials (antibiotic, antiviral, antifungal, and antiparasitic) due to their inappropriate and excessive use has led to some of these diseases becoming a global public health problem owing to an increase in morbidity and mortality rates, long hospital stays, and high healthcare costs.31\n\nTherefore, considering what has already been described, a viable therapeutic alternative is found in natural and complementary medicine based on the use of plant material, its extracts, and derivatives. In recent decades, medicinal plants have become a trend in developing countries, with Moringa oleifera as a promising plant because several studies have demonstrated its therapeutic and pharmacological properties, including neuroprotective, antimicrobial, antiasthmatic, antimalarial, cardioprotective, antidiabetic, antiobesity, hepatoprotective, and anticancer effects.1\n\nChronic diseases have had a significant impact worldwide due to their high mortality rates and the fact that their related therapies often have side effects on patients. Based on this, there is a need to explore other therapeutic alternatives, such as natural treatments, including the use of Moringa oleifera, which has shown positive effects regarding the potential treatment of such diseases over time, as revealed in this study. In the following sections, several in vitro and in vivo studies conducted between 2010 and 2021 on the use of Moringa oleifera in the aforementioned clinical events are described.\n\nCardiovascular diseases are chronic diseases and are of great interest because they rank first as the cause of death worldwide. However, in chronic diseases, another clinical entity attracts the attention of the medical community because of the rapid increase in incidence rates and high associated morbidity. According to data from the Diabetes Atalas, 463 million adults currently live with this disease, and the global projection of cases for 2025 is 438 million, but this prediction has already been exceeded by 25 million cases.32 Making the scenario more complex, this pathology is not diagnosed or is misdiagnosed in low-income countries, increasing the risk of serious complications and mortality. Additionally, the lack of availability of diabetes medications is a challenge. The projections for this disease are not only gloomy regarding the well-being of individuals but also in terms of fiscal detriment to global health systems, as expenses related to the disease are estimated to reach over one billion dollars by 2045.33\n\n3.2.1 Therapeutic properties for chronic diseases\n\nIn India, the native country of the plant, Aju et al.34 evaluated the protective role of the methanolic extract of Moringa oleifera leaves (MOME) in the hearts of diabetic rats and demonstrated that treatment with MOME at a dose of 300 mg/kg/day significantly reduced hyperglycemia and oxidative stress in the hearts of the animals.34 The potential antidiabetic and antioxidant properties of MOME were attributed to the presence of various biologically active compounds, such as heptadecanoic acid, hexadecanoic acid, DL-alpha-tocopherol, 11-14-17-eicosatrienoic acid, and 9-12-15-octadecatrienal, which have been previously associated with the antiarthritic and anticoronary activities of the plant.34\n\nIn line with the antidiabetic study, Khan et al.35 used the aqueous extract of Moringa oleifera leaf (AEMOL) at a dose of 100 mg/kg in streptozotocin-induced diabetic rats to determine the hypoglycemic potential to assess the enzymatic activity, seeking to identify the antioxidant capacity due to the presence of compounds such as phenols.35 However, the evaluation of inhibitory activities and potential radical scavengers of two promising plants (M. oleifera and T. occidentalis) on the enzymes highlighted in diabetes mellitus revealed enzyme inhibition,36 with Moringa oleifera being the major contributor to this event in a dose-dependent manner. Another relevant finding of this study was related to the identification of a greater number of phytoconstituents in Moringa oleifera than in Telfairia occidentalis.36\n\nConcerning the antidiabetic role of Moringa oleifera leaf powder, the chemical composition of this substance has been evaluated with regard to the inhibition of α-amylase enzyme, testing the inclusion of 20 g of Moringa oleifera leaf powder in natural foods and studying in diabetic and healthy patients. From these analyses, it was found that Moringa oleifera leaf powder contains a high amount of protein, fiber, and trace elements, in addition to known polyphenols.37\n\nApproaches focused on demonstrating an association between the potential of leaf extracts and therapy for vascular diseases have evaluated the antihypertensive mechanisms of the aqueous extract of Moringa oleifera leaves (MOE). Aekthammarat et al.38 concluded that MOE induces the synthesis of Nitric Oxide (NO) in endothelial cells, thus reducing peripheral vascular tone and blood pressure (BP), a dependent event on soluble guanylate cyclase (sGC). This induces vasorelaxation through the activation of the eNOS-NO-sGC pathway, allowing us to understand the pharmacological properties of MOE against arterial hypertension.38\n\nThe seeds of Moringa oleifera seeds have also shown potential for evaluating antidiabetic effects. Al-Malki and Rabey39 tested low doses of Moringa oleifera seed powder, 50 and 100 mg/kg, in rats with induced diabetes, and through different methodological approaches, such as biochemical, immunological, physiological, and histological analyses, observed that low doses decreased lipid peroxidation to a greater extent than the 100 mg concentrations, and also proved that the amount of antioxidant enzymes increased in the treated groups. Specifically, in relation to glycosylated hemoglobin, rats treated with M. oleifera showed significantly reduced values, although the most drastic change was associated with the dose of 100 mg/kg.39\n\nThe methanolic extract of Moringa oleifera seeds (MOSE) has been evaluated for its ability to alter serum lipid profiles. An example of this is the assessment carried out by Ajayi et al., 40 where weight gain was observed in untreated animals compared to those treated with this extract. It was also noted that there was a decrease in total cholesterol (<0.05) in experimental animals administered MOSE at 100 mg/kg, but this effect was not significant at 200 mg/kg. Regarding high-density lipoprotein (HDL), it was found that in groups treated with both concentrations of MOSE, this parameter increased, but this increase was more significant at 200 mg/kg.40\n\nTable 1 shows some in vivo and in vitro concerning the potential of extracts obtained from different parts of the plant to counteract some chronic diseases.\n\nThe International Agency for Research on Cancer (IARC) states that in 2020 there were 19.3 million new cases of cancer and nearly 10 million deaths.59 According to the Global Cancer Observatory (GCO), lung cancer is the most commonly diagnosed cancer in men (14.3%), followed by prostate cancer (14.1%) and colorectal cancer (10.6%). In women, the most common type of neoplasia and the one with the highest mortality rate was breast cancer (24.5%), followed by colorectal cancer (10.6%) and lung cancer (8.4%).59 It is predicted that by 2030, there will be a 32% increase in the number of people diagnosed with cancer in the Americas.60\n\nCurrently, the main therapies used against cancer in medical oncology are surgery, hormonal therapy, radiation, immunotherapy, and chemotherapy. Despite their widespread use, these approaches have adverse effects because they affect cells that are in constant division, such as the bone marrow, lining of the mouth and intestines, and hair follicles. The type of side effect depends on the type of medication used, amount administered, and treatment time. The use of conventional approaches such as chemotherapy has resulted in very low survival rates for patients with advanced-stage cancer.61\n\n3.3.1 In vitro antitumor evidence\n\nWith the aim of elucidating the potential antitumor capacity of various extracts from Moringa oleifera, Cuellar et al.62 conducted a study related to the effect of hydrolyzed extracts from the plant leaves on human colon cancer cells, HT-29 and HCT116, showing similar cytotoxic activity in both cell lines compared to untreated cells.62 According to the types of extracts evaluated in the study, it was observed that the aqueous extract, the methanolic extract, and the glucosinolate-rich hydrolysate showed the highest cytotoxic effect on the HCT116 human colon cancer cell line at concentrations of 20.1%, 21%, and 21.5%, respectively, unlike the HT-29 human colon cancer cell line, in which only the aqueous and methanolic extracts showed higher cytotoxicity at concentrations of 19.8% and 22%, respectively.62\n\nTo determine the possible mechanism responsible for the observed tumor cytotoxicity associated with this plant, the apoptotic and antiproliferative activity of the aqueous extract of Moringa oleifera leaf in human melanoma cell lines A375, A2058, and normal human fibroblasts was assessed. This biological activity was evaluated through the implementation of the WST-1 cell proliferation assay and the Annexin V-associated apoptosis assay, showing that the aqueous extract causes growth inhibition due to apoptosis events in the target lines.63 However, there was little effect on the growth of normal human fibroblasts, thus revealing the specificity of this compound.63\n\nTherefore, the aqueous extract of Moringa oleifera can be considered an alternative therapy for the treatment of skin cancer, while keeping in mind the importance of continuing in vitro and in vivo studies that provide scientific information about the biological activity of this plant. Several approaches associated with the study of the antitumor and chemopreventive capacities of Moringa oleifera are summarized in Table 2.\n\nAttempting to explore the potential of the Moringa plant not only regarding its leaves but also other elements, Adebayo et al.64 evaluated the cytotoxic activity and inhibition of cell proliferation of crude extracts and fractions of MO seeds on breast adenocarcinoma cells (MCF7) and normal breast cells (MCF10A) and found an insignificant effect of the crude ethanol extract on the proliferation of MCF7 cells.64 In contrast, the dichloromethane fraction of the crude ethanol extract, the hexane fraction of Moringa oleifera seed, and the crude aqueous extract inhibited proliferation.64 The observed cell inhibition effects in this study were most likely due to the presence of phenols. The hexane fraction of the ethanol extract exhibited the best effect, as it showed antitumor activity against MCF7 cells, while having limited cytotoxicity against normal breast cells.64\n\nTo determine the properties of Moringa oleifera in other tumor cell lines, a study targeting breast cancer cells (MDA-MB-231) and colorectal cancer cells (HCT-8) was conducted with the aim of identifying phenotypic changes, effects on cell viability, apoptosis, and alteration of the cell cycle. The results did not show a significant decrease in cell populations when exposed to different parts of the plant; however, the seed extract decreased cell motility and colony formation in both cell lines, despite not directly affecting their survival.65\n\nRegarding to the whole plant studies Diab et al.91 conducted a research aimed to explore the in vitro antiproliferative potential of extracts from the entire Moringa oleifera plant on cell lines of lung cancer (A549), prostate (PC-3), breast (T47D and MCF-7), colon (HCT-16, Colo-205), and leukemia (THP-1, HL-60) using two methods: cytotoxicity assay and MTT assay. The results showed in vitro cytotoxic activity of the plant extract actively inhibiting the growth of cancer cells in the cell lines A549, PC3, MCF-7, and HCT92; however, it showed a moderate effect on T47D, Colo-205, THP-1, HL-60, and K562 cells.91\n\n3.3.2 In vivo antitumor evidence\n\nIn an effort to identify the potential therapeutic role of Moringa oleifera in preclinical trials, Barhoi et al published in 2021 the results of a study evaluating the cytotoxic activity of this plant in BALB/c mice with mammary adenocarcinoma. The mice were administered aqueous leaf extract for a week, and after follow-up, a reduction in tumor weight and volume was observed with increased survival of the mice, without significant alterations in the liver, kidney, or hematological parameters after the treatment. In parallel, in vitro evaluations were carried out, showing the dose-and time-dependent cytotoxic activity of the plant in two cell lines: HEp-2 human laryngeal carcinoma cells and EAC (Ehrlich Ascites Carcinoma) mouse mammary adenocarcinoma cells. Regarding the mechanisms involved in the observed cytotoxic effects, flow cytometry analysis confirmed the significant induction of tumor cell apoptosis by changing the mitochondrial membrane potential in the EAC cell line.66\n\nAnother in vivo model considered the use of Sprague Dawley rats in which breast cancer was induced through treatment with 7,12-dimethylbenz(a) anthracene (DMBA), in order to analyze whether the combination of ethanolic extract of Moringa leaves and ethanolic extract of papaya leaves (Carica papaya L)93 could delay the appearance of tumor tissue. The results showed that there were different changes in body weight among the groups of rats for 12 weeks, and the appearance of tumor tissue was detected in the 7th week in the DMBA comparison group, while in the positive control group and the combined extract group of Moringa oleifera and Carica papaya leaves, the solid period began to be detected in the tenth week.93 According to histopathological tests, the growth of tumor tissue was found in all test animals, concluding that the combination of ethanolic extract of Moringa and Carica leaves at a dose of 150 mg/kg delayed the formation of cancerous tissue93; therefore, they can be considered as chemopreventive agents.\n\nSimilarly, Sadek et al. evaluated in vivo the chemoprophylactic efficacy of Moringa oleifera leaf ethanolic extract against hepatocellular carcinoma in male Wistar rats (40 male Wistar rats).94 After determining the appearance and histological changes in the liver, they found that rats treated with Moringa oleifera leaf extract (MOLEE) showed a reduction in liver enlargement as well as in the bumps and morphological alterations that this organ had compared to the group of rats treated with diethylnitrosamine (DEN), indicating that MOLEE treatment generated a favorable change in hepatic architecture.94\n\nContinuing the trend regarding the study of ethanolic extracts, in 2020, the results of the effect of MOLEE on signaling pathways in response to DNA damage to protect hepatic tissue from apoptosis triggered by Cobalt Chloride (CoCl2) in 40 male Sprague-Dawley rats were reported. The study showed that MOLEE reduced CoCl2-induced hepatic genotoxicity through the transcriptional induction of DNA damage repair genes,95 thus suggesting that MOLEE is a promising candidate for the food, nutraceutical, and pharmaceutical industries. Several studies approaches associated with the study of the antitumor and chemopreventive capacity of Moringa oleifera are shown in Table 3.\n\nAntimicrobial resistance crises must be urgently managed. The Global Action Plan on Antimicrobial Resistance acknowledges and addresses the variability of resources available to countries to fight antimicrobial resistance and the development of new antimicrobials by the pharmaceutical industry.104 This has led to several studies in the last decade focusing on the biological activity of phytochemicals from Moringa oleifera against different infectious agents.\n\n3.4.1 In vitro antimicrobial properties\n\nWithin the wide range of characteristics exhibited by Moringa oleifera for the treatment of chronic diseases, the potential of extracts from different parts of the plant as antimicrobial agents has also been elucidated. Dzotam et al.105 evaluated the antibacterial activity of the methanolic extract of M. oleifera leaves against sensitive and resistant strains of Escherichia coli, Enterobacter aerogenes, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Providencia stuartii, as well as their synergistic effects with some antibiotics, finding growth inhibition in 13 (68.4%) of the 19 strains used.105 Interestingly, it was also observed that the M. oleifera extract required one of the lowest minimum inhibitory concentrations compared to the other evaluated plants to counteract the growth of a multidrug-resistant strain.105 Additionally, this extract showed synergistic effects with most of the antibiotics tested.105\n\nMore recently and in line with Dzotam’s work, Umamaheswari et al. (2020) demonstrated the antimicrobial role of the plant, specifically against methicillin-resistant Staphylococcus aureus (MRSA) by evaluating the antimicrobial and antibiofilm potential of extracts from four plants, including Moringa oleifera. The ethanolic extract obtained from M. O leaves showed the lowest minimum inhibitory concentration (MIC) (250 μg/mL) and minimum bactericidal concentration (MBC) (500 μg/mL) among the evaluated plants.106 The antimicrobial potential was attributed to terpenoids and flavonoids, which are the main groups of phytoconstituents with antimicrobial properties that are naturally present in plants. Furthermore, M. oleifera extracts showed–30-60% inhibition of biofilm formation, and other findings revealed that the extracts were not toxic and had minimal hemolytic activity.106 Table 4 summarizes some in vitro experimental approaches focused on demonstrating the anti-infectious capacity of different parts of the Moringa oleifera plant.\n\nRegarding the antiviral potential of the plant, the activity of different leaf extracts against the infectivity of the lentiviral vector HIV-1 has been studied. It has been found that all the tested extracts, including methanol (MM), aqueous (AM), and petroleum ether (EM) extracts were active against the vector, inhibiting early events of viral replication in HeLa cells in a concentration-dependent manner, with IC50 values of 7.17 μg AM/mL, 7.72 μg MM/mL, and 7.59 μg EM/mL.107 Another significant finding is related to the selectivity index of M. oleifera extracts, as they showed sufficiently high selectivity towards the lentivirus, indicating that the observed antiviral activities were not due to cytotoxicity, but rather to the presence of phytochemical components such as saponins, alkaloids, glycosides, tannins, carbohydrates, flavonoids, resins, acidic compounds, and proteins.\n\nIt has also been demonstrated that the leaves of this plant possess antiparasitic characteristics, as shown by Cudjoe et al., 108 who studied the short-term (72 h) and long-term (7 days) effects of aqueous leaf extracts from four selected plants collected from the western region of Ghana on the growth of NF54 (chloroquine-sensitive), CamWT_C580Y (artemisinin-sensitive), and IPC 4912 (artemisinin-resistant) strains of Plasmodium falciparum. Long-term treatment with derivatives of Moringa oleifera leaves at a dose of 100 μg/mL inhibited 80% of the development of asexual forms of the NF54 strain.108\n\nSuch antiparasitic potential has been revealed not only in leaves but also in flowers. The anti-Trypanosoma cruzi activity and cytotoxicity in mammals of the aqueous extract of M. oleifera flowers, as well as the trypsin inhibitor protein isolated from this part, called MoFTI, have been evaluated. It was found that both the aqueous extract and MoFTI induced lysis of T. cruzi trypomastigotes with median lethal concentrations at 24 hours (CL50/24 h) of 54.18 ± 6.62 μg/mL and 41.20 ± 4.28 μg/mL, respectively.121 Both products showed low toxicity to murine peritoneal macrophages and Vero cells, with cytotoxic concentrations greater than 400 μg/mL at 50% (CC50).121 This study postulated that the flavonoids present in the extract were responsible for the observed cytotoxicity, as suggested by other studies.\n\nThe above is consistent with the findings from a study conducted by Nova et al. (2018) where treatment with MoFTI for 24 hours induced the lysis of T. cruzi tripomastigotes and did not affect the viability of human peripheral blood mononuclear cells (PBMCs).120 The effects of MoFTI on the immune response of T. cruzi-infected human PBMCs showed that treatment with this compound at a dose of 87 μg/mL for 48 h stimulated the release of tumor necrosis factor (TNF) α and interleukin (IL) 10 by infected PBMCs, compared to those treated with the conventional drug for the acute phase of Chagas disease, benznidazole, which had no effect on cytokine modulation in infected and uninfected cells.120 Thus, MoFTI is a potential trypanocidal and immunomodulatory agent in Chagas disease that can prevent its chronicity, so it should be taken into account and considered for future formulations developed by the pharmaceutical industry.\n\nSimilarly, Moringa oleifera also exhibits antiviral effects in substances obtained from its seeds, as demonstrated in studies on its antiviral properties against influenza A virus (IAV) using methanol extract and apparent regulation of transcription factor EB (TFEB). Initially, Moringa oleifera showed low cytotoxicity towards RAW264.7, and protected infected cells from cytopathic effects (CPE), inhibiting cell lysis by up to 93.7%.123 Furthermore, the hemagglutination assay was positive, indicating that the viral load in the groups treated with the extract was significantly reduced, particularly at concentrations of 5 and 10 μM.123 Additionally, this extract suppressed autophagy in H1N1-infected cells, and it was established that this suppression was dependent on the decrease in TFEB levels in the nucleus of treated cells. Similar to the observations related to the MoFTI protein, the methanol extract of the seed also showed immunomodulatory properties, reflected in the reduction in TNF-α, IL-6, IL-1β, and IFN-β levels, suggesting that this extract may decrease the levels of inflammatory cytokines induced by H1N1 infection by inhibiting TFEB.123\n\nRegarding the potential antiparasitic activity of Moringa oleifera seeds, Kandil et al.124 evaluated the in vitro and in vivo effects of the methanol extract of plant seeds on Fasciola hepatica as an alternative treatment. They found that complete inhibition of development and total death of immature Fasciola hepatica occurred within 48-72 hours after treatment at concentrations of 10, 25, and 50 mg/mL.124 In addition, the results of in vivo assays showed a 20% decrease in the mean egg count per gram of feces two days after treatment in infected rabbits treated with a daily oral dose of 150 mg/kg of body weight of the extract for 3 days. On the last day of treatment, the egg count decreased by 68%, and from the seventh day onwards, no eggs were detected in the feces of the animals.124 Thus, Moringa oleifera exhibited promising and potent activity against fascioliasis.\n\n3.4.2 Therapeutic properties evaluated in silico.\n\nApproaches focused on demonstrating the antimicrobial characteristics of Moringa in preclinical assays are very scarce ( Table 5), but interestingly, studies based on computational tools were found, which were designed to elucidate the specific role of some molecules from M. oleifera extracts, all of which focused on the novel SARS-CoV-2 virus. These in silico studies evaluated active compounds from the plant to determine their inhibitory properties against the Mpro protease of SARS-CoV-2, a key protein involved in the pathogenesis of COVID-19, finding good docking with the protein, with kaempferol showing the highest inhibitory effect against SARS-CoV-2 Mpro. Quercetin, a compound present in moringa, showed significant assembly as well, indicating that the active phytoconstituents of this plant exhibit potential relative inhibitors against SARS-CoV-2 Mpro and pharmacological characteristics similar to hydroxychloroquine, making them possible antiviral candidates in the fight against COVID-19.125–127 Other authors also mention that components such as niazirin, quercetin, moringin,128 apigenin, and ellagic acid,129 have an inhibitory role on the transmembrane serine protease 2 in SARS-CoV-2 infection and inhibition of two non-structural proteins 9/10 of SARS-CoV-2, respectively. Table 5 shows computational studies developed to demonstrate the anti-SARS-CoV-2 potential of Moringa oleifera.\n\nThe compilation of scientific material developed here has allowed not only to understand the research trends of several authors exploring the potential of M. oleifera in different clinical conditions but also to elucidate the geographical landscape of the sources of such publications. As expected, the majority of publications originated from Asia, since the plant is native to these regions, with India and Egypt being the two main countries where research on the biological activity of M. oleifera in human health is conducted, particularly in chronic diseases ( Figure 2A).\n\nA) Studies on chronic diseases B) in vitro studies related to cancer C) in vivo studies related to cancer D) Studies in infectious diseases.\n\nIt is noteworthy that Moringa oleifera leaf extract (MOLE) is known for its various cytoprotective properties owing to its high levels of antioxidants, polyphenols, and flavonoids, which improve organ function by acting as regulators of damage and oxidative stress. An example of this is a study carried out in Egypt by Abou-Zeid et al.47 and Fathy et al.,57 where the group of rats treated with MOLE showed less impact than the untreated group in terms of increased serum markers such as ALT, AST, urea, and creatinine, and decreased levels of albumin and total proteins, indicating protection against hepatic/renal toxicity.\n\nIn Egypt, the neuroprotective activity of the ethanolic leaf extract described by Muhammed et al.53 was reflected in a significant decrease in apoptotic-cerebral marker activity, such as caspase-3 and DNA fragmentation.55 This resulted in nearly normal activity of the neurotransmitter acetylcholine as well as improved mitochondrial activity of NADH dehydrogenase and ATPase after treatment with the extract. These findings indicate that Moringa oleifera extract has an influence on the protection of mitochondrial function in neuronal cells, thus participating in the prevention of neurodegenerative diseases such as Parkinson’s disease caused by environmental factors.55\n\nIndia has the highest number of studies related to Moringa oleifera leaves. One of the research studies was proposed by Barhoi D, Upadhaya P, Barbhuiya S, Giri A, Giri S.66 In 2021, this group developed an in vivo study on the anticancer potential of Moringa oleifera against ascetic and laryngeal cancers. The methodology involved two types of biological assays: the trypan blue dye exclusion assay and the MTT assay. The MTT assay revealed that treatment with Moringa oleifera induced dose- and time-dependent toxicity in both cancer types. This study highlights the potential of Moringa oleifera leaf treatment to induce apoptosis in cancer cells, indicating that this plant could be an excellent candidate for the development of new cancer therapies.\n\nIn the context of in vitro antitumor screening, India again stands out as the country with the highest number of studies, contributing 26% of the overall production ( Figure 2B). In 2010, Sreelatha reported the antiproliferative and apoptotic effects of the aqueous extract of Moringa oleifera leaves on a human tumor cell line (KB), using two types of biological assays, the cell proliferation assay and propidium iodide (PI) staining assay. The results showed that the aqueous extract significantly inhibited the proliferation of the studied tumor cell line and induced morphological changes (such as blistering of cell membrane) after 48 h of treatment, indicating apoptosis.7 Moreover, cell membrane shrinkage and loss of contact with other cells were observed. Similarly, propidium iodide staining revealed nuclear contraction, condensation, and DNA fragmentation in the cells,7 providing evidence of the significant biological effects of this extract, which could be prospectively used as a therapeutic and pharmacological product for treating certain neoplasms.\n\nAnother interesting perspective in the present review involves the identification of regions from which in vivo research on the antitumor activity of Moringa oleifera has been conducted, which is not as abundant as in vitro approaches. In this regard, Egypt has led the production of studies in this area ( Figure 2C), specifically focusing on leaves, contributing to 31% of the total related production. This indicates that Egypt has been actively involved in the research and evaluation of the anticancer potential of Moringa oleifera in vivo. Representative of one of these works are the observations of Khalil (2020), related with the evaluation of the effect of MOLEE on signaling pathways in response to DNA damage to protect hepatic tissue from apoptosis triggered by CoCl2 in Sprague-Dawley rats. This study demonstrated that MOLEE reduces genotoxicity induced by CoCl2, as evidenced by the expression of DNA repair genes.9\n\nFinally, concerning the biological activity of M. oleifera in infectious diseases, India was once again at the top of the list of articles in this field ( Figure 2D). We highlight a study originating from that country concerning the use of extracts from certain plants to synthesize metallic nanoparticles to support the generation of new nanomaterials with more potent and/or novel biological activities. Das et al.118,119 by performing green synthesis of copper120 and bismuth121 nanoparticles from hydroalcoholic leaf extracts revealed considerable antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Enterococcus faecalis, and relatively stronger antifungal activity against Aspergillus niger, Aspergillus flavus, Candida albicans and Candida glabrata, especially a pro-metabolic and usable inhibitory activity against Candida spp.117 These findings suggest that the synthesized copper and bismuth nanoparticles may be promising therapeutic candidates for the treatment of various bacterial and fungal infections, such as candidiasis. Owing to their encapsulation, these nanoparticles can be used in direct medical applications as antimicrobial agents. An ecological advantage of green nanoparticle synthesis is the production of non-toxic materials and the reduction of waste products compared to incinerated nanoparticles synthesized by conventional chemical-thermal methods.\n\nAlthough different parts of the plant have been studied under different conditions, in all experimental and preclinical approaches, the leaf is the most extensively studied raw material, mainly because of the relative ease of obtaining a viable product for testing. However, extracts from parts other than the leaf have also revealed effectiveness in the different research contexts in which they have been tested. Studies associated with chronic diseases and in vivo evaluations of cancer have led to the use of the leaves of this plant, with 73% and 71% of the investigations, respectively ( Figure 3A and 3C), followed by in vitro assays on cancer and studies of antimicrobial potential, with 60% and 56%, respectively, that is, more than half of the investigations ( Figure 3B and 3D). From this part of the plant, most scientific production has been generated, involving different types of extracts, among which aqueous, methanolic, and ethanolic extracts stand out. A small part of the work has studied the ethyl acetate extract; among them, the research carried out by Bamagous et al.43 showed that this extract reverses diabetes markers such as serum levels of glucose and insulin, lipid profile, and liver damage, confirming the results of a histopathological study what was evaluated at the serum level.43\n\nWith regard to the study of cancer, it has already been mentioned that most studies carried out to demonstrate the antitumor role of Moringa oleifera contemplate the leaf as a target element. One of these in vitro approaches was conducted by Khalafalla et al.89 in Egypt in 2010, where different leaf extracts were evaluated to observe the effects of the treatment on the viability of leukemia and hepatocarcinoma tumor cells using the MTT assay. The results showed that the average viability of the treated tumor cells was 25% lower than that of the control cells (human lymphoid cell line), which was 94.6%. Likewise, with regard to the viability of the HpG2 tumor cell line (liver cancer), they observed a significant decrease with respect to treatment with ethanolic extract.89\n\nStudies on the leaves of this plant have been devoted not only to revealing the ability of these extracts to attack tumor cells but also to show their harmlessness to normal cells. Thus, Suphachai in Thailand conducted research on the in vitro antiproliferative activity of two types of Moringa oleifera leaf extracts (methanol and biomethanol) on breast cancer (MCF-7 cell line), liver cancer (HepG2), and human fibroblast cells. It was found that concentrations up to 400 μg/ml of the two extracts did not induce toxicity in normal cells.90 Regarding the two extracts evaluated it was also observed that biomethanol was the one that presented high antioxidant activity and potent antiproliferative activity in cancer cells.90 This study reinforces evidence that Moringa oleifera has great potential in the field of medicine in relation to cancer chemotherapy and chemoprevention.\n\nAs observed in vitro, in vivo approaches also use leaves as their main raw material for research ( Figure 3C). Among these, Cuellar et al.97 focused on determining the physicochemical and nutraceutical properties of moringa leaves and their effects in a model of colorectal carcinogenesis in vivo. By testing Moringa oleifera leaf in male mice it could be evidenced that this extract decreased the activity of harmful fecal enzymes (β-glucosidase, β-glucuronidase, tryptophanase, and urease by up to 40%, 43%, 103%, and 266%, respectively), as well as tumor incidence in male CD1 mice.96 These findings suggest that bioactive compounds in moringa, such as total dietary fiber and phenolic compounds, may have chemopreventive capacity. This is the first study on the suppressive effects of this plant leaf in an in vivo model of colorectal carcinogenesis.\n\nThe biological activity of the plant in infectious diseases, as in the other assays, is the most studied element ( Figure 3D). Ashraf et al.112 when comparing the cytotoxic and anti-influenza potential of ethanolic extract of Moringa oleifera leaves (EEOMOL) and amantadine, an anti-influenza drug, evidenced that this extract showed significantly better (P <0.05) anti-influenza activity (0.78 μg/mL to 100 ug/mL) than amantadine (12.5 ug/mL to 50 ug/mL) (112). Additionally, EEOMOL showed a higher cytotoxic concentration 50 (CC50) (100 μg/mL) than amantadine (50 μg/mL).112 Based on these observations, it can be inferred that the extract could be a breakthrough in combating future influenza outbreaks, especially those caused by the influenza A (H9) virus, which has shown resistance to amantadine due to mutations in the M2 gene.\n\nAnother observation derived from this work is related to the trend that microbiological studies have shown in the past 10 years regarding the type of pathogenic agents and extracts evaluated to reveal the antimicrobial role of the plant. Thus, aqueous and methanolic extracts were used in the highest number of studies ( Figure 4A), and bacteria were the most studied microorganisms ( Figure 4B).\n\nA) Extracts B) Pathogens.\n\nA noteworthy study in the line of antibacterial research was conducted by Ibrahim et al., 110 who evaluated the antibacterial activities of methanolic and aqueous extracts of Moringa oleifera leaves, with and without heat treatment at 45°C, 50°C, and 55°C for 30 and 60 min, to recreate the cooking and frying conditions to which the plant is subjected when used in the diet. The non-heat-treated extracts showed the ability to inhibit the growth of gram-positive bacteria (Staphylococcus aureus and Streptococcus agalactiae) and gram-negative bacteria (Salmonella typhi and Shigella boydii), with the methanolic extract showing a high inhibition zone at 150 mg/mL against S. aureus110; the aqueous extract did not show any inhibitory activity against S. agalactiae at a concentration of 125 mg/mL, which was attributed to the presence of low amounts of active constituents, indicating that the antibacterial activity depends on the concentration of the extract and the solvent used.110\n\nIn contrast, the antibacterial activity of the heat-treated extracts was affected. The methanolic extracts maintained their activity against all tested microorganisms after exposure for 60 min at 50°C, while aqueous extracts lost their activity against Shigella boydii but retained it against other microorganisms.110 Thus, Moringa oleifera could be proposed as an alternative for the control of infections caused by these four bacteria, considering that the thermal treatment of the plant reduces the antimicrobial activity of its phytoconstituents.\n\n\n4. Conclusions and future perspectives\n\nAccording to the reviewed analyses, the countries with the highest number of studies that met the inclusion and exclusion criteria were India, Malaysia, and Egypt. Regarding the review of in vivo cancer studies, Egypt is the country with the highest number of investigations, with 13 included articles. Similarly, in in vitro studies, Egypt was among the top three countries with the highest number of studies on Moringa oleifera. This indicates that Egypt is committed to finding new and less invasive therapies against cancer than traditional approaches. Furthermore, most studies have focused on liver cancer, which is the leading cause of cancer-related death in the country.\n\nBreast cancer is among the most studied neoplasms in the context of this search, which has shown high incidence rates worldwide in recent years. This suggests that researchers, specifically those from Asia and Africa, have been actively seeking alternative treatments to reduce the number of associated cases and deaths. Similar trends have been observed in research conducted in India, although the articles included in this review focused on studying various types of neoplasms, including cervical cancer, which was the third leading cause of death in India in 2020.\n\nIndeed, in line with the study of cancer, 2020 saw the highest amount of research conducted worldwide regarding the antitumor and chemopreventive properties of Moringa oleifera, as indicated in Figure 5. In fact, the study of neoplasms occupied the top position in most of the temporal events that spanned the decade of the study ( Figure 5). This clear trend highlights the need for new approaches and generation of new knowledge in this field.\n\nRegarding the study of the potential associated with different parts of the Moringa oleifera, and according to the findings of this complication, it was determined that the leaf is the element that apparently has the greatest biological capacity; therefore, it is the part where most research was focused, which revealed in the context of the study of cancer potential related to cell viability, cytotoxic activity, and antitumor activity in different neoplasms, than the leaf contains various components that benefit human health, which contributes to maintaining a balance between treatment and the patient’s health status. Likewise, it has come to reduce the adverse effects caused by conventional treatments, which positions it as an alternative natural treatment that is still under constant research.\n\nTherefore, Moringa oleifera is a promising plant with great potential for cancer treatment, as evidenced in both in vitro and in vivo models, as described in the 60 articles analyzed in this study. This is basically due to the phytochemicals and phenolic compounds, such as quercetin and kaempferol, which allow the development of Moringa biological activities such as inhibition of cell viability through the induction of apoptosis and oxidative stress through the generation of reactive oxygen species (ROS), antiproliferative effects, and antitumor activity. In summary, this plant is a promising therapeutic alternative for cancer treatment.\n\nAmong the medicinal effects of Moringa oleifera, one of the most remarkable is its hypoglycemic capacity associated with counteracting one of the most relevant chronic illnesses today, diabetes mellitus, a condition that affects millions of people around the world and that does not have a treatment that achieves its definitive cure. However, there are medicines for its control, but these are not easily accessible to the entire population, and Moringa oleifera is widely distributed worldwide. This hypoglycemic effect is directly related to the inhibition of important enzymes, such as α-amylase and α-glucosidase, whose function is to hydrolyze carbohydrates; when these enzymes are inhibited, they delay their absorption, thus decreasing blood glucose levels. On the other hand, this plant also contributes to minimizing the sequelae of diabetes mellitus by controlling oxidative damage in the presence of multiple antioxidants and protects the target organ against damage caused by reactive oxygen species. It also contributes to counteracting the complications of the disease, such as hepatic lesions.\n\nIn addition to the evident properties of this plant related to chronic diseases, its spectrum of action is not limited to these, as its biological activity has been demonstrated against various microbiological agents. For instance, it has been found that antibacterial activity depends on the concentration of the extract and solvent used. The methanolic extract showed bacterial inhibition, whereas the aqueous extract did not. It is worth noting that antibacterial action has been observed against major pathogens, such as Escherichia coli and Staphylococcus aureus, which are highly prevalent and cause multiple diseases.\n\nLeaves and seeds have demonstrated more effective antiviral potential, as is the case against the influenza A virus, but other viral agents have been studied. Leaf extracts exhibit potent and selective inhibition of the first steps in HIV-1 infectivity, which could serve as antiretrovirals for people suffering from HIV/AIDS, who often seek alternative and complementary therapies.\n\nAs can be seen, there is a wide range of pathologies towards which Moringa oleifera presents important biological activity contributing to counteracting in a similar way to the drugs traditionally used. Despite this, it is necessary to determine the pathology to be treated with a specific dose, as the concentration fluctuates according to various parameters to be controlled.\n\nThe potential use of Moringa oleifera is more evident because of the large number of studies described in this review. In addition, the safety and toxicity of the products derived from this plant have been intensively analyzed both in vitro and in vivo, and a considerable number of studies in humans have been conducted to demonstrate its therapeutic role in various clinical situations. However, despite all this evidence and certain intrinsic characteristics of the plant with respect to its worldwide availability and low growth requirements, the translation of the biological potential of moringa to clinical practice has not yet materialized, a fact that is evidenced by the scarcity of approved clinical trials on studies related to this plant.\n\nM. oleifera is a plant with a great future ahead with a wide use in folklore but currently remains underestimated as a possible therapeutic alternative in modern medicine, therefore, it is considered that to achieve the real position that the derivatives of this plant deserve, it is necessary to develop more comprehensive research in the Western world to support and complement the evidence obtained in regions where the study of this plant dates back longer.\n\nThis study is a faithful reflection of the value and therapeutic potential of this plant, from which advanced therapies could be derived with greater efficacy using a nanotechnological approach while establishing a business model based on bioeconomy.131,132 In the future, drug coating and scaffolding using these medicinal plant extracts in a synergistic manner could be exploited to establish effective treatment strategies.\n\nEthical approval and consent were not required.\n\n\nAuthors contribution\n\nConceptualization: A. B., B. V., K. M., and A.G.; original draft preparation: A. B, B. V, K.M.; writing: A.B,B.V,K.M, and A. G; editing, reviewing, and formatting: C.A.Z.G. and J.S: and Reviewed drafts of the paper: J.S.; Language editing and preparation of tables and/or figures: K.M., A.G.; Final approval of the review to be published. All the authors have read and agreed to the published version of the manuscript.", "appendix": "Data availability\n\nNo underlying data are associated with this article.\n\nFigshare: Data for Biological properties of Moringa oleifera: a review in last decade. https://doi.org/10.6084/m9.figshare.27233943.v3.129,133,134\n\nThis project contains following datasets:\n\n- dataset_1\n\n- dataset_2\n\n- dataset_3\n\n- Protocol\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nFigshare - PRISMA checklist for “Biological properties of Moringa oleifera: aA systematic review inof the last decade” https://doi.org/10.6084/m9.figshare.27233943.v3.129,133,134\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nPopoola JO, Aworunse OS, Oyesola OL, et al.: A systematic review of pharmacological activities and safety of Moringa oleifera. J. HerbMed. 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PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nZuniga-Gonzalez CA: TFP Bioeconomy Impact post Covid-19 on the agricultural economy. PLoS One. 2023; 18(11): e0288885. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nZuniga Gonzalez CA, Jaramillo-Villanueva JL: Frontier model of the environmental inefficiency effects on livestock bioeconomy [version 3; peer review: 3 approved, 1 not approved]. F1000Res. 2024; 11: 1382. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLiberati A, Altman DG, Tetzlaff J, et al.: The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009; 6: e1000100. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSoto JA, Gomez AC, Vásquez BM, et al.: Data for Biological properties of Moringa oleifera: a review in last decade. Dataset. figshare. 2024. Publisher Full Text" }	[ { "id": "342878", "date": "14 Dec 2024", "name": "Micaela Carvajal Alcaraz", "expertise": [ "Reviewer Expertise Plant Sciences" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis work reviews the biological activities of Moringa oleifera, highlighting its antitumor, antimicrobial, and protective effects against metabolic, infectious, and chronic diseases, based on evidence from 129 studies published between 2010 and 2021. The review explores Moringa oleifera across various fields, including medicine and biotechnology, highlighting its versatility and addressing a wide range of bioactivities, including antioxidant, antitumor, antimicrobial, and organ-protective effects, underscoring its therapeutic potential. The reviewed findings open avenues for further exploration into drug development and integrative health strategies involving Moringa oleifera.\nPOINTS 2.- I have notice that there are some other reviews already published with similar subject:\nSJ Stohs, MJ Hartman. Review of the Safety and Efficacy of Moringa oleifera- Phytotherapy Research, 2015 (Ref-1) - Wiley Online Library KT Mahmood, T Mugal, IU Haq. Moringa oleifera: a natural gift-A review- Journal of Pharmaceutical …, 2010 NZ Abd Rani, K Husain, E Kumolosasi. Moringa Genus: A Review of Phytochemistry and Pharmacology. - Frontiers in pharmacology, 2018 (Ref-2) - frontiersin.org L Gopalakrishnan, K Doriya, DS Kumar. Moringa oleifera: A review on nutritive importance and its medicinal application.- Food science and human …, 2016 (Ref-3) - Elsevier\nTherefore, the novelty of this actual one should be highlight and clearly establish the added value and relevance compared to previous works.\nI suggest the following: -Highlight that your review specifically examines the dual potential of Moringa oleifera in tackling both cancer and antimicrobial resistance—two critical and globally relevant health challenges. Also that it integrates data from diverse fields such as medicine, biotechnology, and phytotherapy, offering a broader perspective than reviews focused solely on one discipline. -The review should highlight any newly identified mechanisms, pathways, or potential clinical applications of Moringa oleifera that may not have been discussed extensively in prior reviews. 2.- The conclusions might overstate the potential of Moringa oleifera without sufficient caution about its limitations, such as possible toxicity, variability in efficacy, or challenges in standardizing extracts. This fact should be implemented in discussion or conclusions.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable", "responses": [ { "c_id": "13167", "date": "30 Jan 2025", "name": "C. A. Zuniga-Gonzalez", "role": "Author Response", "response": "We sincerely thank the reviewer for their insightful and constructive feedback, which has significantly contributed to improving the quality of our manuscript. Your suggestions to clearly emphasize the novelty and added value of our review compared to existing literature and to address the limitations of Moringa oleifera have been invaluable. These recommendations will guide us in refining our analysis and ensuring a balanced presentation of findings." } ] }, { "id": "355204", "date": "16 Jan 2025", "name": "Francisco Osorio-Acosta", "expertise": [ "Reviewer Expertise Plant pathology and use of different control methods", "as plant extracts." ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper has an extensive review and explained properly, however it is necessary an English redaction review. The first paragraph in introduction require connection between ideas. Some scientific names are no correctly written (italics are not used), They used a lot of abbreviations, however they don't use or are used just once (MO), furthermore, there are abbreviations that mean the same but are different (MOLE and MOLEE as an example). It is necessary to review all. Page 4. Figure 1 is cited in the text, however does no correspond with the information present, should be placed in other paragraph. Page 4, 1.3. They don't include bibliography in a paragraph. Page 7. 3.2 Correct Atalas, and correct redaction (The seeds of Moringa oleifera seeds have also shown potential...) It should be expected that authors propose better future perspectives.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes", "responses": [ { "c_id": "13169", "date": "30 Jan 2025", "name": "C. A. Zuniga-Gonzalez", "role": "Author Response", "response": "Thank you very much for your thorough review and constructive comments. We greatly appreciate your suggestions, and we have addressed all of the points you raised. The English writing has been revised for better clarity and connection between ideas, and we have corrected the use of scientific names, ensuring proper italics are used. We have also reviewed and standardized the abbreviations throughout the paper, making sure they are consistently applied. Regarding the issues with Figure 1, it has been moved to the appropriate section. Additionally, we included the necessary bibliography in the 1.3 section and corrected the redaction in section 3.2, as you suggested. All these improvements have been made to enhance the overall quality of the manuscript." } ] }, { "id": "355211", "date": "30 Jan 2025", "name": "Pradeep Singh", "expertise": [ "Reviewer Expertise Pharmacognosy & Phytochemistry" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nBiological properties of Moringa oleifera: A systematic review of the last decade This review examines original research papers on Moringa oleifera published from 2010 to 2021. The papers focus on biological properties, especially antitumor activity and possible uses against chronic and infectious diseases. The authors gave in-depth pharmacognostical descriptions and phytochemicals from different parts of Moringa oleifera. They also talked about the plant's traditional uses, antioxidant effects, and potential to fight cancer. activity. The systematic review is compiled by collecting original research articles from various databases like PubMed, Scopus, and Google Scholar. The method used to put this together was very detailed. First, 2700 publications were found in databases. These were then screened to find 410 articles that met certain criteria, such as having to do with Moringa oleifera, chronic diseases, infectious diseases, biological activity, human cancer, antitumor biological activity, in vivo and in vitro activity, and anticancer properties. Finally, 129 (134 listed in reference section) publications were chosen to be included in the final draft of the systematic review. This compilation excludes previously published reviews, editorials, and articles published in languages other than English and Spanish. Suggestions\nAbbreviations like MO, MOE, and MOSE for Moringa oleifera should be used wisely, and uniformity must be maintained throughout the article. Authors can use an abbreviation once at the beginning of the article with a full description, and then only use the abbreviation for further references. The numbers of publications used for this compilation should be the same. Please check 129 publications mentioned in the abstract, 112 written in the second paragraph of the method section, and a total of 134 references listed under the reference section. Authors must review English grammar and sentence construction.\n\nAs mentioned below, recheck references for duplication.\n129. Soto AJ, Gomez AC, Vasquez BM, et al.: A Biological properties of Moringa oleifera: a review in the last decade.Publisher Full Text 134. Soto JA, Gomez AC, Vásquez BM, et al.: Data for Biological properties of Moringa oleifera: a review in last decade. Dataset. figshare. 2024. Publisher Full Text\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) No", "responses": [ { "c_id": "13243", "date": "05 Feb 2025", "name": "C. A. Zuniga-Gonzalez", "role": "Author Response", "response": "Dear Reviewer 3, I sincerely appreciate your valuable feedback and observations. I have carefully reviewed your suggestions and made the necessary revisions in version 2 of the manuscript to improve its clarity and accuracy. First, I have standardized the use of abbreviations for Moringa oleifera (MO, MOE, and MOSE), following your recommendation to ensure consistency throughout the text. I have also corrected the discrepancy in the number of publications mentioned in the abstract, methods section, and reference list, ensuring uniformity in the data presented. Furthermore, I have thoroughly reviewed the English grammar and sentence structure as you suggested, to enhance the flow and readability of the manuscript. Additionally, I have checked and corrected the duplicated references you pointed out, ensuring accuracy and consistency in citation. Thank you once again for your attention to detail. Your feedback has been extremely helpful in improving the quality of the manuscript. Sincerely, Carlos" } ] } ]	1	https://f1000research.com/articles/13-1390
https://f1000research.com/articles/13-1395/v1	20 Nov 24	{ "type": "Research Article", "title": "Dual tasking as a predictor of falls in post-stroke: Walking While Talking versus Stops Walking While Talking.", "authors": [ "Disha Lamba", "Abraham M. Joshua", "Vijaya kumar K", "Akshatha Nayak", "Prasanna Mithra", "Rohit Pai", "Shivananda Pai", "Shyam Krishnan K.", "Vijayakumar Palaniswamy", "Disha Lamba", "Abraham M. Joshua", "Vijaya kumar K", "Akshatha Nayak", "Prasanna Mithra", "Rohit Pai", "Shivananda Pai", "Shyam Krishnan K." ], "abstract": "Background Falls affect 40-70% within the first year and contributing to increased morbidity and reduced quality of life. Dual-task assessments, such as the Walking While Talking (WWT) and Stops Walking While Talking (SWWT) tests, are potential tools for predicting fall risk, but their comparative effectiveness remains underexplored.\n\nMethods This cross-sectional study included 68 stroke survivors who completed WWT-Simple (WWT-S), WWT-Complex (WWT-C), and SWWT assessments, as well as the Berg Balance Scale (BBS) and Falls Efficacy Scale (FES). Spearman correlations assessed relationships between balance, fear of falling, and dual-task performance. Logistic regression identified predictors of fall risk, and Receiver Operating Characteristic (ROC) analysis evaluated predictive accuracy. The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist.\n\nResults BBS scores were strongly negatively correlated with WWT-S (r = -0.734, p < 0.0001) and WWT-C (r = -0.737, p < 0.0001), indicating poorer balance with slower dual-task completion. Positive correlations were found between WWT-S and FES (r = 0.668, p < 0.0001) and WWT-C and FES (r = 0.610, p < 0.0001), linking slower completion times with higher fear of falling. SWWT was significantly negatively correlated with BBS (r = -0.625, p < 0.0001). WWT tests had higher sensitivity (97.8%) and specificity (99%) than SWWT (sensitivity = 68.9%; specificity = 91.3%). Logistic regression identified SWWT (Positive) as a significant predictor of fall risk (p = 0.009), and ROC analysis showed an AUC of 0.911, indicating excellent predictive power.\n\nConclusions Findings highlight the superior predictive value of WWT tests over SWWT in assessing fall risk among stroke survivors. Incorporating dual-task measures into clinical practice may enhance fall risk evaluation, supporting targeted stroke rehabilitation.", "keywords": [ "focus of attention", "cognition", "stroke", "walking", "predictive value of tests", "risk assessment", "ROC curve", "executive function." ], "content": "Introduction\n\nFalls after stroke are recognized as a serious public health challenge worldwide, contributing to increased morbidity and reduced quality of life among stroke survivors.1,2 Falls are quite common in this population due to increased cognitive-motor interference (CMI). This interference impacts their ability to effectively integrate balance, walking, and cognitive tasks.3 Cognitive-motor interference in stroke patients is often characterized by deficits in executive functions, which include challenges with memory, attention, and motor control.1,4,5 Notably, difficulties in performing dual tasks—an essential aspect of executive function—are significant risk factors for falls among stroke survivors.6–8\n\nImpaired postural balance and low falls efficacy are critical factors that contribute to frequent falls in stroke survivors.9,10 Recent studies, such as those by Xu (2018)11 and Sjöholm et al. (2022),1 highlight the connection between reduced balance and an increased risk of falling. There is growing interest in assessing cognitive-motor interference through dual-task paradigms; however, most previous observational research has primarily relied on established tools like the Berg Balance Scale (BBS) and the Tinetti Falls Efficacy Scale (FES) to evaluate balance and fear of falling. Evidence regarding the predictive ability of dual-task performance tests for fall risk in stroke survivors remains limited.\n\nDual-task assessments are shown to be reliable for measuring cognitive-motor performance in stroke survivors,12 yet the comparative effectiveness of different dual-task tests in predicting fall risk is underexplored. Studies by Hofheinz and Mibs (2016)13 have validated dual-task tests, such as the Timed Up and Go Test, as effective predictors of fall risk in older adults. However, further research is needed to see if these findings apply to stroke survivors, who have unique cognitive and motor challenges. Emerging research supports the utility of dual-task paradigms like the WWT and SWWT for assessing CMI and identifying fallers.4,7 These assessments engage higher executive functions that extend beyond automatic walking tasks.14,15 However, a recent predictive analytics study by Abdollahi et al. (2024) highlighted limitations in current dual-task assessments for fall risk prediction, emphasizing the need for more tailored methods.16\n\nWhile the clinical value of dual-task assessments in identifying fall risk is established, there remains a paucity of research examining how stroke survivors perform on both WWT and SWWT tests and how these outcomes correlate with fall efficacy (FES) and balance (BBS). Assessing dual-task performance alongside established scales may provide deeper insight into fall mechanisms among stroke survivors and facilitate the development of targeted cognitive or behavioral interventions.17\n\nTherefore, the objective of this study is to determine whether dual-task performance, specifically the Walking While Talking (WWT) and Stops Walking While Talking (SWWT) tests, is correlated with established fall risk predictors such as the Berg Balance Scale (BBS) and the Falls Efficacy Scale (FES). Additionally, the study aims to compare the predictive ability of WWT and SWWT in identifying fall risk among stroke survivors using these standardized fall prediction tools. Finally, the research seeks to identify which of the dual-task assessments, WWT or SWWT, serves as a superior predictor of fall risk in this population.\n\nWe hypothesize that stroke survivors with poor dual-task performance on the Walking While Talking (WWT) and Stops Walking While Talking (SWWT) tests will exhibit significant associations with fall risk, as evaluated by the Berg Balance Scale (BBS) and the Falls Efficacy Scale (FES) scores. Additionally, we anticipate that there will be a significant difference in the predictive accuracy between WWT and SWWT in determining fall risk among stroke survivors.\n\n\nMethods\n\nA cross-sectional study was conducted to compare dual-task performance between Walking While Talking (WWT) and Stops Walking While Talking (SWWT) in predicting fall risk, as assessed by the Berg Balance Scale (BBS) and the Falls Efficacy Scale (FES). The study adhered to the Declaration of Helsinki (World Medical Association) and was reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.18\n\nA total of 234 potential participants were screened for eligibility (Figure 1), resulting in a final sample of 68 stroke survivors admitted to Kasturba Medical College Hospital (KMCH), Mangalore, affiliated with Manipal Academy of Higher Education (MAHE), Manipal, from March 2021 to March 2022. All participants received a stroke diagnosis from an experienced neurologist affiliated with KMCH. To mitigate selection bias, the study specifically approached individuals diagnosed with stroke by the neurologist and included only those who met predefined inclusion and exclusion criteria. The purpose of the study was clearly explained to eligible participants, and informed consent was obtained from all individuals prior to their participation.\n\nThe inclusion criteria for the study required participants to have experienced a first episode of stroke, maintain a clinically stable status, achieve a Montreal Cognitive Assessment (MoCA) (A official written permission to use MoCA for research purpose has been granted in 2020) score of 26 or higher, demonstrate ambulatory ability, and be able to recite the alphabet in English or their native language. Exclusion criteria included visual impairments, other neurological conditions, and musculoskeletal disorders affecting gait. This selection process aimed to create a homogeneous study population and enhance the reliability of findings related to cognitive-motor interference and fall risk among stroke survivors.\n\nData collection for the study involved a standardized single evaluation session for all participants. A qualified and trained postgraduate student in Neurological Physiotherapy, under the supervision and guidance of the research team members (AN and SK), collected demographic data and scores for the Montreal Cognitive Assessment (MoCA) (We have obtained the official written permisison from the MoCA Copyright owners.), Berg Balance Scale (BBS), Falls Efficacy Scale (FES), Walking While Talking (WWT), and Stops Walking While Talking (SWWT). To minimize order effects, participants were randomly assigned to perform either the WWT or SWWT task first ( Table 1).\n\nCognitive function was screened using the 30-point MoCA test. The MoCA evaluates seven cognitive domains: visuospatial/executive function, naming, attention, language, abstraction, delayed recall, and orientation.19 A MoCA score of 26 or higher served as the cutoff for inclusion.19\n\nFor fall risk assessment, participants underwent evaluations using the BBS and FES. The BBS is a 14-item scale designed to assess static balance and predict fall risk. It has demonstrated high test-retest reliability (ICC = 0.98)20,21and has been validated in the stroke population.22,23 The scale ranges from 0 to 56, with lower scores indicating a higher risk of falling.24,25 The FES is a patient-reported measure that assesses confidence in performing ten daily activities without fear of falling. Higher scores indicate lower confidence, and the FES has shown excellent test-retest reliability (ICC = 0.97).26,27\n\nParticipants completed both WWT and SWWT tests as independent variables. The WWT measures the time taken to walk a 20-foot distance while simultaneously reciting the alphabet. Two versions were used. The simple version requires the participant to recite the alphabet in sequence, while the complex version involves reciting every alternate letter (e.g., A-C-E). Times exceeding 20 seconds for the simple version (WWT-S) or 33 seconds for the complex version (WWT-C) indicate a fall risk. The SWWT evaluates participants’ ability to walk and talk simultaneously. Participants were asked to walk while engaging in a conversation; stopping during this task was noted as a higher fall risk indicator.\n\nAll statistical analysis was conducted using IBM SPSS Statistics for Windows, Version 25.0. Continuous variables were summarized using medians and interquartile ranges (IQRs) due to non-normal data distribution, confirmed by Shapiro-Wilk tests (p < 0.05).\n\nGroup comparisons of BBS and FES scores based on SWWT outcomes (positive vs. negative) were conducted using the Wilcoxon rank-sum test, with W-statistics and p-values reported. The significance level was set at p < 0.001 for these comparisons. Additionally, Spearman’s rank correlation coefficients were calculated to evaluate association between dual-task performance and fall risk measures (BBS and FES). Logistic regression analysis was performed to assess the predictive power of WWT and SWWT, with results presented as model coefficients and p-values.\n\nFor analysis of model discrimination, ROC curve analysis was conducted, reporting the area under the curve (AUC) to determine model discrimination. Sensitivity and specificity for each dual-task test were evaluated to assess clinical utility. Statistical significance was set at p < 0.05 unless stated otherwise for specific tests.\n\n\nResults\n\nA total of 234 stroke participants were screened, of which 68 ambulant participants who met the inclusion and exclusion criteria were included in the study. The mean age of the participants was found to be 63 years. Table 1 presents the demographic and clinical characteristics of the sample. The cohort was predominantly male (70.6%), with the majority (86.8%) having experienced ischemic strokes. In terms of laterality, 55.9% of participants had their left side affected. The median duration since stroke onset was 5 days (IQR: 3-9 days), indicating that the participants were in the early subacute phase of recovery.\n\nFunctional assessments revealed that the median Montreal Cognitive Assessment (MoCA) score was 27 (IQR: 26-28), indicating generally preserved cognitive function among participants. The median Berg Balance Scale (BBS) score was 36 (IQR: 32.25-43.5), suggesting a moderate risk of falls, while the median Falls Efficacy Scale (FES) score was 39 (IQR: 21.5-48.25), reflecting varying levels of confidence regarding fall-related concerns. The dual-task performance metrics indicated that the median time for the Walking While Talking Test—Simple (WWT-S) was 35 seconds (IQR: 28.75-43), and for the Walking While Talking Test—Complex (WWT-C), it was 44 seconds (IQR: 34.75-56.25). In the Stops Walking While Talking (SWWT) test, 48.5% of participants exhibited a positive outcome by stopping while talking, indicating difficulties in dual tasking ( Table 1).\n\nFigure 2 illustrates the Spearman correlation matrix for the dual-task performance measures (WWT-S, WWT-C) and conventional fall prediction scales (BBS, FES). The analysis revealed a strong negative correlation between WWT-S and BBS (r = -0.73), indicating that longer times on the simple walking-while-talking test were associated with poorer balance scores. A similar strong negative correlation was found between WWT-C and BBS (r = -0.734) ( Table 2), reinforcing that prolonged times in the complex dual-task test were linked to lower balance capabilities. Additionally, a moderate positive correlation was observed between WWT-S and FES (r = 0.67), suggesting that slower times correlated with a higher fear of falling. A strong negative correlation between BBS and FES (r = -0.71) indicated that lower balance scores were associated with greater anxiety about falling. These findings underscore the importance of dual-task assessments (WWT-S, WWT-C, SWWT) as valuable indicators of fall risk and balance confidence among stroke survivors ( Table 2).\n\nPositive correlations are red, negative are blue, with color intensity showing strength; boxes show coefficients.\n\nTable 3 summarizes the logistic regression analysis conducted to evaluate the predictive power of dual-task performance measures for fall risk among stroke survivors. The model included the Walking While Talking Test - Simple (WWT-S), Walking While Talking Test - Complex (WWT-C), and the Stops Walking While Talking (SWWT) test as independent variables, with fall risk defined by a Berg Balance Scale (BBS) score of less than 40 as the outcome. The analysis aimed to determine how effectively these dual-task performance measures could predict fall risk in this population, highlighting their potential utility in clinical assessments and interventions for stroke survivors.\n\nThe analysis indicated that the intercept was statistically significant (Estimate = -3.858, p = 0.002), suggesting a baseline probability of fall risk when all predictors are held constant. The Walking While Talking Test - Simple (WWT-S) variable had an estimate of 0.119 (p = 0.060), indicating a positive association with fall risk; however, this association was marginally non-significant at the 0.05 level. This suggests potential relevance that may become significant in larger samples or under different conditions, highlighting the need for further investigation into the relationship between dual-task performance and fall risk among stroke survivors ( Table 3).\n\nAdditionally, sensitivity and specificity analyses revealed that the WWT tests (WWT-S and WWT-C) had high sensitivity (97.8%) and specificity (99%) for predicting fall risk, indicating their strong diagnostic accuracy. In contrast, the SWWT test showed lower sensitivity (68.9%) and specificity (91.3%), though it remained a valuable predictor. These findings underscore the clinical value of dual-task assessments, particularly SWWT, in identifying stroke survivors at risk of falls ( Table 3).\n\nThe Walking While Talking Test - Complex (WWT-C) variable had an estimate of -0.008 (p = 0.820), indicating a negligible and non-significant relationship with fall risk. In contrast, the Stops Walking While Talking (SWWT) variable demonstrated a significant positive association (Estimate = 2.322, p = 0.009), suggesting that participants who stopped walking while talking faced a substantially higher risk of falls. This finding underscores the importance of SWWT as a predictor of fall risk. Overall, the model indicates that while the WWT-S test shows borderline significance, the SWWT outcome is a robust predictor of fall risk among stroke survivors. This highlights the value of dual-task assessments, particularly SWWT, in clinical evaluations of fall risk ( Table 3).\n\nA ROC curve analysis (Figure 3) was conducted to evaluate the predictive accuracy of the logistic regression model for fall risk, which included dual-task performance measures (WWT-S, WWT-C, and SWWT) as predictors. Figure 2 displays the ROC curve, with an Area Under the Curve (AUC) of 0.911, indicating excellent discrimination. This AUC value suggests that the model is highly effective in distinguishing between stroke survivors at risk of falls and those who are not. The ROC curve highlights the utility of dual-task performance assessments in fall risk evaluations. The near-perfect AUC underscores the clinical relevance of incorporating tests like WWT-S, WWT-C, and SWWT into comprehensive fall risk assessments for stroke survivors.\n\nTable 4 shows significant differences in BBS and FES scores between positive and negative SWWT outcomes. Participants who stopped while talking (positive SWWT) had lower BBS scores (W = 994, p < 0.001) and higher FES scores (W = 176, p < 0.001), indicating poorer balance and greater fear of falling. These results emphasize the link between dual-task performance, balance deficits, and fall-related anxiety in stroke survivors.\n\n\nDiscussion\n\nThis study aimed to evaluate the predictive ability of dual-task performance measures, specifically the Walking While Talking (WWT) and Stops Walking While Talking (SWWT) tests, in assessing fall risk among stroke survivors. The findings revealed significant associations between dual-task performance and traditional fall risk measures, emphasizing the value of incorporating these assessments into clinical practice for stroke rehabilitation. Previous research has established the importance of dual-task paradigms in identifying fall risk among older adults and patients with neurological impairments. Abdollahi et al. (2024) reported that changes in gait performance under dual-task conditions were significantly associated with fall risk, particularly in frail elderly populations.16 This aligns with our results, where both WWT-S and WWT-C demonstrated strong negative correlations with the Berg Balance Scale (BBS) (r = -0.73 and r = -0.74, respectively), suggesting that slower dual-task completion times indicate poorer balance and an increased risk of falls in stroke survivors. The strong relationship between dual-task performance and balance observed in our study supports the clinical relevance of these assessments.\n\nConversely, some studies suggest that dual-task assessments offer no significant predictive advantage over single-task evaluations.29 The effectiveness of dual-task assessments may also vary by age group.30 However, the high Area Under the Curve (AUC) observed in our ROC analysis (0.911) for dual-task tests highlights their superior predictive capability. This finding indicates that dual-task assessments, particularly both versions (Simple & Complex) of WWT, offer significant clinical value when used alongside traditional measures like BBS and FES. The high level of discrimination supports their inclusion in comprehensive fall risk assessments for stroke survivors. The high sensitivity (97.8%) and specificity (99%) of the WWT tests show they are very effective at accurately identifying fall risk in stroke survivors. While the SWWT test also has value, its lower sensitivity (68.9%) and specificity (91.3%) make it better suited for quick assessments. These results support using dual-task assessments, especially WWT, in stroke rehabilitation to improve fall prevention strategies.\n\nThe SWWT test demonstrated significant predictive power for fall risk (p = 0.009) in our logistic regression analysis, aligning with research advocating for its use as an effective assessment tool. Lundin-Olsson et al. (1997) first highlighted SWWT as valuable for identifying individuals at higher risk of falls in elderly cohorts.28 Our study extends this application to stroke survivors, revealing that participants who stopped walking while talking (SWWT-positive) had a substantially higher risk of falling, reinforcing its utility as an essential part of dual-task evaluation in stroke rehabilitation programs.\n\nThe findings supports the clinical value of dual-task performance measures, particularly WWT and SWWT tests, in assessing fall risk among stroke survivors. While previous research has underscored the significance of cognitive-motor interference in fall risk,3,4 our results enhance this understanding by demonstrating strong correlations with established measures like BBS and FES. This aligns with studies validating dual-task testing as a proxy for evaluating broader functional deficits.12 The predictive power of WWT (both versions), shown by their high sensitivity and specificity, highlights their potential use in comprehensive stroke rehabilitation programs.13\n\nAlthough our study did not assess gait parameters directly, it is essential to recognize how cognitive-motor interference can affect motor control, contributing to an increased fall risk.8 This is consistent with the understanding that proprioceptive and executive function deficits can influence dual-task performance, impacting balance.16 Incorporating dual-task assessments can provide a more nuanced approach to identifying fall risk beyond traditional single-task methods.\n\nThe relationship between falls efficacy, as measured by the Falls Efficacy Scale (FES), and dual-task performance adds an important dimension to understanding fall risk. Our study found moderate positive correlations between WWT-S and FES (r = 0.67) and WWT-C and FES (r = 0.61), indicating that slower completion times were associated with higher fear of falling. These findings align with studies emphasizing the psychological components of balance confidence and their impact on fall risk. Low confidence in balance, reflected in higher FES scores, has been linked to poorer performance in balance and gait tasks.\n\nThis study’s relatively small sample size of 68 participants, may limit the statistical power and generalizability of the findings to a broader population. Additionally, the cross-sectional design limits our ability to establish causative relationships between dual-task performance and fall risk over time. Furthermore, conducting the study in clinical settings may not fully represent the real-life challenges that stroke survivors face when multitasking in their daily lives, which could impact the study’s relevance. Finally, while we used the Berg Balance Scale (BBS) and Falls Efficacy Scale (FES) as our main measures—both of which are valid—they might not cover all aspects of fall risk for this group. For future research, it would be beneficial to conduct larger studies over a longer period and to look into additional assessment tools. This could improve our understanding and applicability of findings across different patient groups.\n\nThe clinical implications are significant; while the predictive power of SWWT was substantial, the WWT tests demonstrated higher sensitivity and specificity, suggesting they are more effective at accurately identifying individuals at risk. This contrasts with studies finding SWWT to be less sensitive but still valuable for quick assessments. The high sensitivity (97.8%) and specificity (99%) for WWT-S and WWT-C underscore their robustness as reliable indicators for fall risk. Overall, this study contributes to the growing evidence that dual-task performance assessments are crucial for identifying stroke survivors at risk of falls. Acknowledging both significant and non-significant outcomes ensures a balanced discussion that reflects the complexity of dual-task testing in clinical practice. Our findings highlight the superior predictive power of WWT over SWWT, supporting its use in fall risk screening. Future studies should explore longitudinal designs and larger sample sizes to validate these results further and investigate mechanisms underlying dual-task deficits in stroke rehabilitation.\n\n\nAuthor contributions\n\nDL was the principal investigator and enrolled participants for this study. The study was conceptualized by AMJ, AN, and SK. VP conducted the data analysis and led the literature review and critical revision of the manuscript. Supervision of the trial and data collection was carried out by VK, AMJ, and SP, while oversight and guidance during data collection were provided by VP, AN, and SK. RP, VK, and SP made significant contributions to the study design and manuscript preparation. All authors provided critical input and participated in the preparation and final approval of the manuscript.\n\n\nEthics and consent\n\nApproval for the study protocol was obtained on 20/01/2022 from both the Scientific Committee and the Institutional Ethics Committee (Approval #: IEC KMC MLR 01/2022/45) of Kasturba Medical College (KMC) Mangalore, part of the Manipal Academy of Higher Education (MAHE), Manipal. Additionally, the study was registered with The Clinical Trials Registry-India (CTRI/2021/05/033513). The study was conducted in accordance with the ethical principles of the Declaration of Helsinki for research involving human participants Written informed consent was obtained from all participants prior to their inclusion in the study.", "appendix": "Data availability statement\n\nZenodo: Dual Tasking as a Predictor of Falls in Post-Stroke: Walking While Talking versus Stops Walking While Talking, 10.5281/zenodo.14059154.31\n\nThis project contains the following underlying data:\n\n• Thesis_Data_Sheet_Updated: Excel Database of Raw Data\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgment\n\nWe extend our sincere gratitude to all study participants and the Manipal Academy of Higher Education, Manipal, India, for their invaluable support in facilitating this research.\n\n\nReferences\n\nSjöholm H, Hägg S, Nyberg L, et al.: Exploring possible risk factors for time to first fall and 6-month fall incidence in persons with acute stroke. SAGE Open Med. 2022; 10: 205031212210925. Publisher Full Text\n\nDivani AA, Vazquez G, Barrett AM, et al.: Risk factors associated with injury attributable to falling among elderly population with history of stroke. Stroke. 2009; 40(10): 3286–3292. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHyndman D, Ashburn A, Yardley L, et al.: Interference between balance, gait and cognitive task performance among people with stroke living in the community. Clin. Rehabil. 2006; 28(13-14): 849–856. Publisher Full Text\n\nVerghese J, Kuslansky G, Holtzer R, et al.: Walking while talking: effect of task prioritization in the elderly. Arch. Phys. Med. Rehabil. 2007; 88(1): 50–53. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCramer SC, Richards LG, Bernhardt J, et al.: Cognitive deficits after stroke. Stroke. 2023; 54(1): 5–9. Publisher Full Text\n\nZinn S, Bosworth HB, Hoenig HM, et al.: Executive function deficits in acute stroke: relationship to rehabilitation outcome. Arch. Phys. Med. Rehabil. 2007; 88(2): 173–180. Publisher Full Text\n\nHoltzer R, Verghese J, Xue X, et al.: Cognitive processes related to gait velocity: results from the Einstein Aging Study. Neuropsychology. 2006; 20(2): 215–223. PubMed Abstract \| Publisher Full Text\n\nAmbrose AF, Paul G, Hausdorff JM: Risk factors for falls among older adults: a review of the literature. Maturitas. 2013; 75(1): 51–61. Publisher Full Text\n\nChen Y, Du H, Song M, et al.: Relationship between fear of falling and fall risk among older patients with stroke: a structural equation modeling. BMC Geriatr. 2023; 23(1): 647. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBuvarp D, Rafsten L, Abzhandadze T, et al.: A cohort study on longitudinal changes in postural balance during the first year after stroke. BMC Neurol. 2022; 22(1): 324. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nXu T, Clemson L, O’Loughlin K, et al.: Risk factors for falls in community stroke survivors: a systematic review and meta-analysis. Arch. Phys. Med. Rehabil. 2018; 99(3): 563–73.e5. PubMed Abstract \| Publisher Full Text\n\nYang L, He C, Pang MY: Reliability and validity of dual-task mobility assessments in people with chronic stroke. PLoS One. 2016; 11(1). Publisher Full Text\n\nHofheinz M, Mibs M: The prognostic validity of the Timed Up and Go Test with a dual task for predicting the risk of falls in the elderly. Gerontol. Geriatr. Med. 2016; 2: 2333721416637798. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBeauchet O, Dubost V, Revel Delhom C, et al.: French Society of Geriatrics and Gerontology. How to manage recurrent falls in clinical practice: guidelines of the French Society of Geriatrics and Gerontology. J. Nutr. Health Aging. 2011; 15(1): 79–84. PubMed Abstract \| Publisher Full Text\n\nBuracchio T, Dodge HH, Howieson D, et al.: The trajectory of gait speed preceding mild cognitive impairment. Arch. Neurol. 2010; 67(8): 980–986. PubMed Abstract \| Publisher Full Text\n\nAbdollahi M, Rashedi E, Jahangiri S, et al.: Fall risk assessment in stroke survivors: A machine learning model using detailed motion data from common clinical tests and motor-cognitive dual-tasking. Sensors (Basel). 2024; 24(3): 812. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBelgen B, Beninato M, Sullivan PE, et al.: The association of balance capacity and falls self-efficacy with history of falling in community-dwelling people with chronic stroke. Arch. Phys. Med. Rehabil. 2006; 87(4): 554–561. PubMed Abstract \| Publisher Full Text\n\nvon Elm E , Altman DG, Egger M, et al.: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007; 370(9596): 1453–1457. Publisher Full Text\n\nSmith T, Gildeh N, Holmes C: The Montreal Cognitive Assessment: validity and utility in a memory clinic setting. Can. J. Psychiatr. 2007; 52(5): 329–332. PubMed Abstract \| Publisher Full Text\n\nMao HF, Hsueh IP, Tang PF, et al.: Analysis and comparison of the psychometric properties of three balance measures for stroke patients. Stroke. 2002; 33(4): 1022–1027. PubMed Abstract \| Publisher Full Text\n\nChung MM, Chan RW, Fung YK, et al.: Reliability and validity of Alternate Step Test times in subjects with chronic stroke. J. Rehabil. Med. 2014; 46(10): 969–974. PubMed Abstract \| Publisher Full Text\n\nMiyata K, Tamura S, Kobayashi S, et al.: Berg Balance Scale is a valid measure for planning interventions and assessing changes in postural balance in patients with stroke. J. Rehabil. Med. 2022; 54: jrm00359. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKudlac M, Sabol J, Kaiser K, et al.: Reliability and validity of the Berg Balance Scale in the stroke population: a systematic review. Phys. Occup. Ther. Geriatr. 2019; 37(3): 196–221.\n\nConradsson M, Lundin-Olsson L, Lindelöf N, et al.: Berg Balance Scale: intrarater test-retest reliability among older people dependent in activities of daily living and living in residential care facilities. Phys. Ther. 2007; 87(9): 1155–1163. PubMed Abstract \| Publisher Full Text\n\nSchinkel-Ivy A, Wong JS, Mansfield A: Balance confidence is related to features of balance and gait in individuals with chronic stroke. J. Stroke Cerebrovasc. Dis. 2017; 26(2): 237–245. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHellström K, Lindmark B: Fear of falling in patients with stroke: a reliability study. Clin. Rehabil. 1999; 13(6): 509–517. PubMed Abstract \| Publisher Full Text\n\nTinetti ME, Richman D, Powell L: Falls efficacy as a measure of fear of falling. J. Gerontol. 1990; 45(6): P239–P243. Publisher Full Text\n\nLundin-Olsson L, Nyberg L, Gustafson Y: “Stops walking when talking” as a predictor of falls in elderly people. Lancet. 1997; 349(9052): 617. PubMed Abstract \| Publisher Full Text\n\nPeters J, Lauinger A, Mayr M, et al.: Dual-task assessments for predicting future falls in neurologic conditions: a systematic review. Am. J. Phys. Med. Rehabil. 2024; 103(6): 554–560. PubMed Abstract \| Publisher Full Text\n\nAsai T, Oshima K, Fukumoto Y, et al.: Does dual-tasking provide additional value in timed “up and go” test for predicting the occurrence of falls? A longitudinal observation study by age group (young-older or old-older adults). Aging Clin. Exp. Res. 2021; 33(1): 77–84. PubMed Abstract \| Publisher Full Text\n\nPalaniswamy V, Lamba D, Joshua AM, et al.: Dual tasking as a predictor of falls in post-stroke: Walking while talking versus stops walking while talking. Zenodo. 2024. Publisher Full Text" }	[ { "id": "350983", "date": "03 Jan 2025", "name": "Rita Chiaramonte", "expertise": [ "Reviewer Expertise Rehabilitation" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis interesting study showed as dual tasking can be a predictor of falls in post-stroke. Here are my comments. TITLE: I suggest adding the study design in the title. KEYWORDS: I propose to use Mesh keywords to better contextualize future research ABSTRACT:\nIn the background, you started with epidemiologic data, but I suggest avoiding this. Instead, refer to relevant references in the introduction with the correct citation. At the end of the background, explicitly state the aim of the study. In the introduction, you wrote, “Most previous observational research has primarily relied on established tools like the Berg Balance Scale (BBS) and the Tinetti Falls Efficacy Scale (FES) to evaluate balance and fear of falling,” but without references, even though you referred to previous research. I propose adding the necessary references, particularly regarding the correlation of other scales with dual-task performance in stroke patients. In a recent study, the Tinetti gait test was significantly related to TUG, the Tinetti balance test to the Barthel Index, BBS, and TUG. Finally, there is a positive correlation between the use of aids and BBS and the total score of the Tinetti test (Chiaramonte R, et al., 2024 [Ref 1]). You can referred to this.\nMETHODS: Are the patients in the acute or subacute phase of stroke (refer to the days since stroke indicated in Table 1)? FIGURE 1: Add the legend for the acronyms. Also, include the number of patients that remained in the study, in the measurement phase, and in data analysis (and not only in the inclusion criteria). DISCUSSION:\nAt the beginning, avoid showing the aim of the study; focus on the study’s findings. It would be interesting to discuss the most commonly used tests in proprioceptive and Dual-Task Training after stroke. It would be valuable to better contextualize the need to select appropriate assessments for stroke patients both at baseline and after rehabilitation (Chiaramonte R, et al., 2022 [Ref 2]). This is especially important to support your conclusions about future studies that should explore the topic in stroke rehabilitation.\nLIMITATIONS: At the end of the discussion, add a paragraph addressing the study’s limitations.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13207", "date": "30 Jan 2025", "name": "vijayakumar palaniswamy", "role": "Author Response", "response": "Dear Dr. Rita Chiaramonte, University of Catania, Catania, Italy Thank you for taking the time to review our manuscript titled, “Dual tasking as a predictor of falls in post-stroke: A cross-sectional analysis comparing Walking While Talking versus Stops Walking While Talking.” We truly appreciate your insightful and constructive feedback, which has helped us refine and improve our work. Below, we have provided a detailed, point-by-point response to each of your comments. TITLE Reviewer Comment: I suggest adding the study design in the title. Response: We have revised the title to explicitly include the study design: “Dual tasking as a predictor of falls in post-stroke: A cross-sectional analysis comparing Walking While Talking versus Stops Walking While Talking.” KEYWORDS: Reviewer Comment: I propose using MeSH keywords to better contextualize future research. Response: The keywords have been updated to include MeSH terms: “attention,” “cognition disorders,” “stroke rehabilitation,” “walking,” “predictive value of tests,” “risk assessment,” “ROC curve,” and “executive function.” These terms enhance the contextual relevance for future research. ABSTRACT: Reviewer Comment: In the background, you started with epidemiologic data, but I suggest avoiding this. Instead, refer to relevant references in the introduction with proper citations. Response: We revised the background section of the abstract to remove epidemiologic data. It now succinctly highlights the significance of dual-task assessments in stroke rehabilitation with appropriate references. Reviewer Comment: At the end of the background, explicitly state the aim of the study. Response: The aim has been explicitly included: “This study aimed to evaluate the predictive value of WWT and SWWT tests in relation to established measures of fall risk among stroke survivors.” INTRODUCTION: Reviewer Comment: Add references for previous observational research on the correlation of scales like the Berg Balance Scale (BBS) and Tinetti Falls Efficacy Scale (FES) with dual-task performance. Consider including findings from recent studies such as Chiaramonte et al., 2024 [Ref 1]. Response: The necessary references have been added, and the text now reads: “Studies have demonstrated strong correlations between the Tinetti balance test and the Barthel Index, BBS, and TUG, emphasizing their utility in assessing mobility and independence among stroke survivors (Chiaramonte et al., 2024).” METHODS: Reviewer Comment: Are the patients in the acute or subacute phase of stroke? Response: We clarified that participants were in the subacute phase (3 to 11 weeks post-onset), as indicated in Table 1. This is now explicitly stated in the “Participants” subsection. FIGURE 1: Reviewer Comment: Add a legend for the acronyms. Include patient numbers at each phase, such as those who remained in the study, in the measurement phase, and in data analysis. Response: Figure 1 has been updated with: A legend for acronyms (WWT, SWWT, BBS, FES). Patient numbers at each phase: Screened: 234 Eligible: 80 Completed: 68 DISCUSSION: Reviewer Comment: Avoid stating the study’s aim at the beginning. Focus on the findings instead. Response: The discussion now opens with key findings: “This study highlights the significant associations between dual-task performance and traditional fall risk measures, emphasizing the value of incorporating these assessments into clinical practice for stroke rehabilitation.” Reviewer Comment: Discuss the most commonly used tests in proprioceptive and dual-task training after stroke to contextualize the need for selecting appropriate assessments, citing Chiaramonte et al., 2022 [Ref 2]. Response: We expanded the discussion to include a comparison of commonly used tests (e.g., BBS, FES, TUG) and their limitations. This section also underscores the value of dual-task assessments at different stages of stroke rehabilitation, citing Chiaramonte et al. (2022). LIMITATIONS Reviewer Comment: Add a paragraph addressing the study’s limitations. Response: We already included a paragraph addressing the study’s limitations in the original manuscript. Based on the reviewer’s recommendation, we have expanded this section to include additional points: The type and complexity of cognitive tasks during testing may affect performance and fall risk identification. Varying stages of stroke recovery may impact dual-task performance and generalizability. Thank you once again for your thoughtful feedback, which has significantly improved the quality of our manuscript. We hope the revised version meets your expectations and look forward to hearing your thoughts. Kind regards, Vijayakumar Palaniswamy On behalf of all authors" } ] } ]	1	https://f1000research.com/articles/13-1395
https://f1000research.com/articles/13-507/v1	17 May 24	{ "type": "Study Protocol", "title": "Clinical Outcomes of Polyetheretherketone (PEEK) Hybrid Prosthesis in All-on-Four Rehabilitation: A Systematic Review Protocol", "authors": [ "Hanen Boukhris", "Hayet Hajjami", "Souha Ben youssef", "Hayet Hajjami", "Souha Ben youssef" ], "abstract": "Background The “all-on-four” concept represents a significant advancement in dental implantology. particularly beneficial in cases of extensive jaw bone loss where invasive bone regeneration procedures are typically required. However, the successful implementation of this technique necessitates meticulous planning concerning implant selection, materials, and prosthesis design. The recent introduction of PEEK (Polyetheretherketone) in dentistry, especially in all-on-four prosthetics, prompts questions regarding its clinical efficacy and comparative biomechanical and biological advantages over conventional materials such as titanium and zirconia. While some studies have compared PEEK with other materials, systematic reviews evaluating its efficacy are scarce. This systematic review protocol intends to assess the evidence regarding the viability of PEEK as a potential alternative within the all-on-four approach in dental implantology.\n\nMethods This systematic review protocol will adhere to the Cochrane Handbook for Systematic Review of Interventions and align with the Methodological Expectations of the Cochrane Intervention Reviews (MECIR) guidelines. Utilizing a comprehensive search strategy, multiple databases, including PubMed, EMBASE, Scopus, EBSCO, Web of Science, Cochrane Central, and registries of clinical trials, will be explored. The search aims to identify randomized controlled trials and non-randomized studies investigating the application of PEEK in the all-on-four approach for dental procedures. Emphasizing clinically relevant outcomes such as implant survival, prosthesis success, peri-implant complications, and patient satisfaction, this review aims to provide insights into the effectiveness and potential benefits of using PEEK in all-on-four prosthetics. Non-randomized studies will be assessed for bias using ROBINS-I, while randomized controlled trials will undergo evaluation with the Cochrane Risk of Bias assessment tool, ROB II.\n\nDiscussion The outcomes derived from this systematic review hold great significance for dental practitioners exploring the all-on-four concept. Understanding PEEK’s advantages and limitations compared to titanium and zirconia facilitates tailored treatment plans, enhancing success and satisfaction, ultimately improving dental care quality.\n\nSystematic review registration PROSPERO: CRD42024531175 (Registered on 13/04/2024).", "keywords": [ "All-on-four", "PEEK (Polyetheretherketone)", "Full-arch implant", "Systematic review", "Dental materials", "Success rates", "Complications", "Clinical outcomes" ], "content": "Introduction\n\nIn the field of clinical dentistry, the merging of three-dimensional (3D) printing methods introduces a pioneering challenge in restorative dentistry. Leading this evolution are techniques such as digital light processing and stereolithography.1–3 Despite rapid technological advancements propelled by patent expirations and widespread acceptance in dentistry, their adoption in clinical practice hinges primarily on the availability of suitable materials. These materials must ensure precise fabrication and possess requisite biological and physical properties.3 Polymeric materials, notably ultra-high-performance variants like PEKK and PEEK, have garnered attention for their outstanding mechanical properties. PEEK, established in medical applications since the 1990s, has demonstrated success in various procedures, such as spinal fusions and orthopedic surgery.4–6 The potential utilization of these materials in dental prostheses and implants, including the “all-on-four concept,” has attracted considerable interest from both researchers and clinicians.7,8\n\nThe “all-on-four concept” offers a simplified approach to rehabilitation, introduced in the early 2000s to provide a fixed, comfortable solution for fully edentulous patients with atrophic jaws, while avoiding costly and complex regenerative procedures.9,10\n\nThis method has evolved over time, initially utilizing fused metallic frameworks or milled bars for prostheses construction. Traditionally, titanium or cast metal alloy frameworks were favored for their mechanical properties. However, despite initial success rates, issues such as prosthesis fractures, particularly with polymethylmethacrylate (PMMA) prostheses designed for maxillary use, have prompted exploration of alternative materials.11–13 Recent suggestions to incorporate polymers into all-on-four prostheses aim to enhance patient satisfaction and confidence, addressing challenges associated with prosthesis fractures and failures.14,15\n\nTherefore, this proposed systematic review seeks to gather data on the clinical performance of PEEK as a restorative material for all-on-four prostheses, in comparison to alternative materials such as titanium and zirconia. This survey is crucial for dentists. It provides essential data for making informed decisions regarding the utilization of PEEK in the all-on-four concept.\n\n\nProtocol\n\nThe systematic review will follow the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) checklist.16–18 It will also adhere to guidelines outlined in the Methodological Expectations of Cochrane Intervention Reviews and Cochrane Handbook for Systematic Review of Interventions.19,20 The protocol has been officially recorded in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42024531175 on 13/04/2024.\n\nPrimary objectives:\n\n• To evaluate the efficacy of PEEK (Polyetheretherketone) in the all-on-four concept, comparing it to conventional materials like titanium and zirconia.\n\n• To examine related clinical outcomes, including implant survival rates, prosthesis success, patient satisfaction levels, and incidences of peri-implant complications.\n\nSecondary objectives:\n\n• Identify any potential advantages or limitations of using PEEK in all-on-four prosthetics compared to traditional materials.\n\n• Provide evidence-based recommendations for clinicians regarding the selection of materials for all-on-four procedures.\n\n• Identify any gaps in the existing literature and suggest potential directions for future research.\n\nThe eligibility criteria are organized based on the PICOS framework (Participant-Intervention-Comparison-Outcome-Study Design). This framework aims to identify the key components of the research question.\n\nThe research question for this systematic review is: Does the choice of prosthetic material, especially PEEK (Polyetheretherketone), impact success rates in all-on-four dental implant concept compared to titanium and zirconia?\n\n✓ Types of participants: This systematic review will focus on patients who have received all-on-four implant-supported fixed prostheses. Eligible participants must not have medical conditions that could affect bone healing or metabolism, such as diabetes, hypertension, or cardiovascular diseases. However, smokers or those who have undergone chemotherapy or radiation therapy will be excluded due to potential impacts on bone healing.\n\n✓ Types of interventions: This systematic review will center on the use of PEEK (Polyetheretherketone) as the prosthetic material in all-on-four concepts. The minimum follow-up period will be six months. The analysis will focus on evaluating the effectiveness of PEEK relative to conventional materials.\n\n✓ Types of outcomes: The most important outcome will be the success rate of all-on-four prosthesis. Success will be assessed based on criteria including implant stability, peri-implant soft tissue health, prosthetic stability and function, patient satisfaction, and absence of major complications such as peri-implantitis. These assessments will be conducted at various time points.\n\nMeasures of effect: The main outcome (success rate) will be quantified using the risk ratio (relative risk) or odds ratio, depending on the available data in the included studies. These measures will evaluate the likelihood of success with PEEK prosthetic material compared to alternative materials in all-on-four rehabilitations.\n\nAdditionally, risk differences and the number needed to treat may be calculated to provide further insights into the clinical significance of any differences observed in success rates between the two groups.\n\n✓ Study types: This systematic review will involve randomized controlled trials as well as non-randomized controlled trials (non-RCTs). Additionally, observational studies, including cohort and case-control studies, will be considered if they adhere to at least 15 criteria from the STROBE quality guide.21–23 Furthermore, comparative studies, such as quasi-experimental designs, will be included if they compare outcomes of all-on-four rehabilitation using PEEK prosthetic material with alternative materials. Exclusion criteria will involve individual case reports and letters to the editor due to limited generalizability, while non-English studies will be excluded to mitigate language bias and resource constraints. Additionally, animal studies will not be considered. Studies with insufficient outcome data will also be excluded to ensure the reliability of the review.\n\nThe improved search strategy will utilize both keywords and controlled vocabulary terms specific to the topic of interest, ensuring a thorough exploration of relevant literature.\n\nIn addition to MEDLINE, other databases such as EMBASE, Scopus, EBSCO, Cochrane Central and Web of Science will be systematically searched to minimize the risk of missing relevant studies.\n\nTo ensure inclusivity, efforts will be made to identify unpublished literature and ongoing clinical trials through sources such as conference proceedings, dissertations, and clinical trial registries. The advisory board will play a crucial role in guiding the identification of grey literature sources and analyzing their relevance to the review.\n\nMoreover, the search strategy will be complemented by manually searching through the bibliographies of included studies to identify additional articles that may not have been identified through electronic searches alone. This approach will help to minimize the risk of publication bias and ensure an exhaustive overview of the existing evidence.\n\nAfter conducting a thorough search across all identified databases and removing duplicate papers, two reviewers will independently assess the titles and abstracts of potentially eligible articles. Articles meeting the initial eligibility criteria will undergo a full-text examination. Additionally, reviewers will carefully examine the bibliography of selected articles to identify further relevant studies. Papers meeting the selection criteria will proceed to the data extraction stage.\n\nAny differences between the reviewers during the selection phase will be addressed through discussion. If needed, an additional reviewer (SB) will be engaged to assist in reaching a consensus and maintaining the integrity of the selection process.\n\nThe findings of the search and selection process will be meticulously documented and reported in the final systematic review, ensuring compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.19,20\n\nTo ensure a thorough evaluation of bias within the included studies, two review authors (HB, HH) will independently conduct assessments using the revised Cochrane Risk of Bias Assessment Tool (ROBII) and the Newcastle-Ottawa Scale (NOS).24,25 These established tools will facilitate our analysis of multiple aspects, including participant recruitment, classification of interventions, adherence to intended protocols, data completeness, outcome assessment, and reporting of results.\n\nEach identified risk will be categorized as low, high, serious, or moderate, allowing for a nuanced understanding of the quality of evidence.\n\nIf there are any discrepancies between the review authors, they will be addressed through thorough comprehensive discussion or, if required, consultation with a third reviewer.\n\nTwo independent reviewers (HB, HH) will conduct data extraction using a template designed for this purpose, which has been carefully evaluated during a pilot phase.\n\nIn the data extraction phase, any discrepancies will be addressed through discussion by the two reviewers as the initial step. If consensus cannot be achieved, (SB) will be consulted for further input. Final decisions will be made based on majority agreement. In instances where information or data is unpublished or missing, attempts will be made to contact the study authors to request the necessary details. If sufficient data are obtained, additional pertinent statistical analyses will be conducted.\n\nThe analysis of results and data will involve descriptive statistics, such as mean and median, along with measures of dispersion. Frequencies and proportions will be calculated for all variables. The findings will be presented through both textual descriptions and tables, utilizing narrative synthesis.\n\nSubgroup analyses may be conducted if feasible, and sensitivity analyses will assess the robustness of findings.\n\nIf considered suitable, a meta-analysis will be conducted utilizing random-effects models to combine data from studies with methodology and outcome homogeneity. To assess statistical heterogeneity, comprehensive tests like the Chi-squared, Tau-squared, and I-squared metrics will be used. Heterogeneity levels will be systematically categorized, from low to high or severe, to interpret observed variability. These findings will be illustrated through a forest plot, providing a clear visualization of combined study effects. In identifying potential sources of heterogeneity, thorough subgroup analyses will be conducted. These analyses will examine key characteristics impacting incidence or prevalence estimates. The aim is to enhance the objectivity of the findings by investigating these factors thoroughly.\n\nMoreover, to address potential publication bias, a funnel plot will be utilized, grouping studies in sets of ten for meta-analysis. The plot’s symmetry will then be carefully assessed using the Egger test to identify any bias in the included studies.\n\n\nDiscussion\n\nThe findings of this proposed systematic review hold importance for dentists specializing in dental implantology. They will play a critical role in enhancing patient care for the all-on-four concept.\n\nBy consolidating existing evidence on PEEK’s use in all-on-four prosthetics, this review helps clinicians make informed decisions about material selection. Understanding both the potential benefits and limitations of PEEK compared to traditional materials like titanium and zirconia allows dentists to personalize treatment plans, enhancing success and satisfaction.\n\nConsequently, this review serves as a valuable resource for guiding clinical practice and elevating the quality of dental care provided.\n\nNo ethical approval is needed for this systematic survey. The authors intend to present the findings at target conferences and publish the research findings in a peer-reviewed journal adopting open science practices.\n\nThis systematic review is currently in the data analysis process. The protocol of this systematic review was submitted to PROSPERO registry on 13th April, 2024 (CRD42024531175).", "appendix": "Data availability\n\nNo data are associated with this article.\n\nFigshare: PRISMA-P checklist for Clinical Outcomes of Polyetheretherketone (PEEK) Hybrid Prosthesis in All-on-Four Rehabilitation: A Systematic Review https://doi.org/10.6084/m9.figshare.25662519.v1. 26\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nArcila L, de Carvalho Ramos N , Bottino M, et al.: Indications, materials and properties of 3D printing in dentistry: a literature overview. ResSocDev. 2020; 9(11). Publisher Full Text\n\nRevilla-León M, Sadeghpour M, Özcan M: An update on applications of 3D printing technologies used for processing polymers used in implant dentistry. Odontology. 2020; 108(03): 331–338. PubMed Abstract \| Publisher Full Text\n\nKessler A, Hickel R, Reymus M: 3D printing in dentistry-state of the art. Oper. Dent. 2020; 45(01): 30–40. Publisher Full Text\n\nAlsadon O, Wood D, Patrick D, et al.: Fatigue behavior and damage modes of high performance poly-ether-ketone-ketone PEKK bilayered crowns. J. Mech. Behav. Biomed. Mater. 2020; 110: 103957. PubMed Abstract \| Publisher Full Text\n\nZhao Y, Wong HM, Wang W: Cytocompatibility, osseointegration, and bioactivity of three-dimensional porous and nanostructured network on polyetheretherketone. Biomaterials. 2013; 34(37): 9264–9277. PubMed Abstract \| Publisher Full Text\n\nBae SY, Park JY, Jeong ID, et al.: Three-dimensional analysis of marginal and internal fit of copings fabricated with polyetherketoneketone (PEKK) and zirconia. J. Prosthodont. Res. 2017; 61(02): 106–112. PubMed Abstract \| Publisher Full Text\n\nDawson JH, Hyde B, Hurst M, et al.: Polyetherketoneketone (PEKK), a framework material for complete fixed and removable dental prostheses: a clinical report. J. Prosthet. Dent. 2018; 119(06): 867–872. PubMed Abstract \| Publisher Full Text\n\nMaló P, de Araújo Nobre M , Moura GC: Short-term report of an ongoing prospective cohort study evaluating the outcome of full-arch implant-supported fixed hybrid polyetheretherketone-acrylic resin prostheses and the All-on-Four concept. Clin. Implant. Dent. Relat. Res. 2018; 20(05): 692–702. PubMed Abstract \| Publisher Full Text\n\nDurkan R, Oyar P, Deste G: Maxillary and mandibular all-on-four implant designs: a review. Niger. J. Clin. Pract. 2019; 22(08): 1033–1040.\n\nBhering CLB, Mesquita MF, Kemmoku DT, et al.: Comparison between all-on-four and all-on-six treatment concepts and framework material on stress distribution in atrophic maxilla: a prototyping guided 3D-FEA study. Mater. Sci. Eng. C. 2016; 69(69): 715–725. PubMed Abstract \| Publisher Full Text\n\nLee KS, Shin SW, Lee SP, et al.: Comparative evaluation of a four-implant-supported polyetherketoneketone framework prosthesis: a three-dimensional finite element analysis based on cone beam computed tomography and computer-aided design. Int. J. Prosthodont. 2017; 30(06): 581–585. PubMed Abstract \| Publisher Full Text\n\nZeller B, Stöckli S, Zaugg LK: Biofilm formation on metal alloys, zirconia and polyetherketoneketone as implant materials in vivo. Clin. Oral Implants Res. 2020; 31(11): 1078–1086. PubMed Abstract \| Publisher Full Text\n\nFerreira MB, Barão VA, Faverani LP, et al.: The role of superstructure material on the stress distribution in mandibular full-arch implant-supported fixed dentures. A CT-based 3D-FEA. Mater. Sci. Eng. C. 2014; 35(01): 92–99. PubMed Abstract \| Publisher Full Text\n\nDieguez-Pereira M, Brizuela-Velasco A, Chavarri-Prado D, et al.: The utility of implant-supported fixed dental prosthesis material for implant micromovement and peri-implant bone microstrain: a study in rabbit tibia. Int. J. Oral Maxillofac. Implants. 2020; 35(06): 1132–1140. PubMed Abstract \| Publisher Full Text\n\nLee KS, Shin MS, Lee JY, et al.: Shear bond strength of composite resin to high performance polymer PEKK according to surface treatments and bonding materials. J. Adv. Prosthodont. 2017; 9(05): 350–357. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMoher D, Liberati A, Tetzlaff J, et al.: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009; 6(7): e1000097. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMoher D, Shamseer L, Clarke M, et al.: Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst. Rev. 2015; 4(1): 1. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMigliavaca CB, Stein C, Colpani V, et al.: How are systematic reviews of prevalence conducted? A methodological study. BMC Med. Res. Methodol. 2020 [cited 2020 Dec 12]; 20(1): 96. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHiggins JPT, Thomas J, Chandler J, et al.: Cochrane Handbook for systematic reviews of interventions version 6.1 (updated September 2020). London: Cochrane; 2020.\n\nHiggins JPT, Lasserson T, Chandler J, et al.: Methodological Expectations of Cochrane Intervention Reviews. London: Cochrane; February 2021. Version. MECIR Version February 2021 clean final_1.\n\nSTROBE Statement-Checklist of items that should be included in reports of cohort studies.[cited 2020 Dec 10].\n\nSTROBE Statement-Checklist of items that should be included in reports of cross-sectional studies.[cited 2020 Dec 10].\n\nChecklist for Randomized Controlled Trials Critical Appraisal tools for use in JBI Systematic Reviews.[cited 2020 Dec 10].\n\nSterne JAC, Savović J, Page MJ, et al.: RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ (Clinical research ed.). 2019; l4898. Publisher Full Text\n\nWells GA, Shea B, O’Connell D, et al.: The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute; Accessed January 20, 2024. Reference Source\n\nBoukhris H: PRISMA-P checklist for Clinical Outcomes of Polyetheretherketone (PEEK) Hybrid Prosthesis in All-on-Four Rehabilitation: A Systematic Review Protocol. Dataset. figshare. 2024. Publisher Full Text" }	[ { "id": "300937", "date": "04 Oct 2024", "name": "Saja Muhsin", "expertise": [ "Reviewer Expertise Dental Material Sciences", "Prosthodontics", "Research Methodoldy (Dental field)" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary; Two independent reviewers will use the Cochrane Risk of Bias Tool and the Newcastle-Ottawa Scale to assess studies, addressing discrepancies through discussion or a third reviewer to ensure a comprehensive evaluation of bias. Data extraction will be performed independently, with differences resolved similarly. Descriptive statistics and narrative synthesis will summarize findings, with subgroup and sensitivity analyses enhancing robustness. If feasible, a random-effects meta-analysis will be conducted, using Chi-squared, Tau-squared, and I-squared tests to assess heterogeneity. Funnel plots and the Egger test will evaluate publication bias, aiming for objective and reliable results.\nTo ensure the article is scientifically sound, the authors should focus on the following specific points: 1. Bias Assessment Tools: Justify the choice of the Cochrane Risk of Bias Tool (ROBII) and the Newcastle-Ottawa Scale (NOS) for assessing bias. Explain how these tools complement each other and their relevance to the study design. 2. Discrepancy Resolution: Provide detailed procedures for resolving discrepancies between reviewers. Specify criteria for involving a third reviewer and how to achieve consensus to enhance transparency. 3. Data Extraction Template: Include a comprehensive description of the data extraction template and the pilot phase evaluation. This ensures the template's effectiveness and reliability in capturing relevant data. 4. Unpublished/Missing Data: Outline the specific steps and methods for contacting study authors to obtain unpublished or missing data. Clarify how these data will be integrated into the analysis and the impact on overall findings. 5. Statistical Analyses: Elaborate on the statistical methods, including how descriptive statistics, frequencies, and proportions will be calculated. Provide clear definitions and justifications for the measures of dispersion used. 6. Subgroup and Sensitivity Analyses: Detail the criteria for conducting subgroup analyses and the factors considered in sensitivity analyses. Explain how these analyses will contribute to understanding the robustness and generalizability of the findings. 7. Meta-Analysis Criteria: Specify the criteria for including studies in the meta-analysis, particularly the definitions of methodological and outcome homogeneity. Justify the use of random-effects models and provide a rationale for the selected tests (Chi-squared, Tau-squared, and I-squared) to assess heterogeneity. 8. Heterogeneity Categorization: Clearly define the categories of heterogeneity (low, high, severe) and explain the thresholds or criteria used to classify them. This aids in interpreting the variability among included studies. 9. Publication Bias: Provide a detailed methodology for creating and interpreting the funnel plot and using the Egger test. Explain the rationale for grouping studies in sets of ten and how symmetry will be assessed to identify publication bias. 10. Visualization of Results: Ensure that the forest plot and any other visualizations are clearly described and justified. Explain how these visual tools will aid in the interpretation and presentation of the combined study effects. By addressing these points, the authors can strengthen the methodological rigour and scientific validity of their study, making it more robust and reliable.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes", "responses": [] }, { "id": "350243", "date": "17 Jan 2025", "name": "Marwa Emam", "expertise": [ "Reviewer Expertise Fixed prosthodontics", "dental materials", "digital dentistry", "implant biomechanics." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe report contains minor issues regarding the clarity of its English language. Editing is required to improve the flow and enhance the understandability of the sentences.\nIntroduction Section:\nIt is unclear whether only in vivo studies will be included, as outcomes cannot be effectively investigated through in vitro studies. The first sentences of the introduction should focus on implant dentistry or the available dental materials for CAD/CAM manufacturing, rather than 3D printing manufacturing. There is no need to mention PEKK since it will not be included in the review. Additionally, abbreviations should only be used after the full term has been introduced. A brief mention of the material’s composition and its related properties should be included here. PMMA is primarily a provisional material, so comparing it with PEEK is somewhat inappropriate. Instead, titanium and Co-Cr should be highlighted as they are considered the gold standard. Mention the advantages zirconia and PEEK bring to clinical outcomes.\n\nObjectives (Primary Objectives):\nHave you considered including base metals? How will each outcome be measured, and will aesthetic success be evaluated?\n\nEligibility Criteria:\nThere is a significant difference between “success” and “survival.” The report should specify the measured outcomes, and the terms should not be used interchangeably.\n\nMeasures of Effect:\nThe methods used to assess all parameters should be clearly defined and explicitly stated.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes", "responses": [ { "c_id": "13165", "date": "23 Jan 2025", "name": "Hanen Boukhris", "role": "Author Response", "response": "Dear Reviewer, Thank you for your valuable feedback on our systematic review protocol. We appreciate your careful consideration of the manuscript and your insightful comments, which will help improve the clarity and precision of the report. Below, we address each of your reservations: Clarity of English Language: We recognize the importance of clear and concise language in scientific writing. We will thoroughly revise the manuscript to improve the flow and readability, ensuring that sentences are more straightforward and easier to follow. A native English speaker will assist with the final editing to enhance the language quality further. Introduction Section: In vivo vs. In vitro studies: We understand the need for clarification regarding the inclusion criteria for in vivo studies. We will revise the introduction to explicitly state that only in vivo studies will be included in the review, as outcomes cannot be effectively evaluated through in vitro studies. Focus on Implant Dentistry: We acknowledge that the introduction should primarily focus on implant dentistry rather than 3D printing manufacturing. The first sentences will be rephrased to center on available dental materials for CAD/CAM manufacturing, as this aligns better with the focus of the review. PEKK Mention: We will remove the mention of PEKK from the introduction as it will not be part of the review, streamlining the discussion. Material Composition and Properties: We agree with your suggestion to include a brief mention of PEEK's composition and its relevant properties in the introduction. This information will be incorporated to provide a better context for readers. Comparison of PMMA with PEEK: We acknowledge that PMMA is primarily a provisional material, and comparing it with PEEK may not be entirely appropriate. In light of this, we will revise the text to focus more on titanium and Co-Cr alloys as the gold standard materials for all-on-four prosthetics. Additionally, we will highlight the clinical advantages that zirconia and PEEK bring to the outcomes of such treatments. Objectives (Primary Objectives): Inclusion of Base Metals: We will consider incorporating base metals into the review, as their inclusion may provide a more comprehensive comparison. This will be reflected in the revised primary objectives. Outcome Measures and Aesthetic Success: We will provide clearer details on how each outcome will be measured, including the evaluation of aesthetic success, which is crucial for patient satisfaction and clinical outcomes. Eligibility Criteria: Clarification of \"Success\" vs. \"Survival\": We will ensure that the terms \"success\" and \"survival\" are clearly defined and not used interchangeably. The manuscript will specify how each outcome is measured, distinguishing between these two concepts. Measures of Effect: We will revise the manuscript to clearly define the methods used to assess each outcome, including the rationale behind the selection of these measures. The objectives of the study will be more explicitly stated to ensure clarity. Study Design Appropriateness: We will revisit the study design section and provide a more thorough explanation of why the chosen design is appropriate for addressing the research question, ensuring that all methodological details align with the objectives of the review. We believe that these revisions will strengthen the manuscript and enhance its clarity and precision. Once again, we appreciate your constructive feedback, and we are confident that the revised version will meet your expectations. Sincerely," } ] } ]	1	https://f1000research.com/articles/13-507
https://f1000research.com/articles/11-568/v1	25 May 22	{ "type": "Research Article", "title": "Behavioural patterns of university students during the COVID-19 pandemic: A cross-sectional study of the effects of active transportation, uninterrupted sitting time, and screen use on physical activity and sitting time", "authors": [ "Gonzalo Marchant", "Guillaume Chevance", "Andrés Ladino", "Brice Lefèvre", "Nicolas Jacquemond", "Guillaume Chevance", "Andrés Ladino", "Brice Lefèvre", "Nicolas Jacquemond" ], "abstract": "Background: The closure of universities due to the coronavirus disease 2019 (COVID-19) pandemic may alter the behaviour of students. This study aimed to determine the effect of the pandemic on physical activity and sitting time in French students prior to confinement and during confinement. Methods: This was a cross-sectional study based on data collected via an online questionnaire for university students during the second confinement in France (between October and December 2020). Participants (N= 2873) completed the International Physical Activity Questionnaire, which assessed physical activity and sedentary behaviour, and contained questions about modes of transport, and perception of uninterrupted sitting time and screen time prior to confinement and during confinement. Multiple regression models assessed how active transportation, uninterrupted sitting time, and screen time studying increased or reduced confinement effects on physical activity and sitting time. Results: The regression models showed that physical activity decreased during confinement for students who engaged in more prolonged periods of active transportation prior to confinement. Moreover, the perception of long, uninterrupted sitting time and high screen time prior to confinement significantly increased sitting time during confinement. Students who adopted the most active transport time prior to confinement were the least likely to increase their screen time during confinement. Conclusions: Confinement reduced physical activity levels and increased sitting time, mainly among students who adopted active transport and accumulated longer uninterrupted sitting time. Students who combined-long periods of uninterrupted sitting time with high screen use could be a riskier profile for health. Analysis of physical activity time and sitting position should include its accumulation patterns.", "keywords": [ "Universities", "sitting position", "transportation", "lifestyle", "young people" ], "content": "Introduction\n\nThe confinement caused by the coronavirus disease 2019 (COVID-19) pandemic reduced the physical activity levels of university students1 by reducing active transportation to commute2 and increased sitting time and screen time.3\n\nAdopting active transportation, which includes any human-powered forms of travel, such as walking or cycling, makes people achieve the recommended physical activity levels for health (i.e., 150 minutes/week moderate physical activity).4 Students who adopt active transportation display higher physical activity levels than those who do not adopt it.5–7\n\nAlthough the threshold for physical activity to achieve health benefits is well defined, this is not the case for sitting time.8 Despite this lack of evidence, recent studies suggest that uninterrupted sitting for periods longer than 30 minutes has a detrimental impact on health.9 A threshold of six to eight hours per day of sitting and three to four hours of television is a health risk.10 Students spend more than six hours per day studying while sitting down,11 thus increasing health risks when sitting time accumulates uninterrupted.12 Besides this sitting time, students increasingly use screens to study,13 mainly computers.14\n\nWhile there has been a tendency to associate screens with sitting time, screen use does not always reflect that behaviour.15 Regardless of sitting time, screen time could be an independent health risk factor.16 Furthermore, the relationship between physical activity, sitting time and screen time is mixed. A systematic review showed no association between physical activity and sitting time.17 Even high physical activity levels do not mitigate the adverse effects of high screen time on health.18 Some studies have shown that students’ physical activity levels are negatively associated with sitting time,19 where high sitting time displaces total physical activity time,20 mainly light physical activity.21 Similarly, when people spend more than six hours sitting, they replace that time with walking and moderate to vigorous physical activity.22\n\nMost studies about confinement in the COVID-19 pandemic have focused on total times of changes in physical activity levels, sitting time and screen time. For this reason, the main objective of this study was to assess if active transportation time, uninterrupted sitting time, and screen time spent studying prior to confinement were factors influencing these changes (Figure 1).\n\nIPAQ=International Physical Activity Questionnaire.\n\nH1: The first hypothesis was that the longer the duration in minutes of students' active transportation trips prior to confinement, the greater the reduction in their physical activity levels, excluding active transportation time during confinement.\n\nH2: The second hypothesis was that the greater the uninterrupted sitting time prior to confinement in students, the greater the increase in the amount of time they would spend sitting during confinement.\n\nH3: The third hypothesis was for screen time; due to the increase in online courses during confinement, the longer the screen time studying prior to confinement in students, the greater the increase in their screen time during confinement.\n\nH4: Finally, we hypothesised that there would be no relationship between active transportation, sitting time and screen time during confinement.\n\n\nMethods\n\nThis was a cross-sectional study. Students from 16 faculties enrolled (N=6705) in the university sports service (SUAPS) received an invitation via the institutional e-mails to a health webinar for French students (Webex®) (November 10, 2020) on physical activity and confinement. A link to an online questionnaire was then sent to each student via the institutional e-mail addresses, except for sports sciences students. Due to the type of training, these students were the only ones who partially maintained physical activities during the confinement, which would bias the data. The questionnaire was a voluntary survey, and it was available on the Drag n Survey® platform between November 10th and 18th, 2020. The survey used in this study is available as Extended data.23 There was a separate informed consent page where students agreed to participate by checking a checkbox. There were non-monetary incentives to participate. Participants could obtain the final results of the study. A total of 2986 students visited the website and agreed to participate in the study and only 2873 completed the screening questionnaire. Each questionnaire included a completeness check with forced response items (i.e., highlight mandatory items). In order to prevent a single user from filling in the same questionnaire multiple times, one response per IP address was possible (the flowchart is shown in Figure 2).\n\nThe National Commission for Data Protection and Liberties (CNIL-France) approved the study (2221060v0-CNIL). The final decision was determined on 8th February 2021. The posteriori approval of our study is because it was not possible to know that the second wave of COVID-19 would occur in France. The protocol was submitted one week before the second Covid wave in France and initially this study was only supposed to investigate the effects of the first wave of COVID-19. We then adapted the protocol to examine the condition of confinement in the second wave of the pandemic.\n\nThe statement followed the Declaration of Helsinki and the French methodological reference MR-01. Students who visited the informed consent page and agreed to participate were considered to have provided informed consent. If participants did not want to participate in the survey, they could turn off the electronic questionnaire and drop out.\n\nDemographics. Information was collected, including sex and age in years (open-ended question).\n\nPhysical activity. Participants answered questions about how much time and how many days they spent doing moderate and vigorous physical activities during the previous seven days: First, “prior to the confinement” and then “during the confinement”. The survey was based on the International Physical Activity Questionnaire (IPAQ) short form.24\n\nTransportation type for commuting. Participants were asked what type of transport they habitually used to commute to university (open-ended question). Following which, the participants answered the following question: “On a typical day (prior to confinement), how many minutes do you spend carrying out active transportation?”. A definition of active transportation was then proposed to the participants in the following statement: “Active transportation is defined as any form of human-powered transportation (e.g., walking and cycling)”.\n\nSitting time. The IPAQ short form included the following question: “In the past seven days, how much time did you spend sitting during a weekday? (i.e., hours and minutes per day)”. For this study, this question was asked prior to confinement and during confinement.\n\nUninterrupted sitting time. Students reported the average time of uninterrupted sitting. The question was, “On average (prior to confinement), how long do you sit without getting up? (hours and minutes)”.\n\nScreen time. Students indicated average minutes per day of screen-time usage prior to and during confinement. The question posed with regards to their time prior to the confinement was: “Normally (prior to confinement), how many hours on average per day do you spend in front of a screen (computer, tablet, smartphone, TV…)?”. The question posed with regards to their time during the confinement was: “How many hours on average per day (during confinement) do you spend in front of a screen (computer, tablet, smartphone, TV)?”.\n\nScreen time studying. Students reported their average daily hours using a computer (i.e., desktop, laptop, tablet) or smartphone to study. The question posed was, “Normally (prior to confinement), how many hours on average per day do you spend in front of a screen studying (computer, tablet, smartphone)?”. The question posed with regards to their time during the confinement was: “Normally (during confinement), how many hours on average per day do you spend in front of a screen studying (computer, tablet, smartphone)?”.\n\nWe calculated the differences (i.e., delta Δ) in physical activity, sitting and screen time between the period prior to confinement and the period during confinement, using Microsoft Excel version 16.48 (RRID:SCR_016137). These differences were the dependent variables for four multiple regression models. Sex and age were included in the regression models as control variables to assess the impact of confounding variables. A graphic method of generalized additive models (GAM)25 examined subgroups and interactions. The graphs are available as Extended data.26 All missing data were removed.\n\nThe models were used to prove our fourth hypothesis. The first regression model was for moderate physical activity and the second regression model was for vigorous physical activity. Both models were used to test the first hypothesis, which stated that the longer time a student adopted active transportation, the greater the reduction in physical activity minutes during confinement. The third model tested the second hypothesis that those who spent longer sitting for an uninterrupted time prior to confinement, the greater the increase in sitting time during confinement. The fourth model tested the third hypothesis, which suggested that the higher time students spent in front of a screen for study, the greater the increase in screen time during confinement. All regression analyses were performed with RStudio (2021.09.0) (RRID:SCR_000432) and the package lme4 (RRID:SCR_015654).27\n\n\nResults\n\nTable 1 presents the characteristics of 2873 students.32 Overall, the sample was balanced between men (46%) and women (54%). They were aged between 18 and 29 years old (M=19.93, SD=1.76) and they were, according to IPAQ classification, inactive prior to confinement (60%). Students adopted walking (70%) as a mode of active commuting, 17% participated in cycling, 8% were passive commuters (e.g., car, bus, underground), 3% combined walking and cycling, and 2% adopted any combination of active and passive transport (e.g., bus, tramway and walking or tramway and cycling). The average duration of active transportation, prior to confinement, was approximately 30 minutes per trip. Moreover, the students spent approximately eight hours sitting down per day and with an average uninterrupted sitting time of almost 100 minutes. Students spent more than 10 hours per day using screens, of which approximately five hours were for studying and five hours outside of study hours. Analyses of the GAM models did not show the presence of subgroups within the data or interactions between variables.26\n\nFour multiple regression models assessed the extent to which active transportation, uninterrupted sitting time, and screen time studying before confinement exacerbated or attenuated the effects of confinement on total physical activity time and sitting time. Multiple regression models showed that when there was a negative effect in changes, it opposes the effect of confinement, if there is a positive change effect, it increases the impact of confinement.\n\nH1: The first hypothesis was that the longer the duration in minutes of students' active transportation trips prior to confinement, the greater the reduction in their physical activity time during confinement.\n\nTo evaluate our first hypothesis, we conducted two multiple regression analyses (Table 2), one for moderate physical activity (Model 1) and one for vigorous physical activity (Model 2). The results of the first model indicated that five predictors explained 47% of the variance in moderate physical activity time (R2adjusted=0.46, F(9,2863)=283.1, p<0.001). Older students (βage=-0.73, p<0.001), as well as those who accumulated more moderate physical activity (β=-0.71, p<0.001) and sitting time prior to confinement (β=-0.01, p<0.001), had significantly less reduction in their moderate physical activity levels during confinement. It was found that active transportation time predicted a larger reduction in moderate physical activity (β=0.16, p<0.001), as did vigorous physical activity prior to confinement (β=0.07, p<0.001).\n\n* p<0.05;\n\n p<0.01;\n\n* p<0.001.\n\nThe second model showed that three predictors explained 64% of the variance in vigorous physical activity (R2adjusted=0.64, F(9,2863)=580, p<0.001). Students who engaged in vigorous physical activity (β=-0.95, p<0.001) for more minutes prior to confinement showed significantly less reduction in vigorous physical activity during confinement. Conversely, students who presented higher amounts of moderate physical activity prior to confinement (β=0.05, p<0.01) showed a significantly greater reduction in their levels of vigorous physical activity.\n\nH2: The second hypothesis was that the greater the uninterrupted sitting time prior to confinement in students, the greater the increase in the amount of time they would spend sitting during confinement.\n\nIn the case of our second hypothesis, a multiple linear regression (Table 3) showed four predictors (Model 3) explaining 49% of the variance in students’ sitting time (R2adjusted=0.49, F(9,2863)=318.8, p<0.001). Students’ siting time (β=-0.97, p<0.001) and screen time studying (β=-0.07, p=0.001) prior to confinement significantly predicted a smaller increase in sitting time during confinement. Conversely, the greater the uninterrupted sitting (β=0.62, p<0.001) and screen time (β=0.29, p<0.001) prior to confinement, the greater the increases in sitting time during confinement.\n\n* p<0.05;\n\n p<0.01;\n\n* p<0.001.\n\nH3: The third hypothesis was for screen time; due to the increase in online courses during confinement, the longer the screen time studying prior to confinement in students, the greater the increase in their screen time during confinement.\n\nRegressions (Table 3) showed that four predictors explained 20% of the variance in screen time during confinement (R2adjusted=0.19, F(9,2863)=79.54, p<0.001). Active transportation (β=-0.52, p<0.01), screen time prior to confinement (β=-0.45, p<0.001), and screen time studying (β=-0.09, p<0.001) predicted a lower increase in screen time during confinement. Only uninterrupted sitting (β=0.43, p<0.001) significantly predicted a higher increase of screen time during confinement (Model 4).\n\nH4: Finally, we hypothesised that there would be no relationship between active commuting, sitting time and screen time during confinement.\n\nMultiple regression results on changes in moderate physical activity showed that the reduction in moderate physical activity levels was less significant for students who spent more time sitting prior to confinement (β=-0.01, p<0.001). Model 2 showed no relationship between vigorous physical activity and either sitting or screen time. Model 3 showed no relationship between physical activity behaviour and sitting time or screen time. Finally, there was a negative relationship between the increase of screen time during confinement and active transportation minutes prior to confinement (Model 4). Students who adopted active transportation showed a less significant increase in screen time during confinement (β=-0.52, p=0.001).\n\n\nDiscussion\n\nThe main objective of this study was to determine whether the adoption of active transportation, uninterrupted sitting time, and screen study time predicted changes in physical activity, sitting time and screen time in students during confinement.\n\nWhile studies on confinement and its effects on university students showed that it reduced physical activity levels in this population, to our knowledge, only one study has shown that active transportation reduction might be associated with this decrease.2 For this reason, in our study, an amplifying effect of active transportation time on reducing students' physical activity levels during confinement was hypothesised and confirmed. Students who spent time undertaking active transportation to university and vigorous physical activity levels prior to confinement predicted a significant reduction in moderate physical activity levels during confinement. However, active transportation time does not predict changes in vigorous physical activity levels during the confinement period. Active transportation is considered a physical activity characterised by light to moderate intensity28; the students in this study adopted walking to the university prior to confinement.\n\nMoreover, active transportation could be part of students' daily routines, given that the city the study took place in has high active transportation rates (Walk Score® city of Villeurbanne: 89 errands can be accomplished on foot and very bikeable: 70-89).31 However, the suspension of campus lectures reduced active commuting, decreasing overall moderate physical activity levels. This factor explains why active transportation time did not predict a greater reduction in vigorous physical activity levels. In addition, students were inactive and spent no more than 30 minutes per day in physical activity, coupled with reduced movement perimeter during confinement (i.e., 5 km around the house).\n\nOne might have expected that moderate and vigorous physical activity levels before confinement would explain changes in the respective levels during confinement. However, a crossover effect was found between physical activity levels. On the one hand, the more time spent in vigorous physical activity, the greater the reduction in moderate physical activity time and vice-versa. This result could be because physical activity levels are part of a continuum29 in which if more time is spent in vigorous intensities, more time is also spent in moderate activities. For students who spent more time in moderate physical activity prior to confinement, their practice during confinement was limited to that intensity, and vigorous physical activity was reduced more significantly.\n\nOur second hypothesis was confirmed; the longer the uninterrupted time spent in a seated position before confinement, the more the students increased their time in that position during confinement. Furthermore, this increased time was exacerbated by the screen's use during confinement. Uninterrupted sitting time has been identified as a health risk factor in adults.9 This behaviour pattern is particularly marked in university students who accumulate this time during their lectures.30 Consequently, the point is the accumulation pattern of sitting time (i.e., how this time accumulates). For example, two students might accumulate six hours in total, but one will do so in three periods of two hours each and another in six periods of one hour.\n\nRegarding the positive association between sitting time and screen use, it is likely that the online courses during the pandemic period have increased the association between screen use and sitting in university students, increasing the use of screens to study.14 Similarly, screen use in students could be interpreted as a proxy for time spent sitting.\n\nThe third hypothesis postulated that the more time students used screens prior to confinement, the more they would increase this time during confinement. The results did not confirm this hypothesis; on the contrary, the more time spent using screens prior to confinement, the smaller the increase in this behaviour. One possible explanation could be that high time spent using screens did not undergo significant modifications since screen-based devices have become pervasive in students' lives.14 Likewise, the time students spent using screens could be independent of the confinement factor. However, screen time would not be independent of the uninterrupted time spent sitting since the longer the prolonged periods of this behaviour, the greater the increase in screen time. Thus, it could be postulated that students defined as prolongers of sitting time21 would be more prone to prolonged use of screens and vice-versa.\n\nThe last hypothesis postulated that there would be no relationship between active transportation times, sitting, and screen time was partially confirmed. The relationship between moderate physical activity and students' sitting time showed that low levels of physical activity could coexist with high levels of sitting time in students. This inactive-sedentary profile should be the most alarming health risk factor. Inactivity itself results in low levels of physical and mental health, but if it is associated with high levels of sitting time, there is a potentially higher risk of suffering from metabolic diseases or exacerbating risk for mortality.20 Another element highlighted is the “protective” effect of time spent in active transportation. This study highlight that the more time students adopted active transportation, the less they increased screen use in confinement. This phenomenon could reflect a negative association between the two behaviours and that somehow, screen time would be displaced by active transportation time.22 Similarly, students who adopt active transportation are generally more active people5 and spend less time using screens.\n\nThe present study is not free of limitations. Behaviours were measured via questionnaires, leading to the overestimation of physical activity and underestimation of sitting time. This phenomenon is associated with social desirability. The students who could answer this questionnaire had access to the internet and were enrolled in the health seminars offered during the pandemic.\n\n\nConclusions\n\nOur study confirms that active transportation is the primary source of physical activity in the daily lives of university students. Similarly, the time young people spend studying contributes to the accumulation of high levels of sitting time, which the use of screens could exacerbate. Finally, the ubiquity of screens and their association with sedentary behaviours could induce prolonged sitting positions, generating patterns of behaviour that are riskier for students' health. Therefore, the study of online courses and e-learning on physical activity levels and sitting time remains undetermined.\n\n\nData availability\n\nFigshare: Uni_dataCovid19 (spreadsheet data of questionnaire results). https://doi.org/10.6084/m9.figshare.19583821.32\n\nFigshare: Questionnaire Uni (study questionnaire).\n\nhttps://doi.org/10.6084/m9.figshare.19778761.23\n\nFigshare: GAM_RGraphs_uni (GAM graphs to examine subgroups and interactions). https://doi.org/10.6084/m9.figshare.19630434.26\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).", "appendix": "References\n\nLopez-Valenciano A, Suarez-Iglesias D, Sanchez-Lastra MA, et al.: Impact of COVID-19 Pandemic on University Students' Physical Activity Levels: An Early Systematic Review. Front. Psychol. 2020; 11: 624567.\n\nGenin PM, Lambert C, Larras B, et al.: How Did the COVID-19 Confinement Period Affect Our Physical Activity Level and Sedentary Behaviors? Methodology and First Results From the French National ONAPS Survey. J. Phys. Act. Health. 2021; 18(3): 296–303. PubMed Abstract \| Publisher Full Text\n\nRomero-Blanco C, Rodriguez-Almagro J, Onieva-Zafra MD, et al.: Physical Activity and Sedentary Lifestyle in University Students: Changes during Confinement Due to the COVID-19 Pandemic. Int. J. Environ. Res. Public Health. 2020; 17(18). PubMed Abstract \| Publisher Full Text\n\nFlint E, Webb E, Cummins S: Change in commute mode and body-mass index: prospective, longitudinal evidence from UK Biobank. Lancet Public Health. 2016; 1(2): e46–e55. PubMed Abstract \| Publisher Full Text\n\nCrist K, Brondeel R, Tuz-Zahra F, et al.: Correlates of active commuting, transport physical activity, and light rail use in a university setting. J. Transp. Health. 2021; 20: 100978. Publisher Full Text\n\nSisson SB, Tudor-Locke C: Comparison of cyclists' and motorists' utilitarian physical activity at an urban university. Prev. Med. 2008; 46(1): 77–79. PubMed Abstract \| Publisher Full Text\n\nSahlqvist S, Song Y, Ogilvie D: Is active travel associated with greater physical activity? The contribution of commuting and non-commuting active travel to total physical activity in adults. Prev. Med. 2012; 55(3): 206–211. PubMed Abstract \| Publisher Full Text\n\nBull FC, Al-Ansari SS, Biddle S, et al.: World Health Organization 2020 guidelines on physical activity and sedentary behaviour. Br. J. Sports Med. 2020; 54(24): 1451–1462. PubMed Abstract \| Publisher Full Text\n\nBellettiere J, Winkler EAH, Chastin SFM, et al.: Associations of sitting accumulation patterns with cardio-metabolic risk biomarkers in Australian adults. PLoS One. 2017; 12(6): e0180119. PubMed Abstract \| Publisher Full Text\n\nPatterson R, McNamara E, Tainio M, et al.: Sedentary behaviour and risk of all-cause, cardiovascular and cancer mortality, and incident type 2 diabetes: a systematic review and dose response meta-analysis. Eur. J. Epidemiol. 2018; 33(9): 811–829. PubMed Abstract \| Publisher Full Text\n\nMoulin MS, Irwin JD: An assessment of sedentary time among undergraduate students at a Canadian university. Int. J. Exerc. Sci. 2017; 10(8): 1116–1129.\n\nDiaz KM, Howard VJ, Hutto B, et al.: Patterns of Sedentary Behavior and Mortality in U.S. Middle-Aged and Older Adults: A National Cohort Study. Ann. Intern. Med. 2017; 167(7): 465–475. PubMed Abstract \| Publisher Full Text\n\nMontagni I, Guichard E, Carpenet C, et al.: Screen time exposure and reporting of headaches in young adults: A cross-sectional study. Cephalalgia. 2016; 36(11): 1020–1027. PubMed Abstract \| Publisher Full Text\n\nCastro O, Bennie J, Vergeer I, et al.: How sedentary are university students? A systematic review and meta-analysis. Prev. Sci. 2020; 21(3): 332–343. PubMed Abstract \| Publisher Full Text\n\nClark BK, Healy GN, Winkler EA, et al.: Relationship of television time with accelerometer-derived sedentary time: NHANES. Med. Sci. Sports Exerc. 2011; 43(5): 822–828. PubMed Abstract \| Publisher Full Text\n\nHamer M, Yates T, Demakakos P: Television viewing and risk of mortality: exploring the biological plausibility. Atherosclerosis. 2017; 263: 151–155. PubMed Abstract \| Publisher Full Text\n\nRhodes RE, Mark RS, Temmel CP: Adult sedentary behavior: a systematic review. Am. J. Prev. Med. 2012; 42(3): e3–e28. Publisher Full Text\n\nEkelund U, Steene-Johannessen J, Brown WJ, et al.: Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonised meta-analysis of data from more than 1 million men and women. Lancet. 2016; 388(10051): 1302–1310. Publisher Full Text\n\nCastro O, Bennie J, Vergeer I, et al.: Correlates of sedentary behaviour in university students: A systematic review. Prev. Med. 2018; 116: 194–202. PubMed Abstract \| Publisher Full Text\n\nDunstan DW, Dogra S, Carter SE, et al.: Sit less and move more for cardiovascular health: emerging insights and opportunities. Nat. Rev. Cardiol. 2021; 18(9): 637–648. PubMed Abstract \| Publisher Full Text\n\nSaunders TJ, McIsaac T, Douillette K, et al.: Sedentary behaviour and health in adults: an overview of systematic reviews. Appl. Physiol. Nutr. Metab. 2020; 45(10 (Suppl. 2)): S197–S217. PubMed Abstract \| Publisher Full Text\n\nStamatakis E, Gale J, Bauman A, et al.: Sitting Time, Physical Activity, and Risk of Mortality in Adults. J. Am. Coll. Cardiol. 2019; 73(16): 2062–2072. Publisher Full Text\n\nMarchant G: Questionnaire Uni. figshare. Figure. [Dataset]. 2022. Publisher Full Text\n\nCraig CL, Marshall AL, Sjostrom M, et al.: International physical activity questionnaire: 12-country reliability and validity. Med. Sci. Sports Exerc. 2003; 35(8): 1381–1395. PubMed Abstract \| Publisher Full Text\n\nWood SN: Generalized Additive Models: An Introduction with R. (2nd ed.).Chapman and Hall/CRC;2017. Publisher Full Text\n\nMarchant G: GAM_RGraphs_uni. figshare. Figure. [Dataset]. 2022. Publisher Full Text\n\nBates D, Mächler M, Bolker B, et al.: Fitting Linear Mixed-Effects Models Using lme4. J. Stat. Softw. 2015; 67(1): 1–48. Publisher Full Text\n\nAinsworth BE, Haskell WL, Herrmann SD, et al.: 2011 Compendium of Physical Activities: a second update of codes and MET values. Med. Sci. Sports Exerc. 2011; 43(8): 1575–1581. PubMed Abstract \| Publisher Full Text\n\nEijsvogels TM, George KP, Thompson PD: Cardiovascular benefits and risks across the physical activity continuum. Curr. Opin. Cardiol. 2016; 31(5): 566–571. PubMed Abstract \| Publisher Full Text\n\nDeliens T, Deforche B, De Bourdeaudhuij I, et al.: Determinants of physical activity and sedentary behaviour in university students: a qualitative study using focus group discussions. BMC Public Health. 2015; 15: 201. PubMed Abstract \| Publisher Full Text\n\nHall CM, Ram Y: Walk score® and its potential contribution to the study of active transport and walkability: A critical and systematic review. Transp. Res. Part D: Transp. Environ. 2018; 61: 310–324. Publisher Full Text\n\nMarchant G: Uni_dataCovid19. figshare. [Dataset]. 2022. Publisher Full Text" }	[ { "id": "150195", "date": "11 Oct 2022", "name": "Akhmad Habibi", "expertise": [ "Reviewer Expertise Statistics", "educational technology" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper has the potential to contribute to the related fields. However, some improvements should be considered:\nLit. review related to the four hypotheses should be supported by prior studies.\na.\n\nH1: The first hypothesis was that the longer the duration in minutes of students’ active transportation trips prior to confinement, the greater the reduction in their physical activity levels, excluding active transportation time during confinement.\nb.\n\nH2: The second hypothesis was that the greater the uninterrupted sitting time prior to confinement in students, the greater the increase in the amount of time they would spend sitting during confinement.\nc.\n\nH3: The third hypothesis was for screen time; due to the increase in online courses during confinement, the longer the screen time studying prior to confinement in students, the greater the increase in their screen time during confinement.\nd.\n\nH4: Finally, we hypothesized that there would be no relationship between active transportation, sitting time and screen time during confinement.\nIt is essential to integrate previous work discussed and critiqued in the literature review and discussion sections with the findings and tone of the study and bring out what was done in this study which addressed some of the shortcomings of those studies.\n\nThe gap between this research and prior research should also be more detailed. Besides, the significance of the current study is recommended to be more clear and more novel. In this sentence, “Most studies about confinement in the COVID-19 pandemic have focused on total times of changes in physical activity levels, sitting time, and screen time. For this reason, the main objective of this study was to assess if active transportation time, uninterrupted sitting time, and screen time spent studying prior to confinement were factors influencing these changes”. The studies are not cited and elaborated on. I suggest that the authors elaborate more on them, highlights on each finding of the works should be informed.\n\nWith N=2873 samples involved in the study, the authors need to conduct normality tests like Q-Q plot, skewness, and Kurtosis. The normality test is used to determine whether sample data has been drawn from a normally distributed population (within some tolerances). Without this, bias could be high for further statistical analysis.\n\nThe conclusion could be improved to motivate the related communities to get down to actionable, practical, and academic implications. The authors missed the limitation, implications, and recommendations for practical and theoretical sections. Please include those parts in the conclusion of the study.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "10670", "date": "13 Feb 2024", "name": "Gonzalo Marchant", "role": "Author Response", "response": "Dear Colleague, First of all, we would like to thank you for your comments and suggestions. Secondly, you will find our detailed responses to your comments in the following lines. Thus, you will see your comments followed by our answers, including the references that allowed us to complete our arguments. Lit. review related to the four hypotheses should be supported by prior studies. Answer 1: As requested, we have further developed our propositions, including new references in the introduction section, to complete the arguments according to our hypotheses. a. H1: The first hypothesis was that the longer the duration in minutes of students’ active transportation trips prior to confinement, the greater the reduction in their physical activity levels, excluding active transportation time during confinement. Answer 1.a: We justified the first hypothesis with the following arguments: Students who use active transportation are more active than those who do not. Among those who do, those who take longer trips also have a higher total physical activity time. Consequently, confinements reduce the active transportation to the university, thus reducing the total physical activity of the more active students during this period. Please see references in the first paragraph: Motevalli et al., 2023; Meyer et al., 2020. The second paragraph includes Yang et al., 2012 reference to complete our arguments according to the first hypothesis. b. H2: The second hypothesis was that the greater the uninterrupted sitting time prior to confinement in students, the greater the increase in the amount of time they would spend sitting during confinement. c. H3: The third hypothesis was for screen time; due to the increase in online courses during confinement, the longer the screen time studying prior to confinement in students, the greater the increase in their screen time during confinement. Answer 1.b and 1.c: For the second and third hypotheses, we have given two arguments to improve the theoretical framework that allows us to justify them. Thus, we considered that having online courses during confinement increases students' time spent sitting in front of a screen (Please see Castro et al., 2021 reference). The second argument considers the literature showing that screens increase sitting time as it is uninterrupted and longer. Please see the reference Castro et al., 2021. d. H4: Finally, we hypothesized that there would be no relationship between active transportation, sitting time and screen time during confinement. Answer 1.d: Regarding the fourth hypothesis; the new version includes arguments explaining why we think there are no relationships between active transport, sitting time, and screen time. Please see references Heller et al., 2023; Trott et al., 2022. It is essential to integrate previous work discussed and critiqued in the literature review and discussion sections with the findings and tone of the study and bring out what was done in this study, which addressed some of the shortcomings of those studies. Answer 1.d1: We have included this information in the literature review and present the elements that allow us to advance knowledge about the levels of physical activity and sedentary behaviors in university students. Answer 1.d1 bis: The literature review section includes new articles and analyses that allow us to highlight elements missing from previous studies. The main argument has to do with the type of variables included (e.g., duration of active transport journeys and uninterrupted sedentary time, duration of time spent using screens to study) in this study and the behaviours assessed (active transport, sedentary behavior, and screen use). 2. The gap between this research and prior research should also be more detailed. Besides, the significance of the current study is recommended to be more clear and more novel. In this sentence, “Most studies about confinement in the COVID-19 pandemic have focused on total times of changes in physical activity levels, sitting time, and screen time. For this reason, the main objective of this study was to assess if active transportation time, uninterrupted sitting time, and screen time spent studying prior to confinement were factors influencing these changes”. The studies are not cited and elaborated on. I suggest that the authors elaborate more on them, highlights on each finding of the works should be informed. Answer 2: We have detailed the arguments that allow us to show the gap between this research and previous ones. In addition, we have added new literature to elaborate these arguments in a more complete, precise and coherent way. Consequently, we have modified the sentences and content you have indicated. 3. With N=2873 samples involved in the study, the authors need to conduct normality tests like Q-Q plot, skewness, and Kurtosis. The normality test is used to determine whether sample data has been drawn from a normally distributed population (within some tolerances). Without this, bias could be high for further statistical analysis. Answer 3: We are aware that our independent variables do not follow a normal distribution. Thank you for this comment. However, two arguments allowed us to carry out the multiple regression analyses. Our sample size is 2873 students. According to the Central Limit Theorem, as sample sizes get larger, the distribution of the means approaches a bell curve even when the underlying distribution is highly skewed (Fisher, 2011; Sainani, 2012). Consequently, biases could be important in small samples (≤ N= 80). Thus, for our sample, linear regression provides a convenient and practical alternative (Lumley et al., 2002). The second argument concerns physical activity behaviors. For example, data about physical activity is rarely bell-shaped. Instead, these follow a right-skewed distribution: they have a cluster of values at zero or zero-inflated distributions (non-practitioners for moderate-to-vigorous physical activity), another bunch in the low-to-moderate range, and a few extreme values to the right (highly active). For more information, see: - Fischer, Hans (2011). A History of the Central Limit Theorem: From Classical to Modern Probability Theory (PDF). Sources and Studies in the History of Mathematics and Physical Sciences. New York: Springer. doi:10.1007/978-0-387-87857-7. - Lumley T, Diehr P, Emerson S, Chen L. The importance of the normality assumption in large public health data sets. Annu Rev Public Health. 2002;23:151-69. doi: 10.1146/annurev.publhealth.23.100901.140546. - Sainani KL. Dealing with non-normal data. PM R. 2012 Dec;4(12):1001-5. doi: 10.1016/j.pmrj.2012.10.013. 4. The conclusion could be improved to motivate the related communities to get down to actionable, practical, and academic implications. The authors missed the limitation, implications, and recommendations for practical and theoretical sections. Please include those parts in the conclusion of the study. Answer 4 : We included the limitations and proposed practical and theoretical recommendations about our results in the study's conclusion." } ] }, { "id": "180217", "date": "20 Jul 2023", "name": "Noémie Lienhart", "expertise": [ "Reviewer Expertise Sport psychology", "elite athletes", "parents", "coaches", "self determination theory", "coping" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall, this study sought to determine whether the adoption of active transportation, uninterrupted sitting time, and screen study time predicted changes in physical activity, sitting time, and screen time in students during confinement. I think this has the potential to contribute to physical activity and sitting time fields. However, there are several concerns that I have with the manuscript. I have outlined them below, including general and specific comments.\nGeneral comments:\nThe whole study is based on the closure of the universities and therefore the e-teaching during this second lockdown (October to December 2020). At that time, however, universities had the right to organize face-to-face teaching under some conditions. The situation was dependent on the faculty and even the year of study. If the authors do not have this information, they must consider this situation in their interpretation.\n\nRecall bias does not appear to be considered by the authors. However, prior to confinement data are collected during confinement and this bias can be very significant.\n\nIntroduction: the interest and direction of hypothesis 4 were not discussed in the light of the literature in the introduction part.\n\nMethods: Were participants required to attend the webinar to receive the link? What was the content of the webinar? Depending on this, participants may have adapted their responses.\n\nDiscussion: authors must make a real effort to present the practical applications of their work. Outside of the pandemic, what can we learn from this work?\nSpecific comments:\nAbstract: The wording of the objective is confusing. It is not the effect of the pandemic on pre-lockdown and lockdown that is being explored but the effect of active transportation, uninterrupted sitting time, and screen study time on physical activity and sitting time during the lockdown.\n\nIntroduction: I don’t understand what hypothesis 3 is based on. The increase in online courses during confinement is a phenomenon independent of the screen time prior to confinement.\n\nMeasures – Physical activity and Sitting time: Be careful of inconsistency. A sentence mentions that the data of the last seven days are requested while in the example it is mentioned “prior to confinement” and “during the confinement”.\n\nMeasures: Some data were measured only on weekdays while others are measured in general. Why sitting time, uninterrupted sitting time, screen time, and screen time studying data were not measured separately for weekdays and weekends? We might hypothesize there are differences.\n\nStatistical analysis: Why sex and age were included in the regression model as control variables? You need to justify this in the introduction part.\n\nStatistical analyses: the 4th hypothesis is not mentioned.\n\nResults: “Students spent more than 10 hours per day using screens, of which approximately five hours were for …”. Please specify “during confinement” if this data refers to this period.\n\nTable 1: The data in the right-hand column is based on headcount, not frequency.\n\nHypothesis: Please reformulate “Multiple regression models showed that when there was a negative effect in changes, it opposes the effect of confinement, if there is a positive change effect, it increases the impact of confinement.” for the lecturer.\n\nTables 2 and 3: Does “habitual” corresponds to data during confinement? This term is not used in the manuscript.\n\nResults – H3: Is this the screen time to study before confinement that predicts a lower increase in screen time during confinement?\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "10671", "date": "13 Feb 2024", "name": "Gonzalo Marchant", "role": "Author Response", "response": "Dear Colleague, First of all, we appreciate your time and constructive comments so that we can improve our work. In the following lines, we detail each of the responses to your comments. Our response is presented after each of your comments. General comments: The whole study is based on the closure of the universities and therefore the e-teaching during this second lockdown (October to December 2020). At that time, however, universities had the right to organize face-to-face teaching under some conditions. The situation was dependent on the faculty and even the year of study. If the authors do not have this information, they must consider this situation in their interpretation. Answer 1: We are aware of this limit. However, we did not control it because the whole university was closed when the questionnaire was online. We include this factor as a limitation of our study. Recall bias does not appear to be considered by the authors. However, prior to confinement data are collected during confinement and this bias can be very significant. Answer 2: We include this recall bias in the limits section. Introduction: the interest and direction of hypothesis 4 were not discussed in the light of the literature in the introduction part. Answer 3: We complete this literature and include new arguments to make them more coherent with our fourth hypothesis. Please see the references Heller et al., 2023; Trott et al., 2022 (Fifth paragraph of introduction section). Methods: Were participants required to attend the webinar to receive the link? What was the content of the webinar? Depending on this, participants may have adapted their responses. Answer 4: The Webinar was about physical (in) activity and sedentary behaviours. The duration was 15 minutes. It was before questionnaires. Students received via email the link to the questionnaire after the Webinar. However, the response turnaround time varied between a few minutes (e.g., 15 minutes after the Webinar) and several days (e.g., five days). We included this information in the method section and its limitations. Discussion: authors must make a real effort to present the practical applications of their work. Outside of the pandemic, what can we learn from this work? Answer 5: In the discussion, we have argued the implications that could help to study the levels of physical activity of students and advance in the promotion of physical activity and the fight against a sedentary lifestyle in the university. Specific comments: Abstract: The wording of the objective is confusing. It is not the effect of the pandemic on pre-lockdown and lockdown that is being explored but the effect of active transportation, uninterrupted sitting time, and screen study time on physical activity and sitting time during the lockdown. Answer 1: We modified the objective in the abstract as it’s suggested, thanks for pointed it out. Introduction: I don’t understand what hypothesis 3 is based on. The increase in online courses during confinement is a phenomenon independent of the screen time prior to confinement. Answer 2: Hypothesis 3 is linked to screen time to study. University students use screens to study (i.e., computers). The computer use is also a prevalent behavior in this population. Therefore, the explosion of this type of screen use increased during Covid. We included new references to present this idea. Please see Castro et al., 2021 reference). Measures – Physical activity and Sitting time: Be careful of inconsistency. A sentence mentions that the data of the last seven days are requested while in the example it is mentioned “prior to confinement” and “during the confinement”. Answer 3: You are right; there was an inconsistency in these phrases. We did not see them when we created the online questionnaire, as we used the IPAQ statement. We should have modified this sentence. We have now modified it so that this element will be considered in other studies. Measures: Some data were measured only on weekdays while others are measured in general. Why sitting time, uninterrupted sitting time, screen time, and screen time studying data were not measured separately for weekdays and weekends? We might hypothesize there are differences. Answer 4: we considered only week days because we measured the university context or time when students were “at university”, having lectures. Another idea was to measure physical activity with a validated questionnaire (IPAQ); for that reason, the measure was a general one. We modified the sentences to improve the questionnaires’ consistency in case other projects want to assess the same behaviors. Statistical analysis: Why sex and age were included in the regression model as control variables? You need to justify this in the introduction part. Answer 5: We included the sentences to justify the inclusion and control of these variables in our models. Please see the reference Motevalli et al., 2023. Statistical analyses: the 4th hypothesis is not mentioned. Answer 6: We mentioned the four models which allowed us to test our fourth hypothesis. Please see this modification in statistical analysis. Results: “Students spent more than 10 hours per day using screens, of which approximately five hours were for …”. Please specify “during confinement” if this data refers to this period. Answer 7: We specified that the data was during confinement. Table 1: The data in the right-hand column is based on headcount, not frequency. Answer 8: We changed frequency by “n” on Table 1. Hypothesis: Please reformulate “Multiple regression models showed that when there was a negative effect in changes, it opposes the effect of confinement, if there is a positive change effect, it increases the impact of confinement.” for the lecturer. Answer 9: We reformulated the phrase you indicated. Tables 2 and 3: Does “habitual” corresponds to data during confinement? This term is not used in the manuscript. Answer 10: “Habitual” corresponds to data in “normal periods” without confinement. We include this information in the table 2 and 3. Results – H3: Is this the screen time to study before confinement that predicts a lower increase in screen time during confinement? Answer 11: It’s the screen time to study before confinement. It was modified in the H3." } ] } ]	1	https://f1000research.com/articles/11-568
https://f1000research.com/articles/11-397/v2	22 Apr 22	{ "type": "Research Article", "title": "Alteration in central vascular and cognitive functions during simulated work conditions in males – a secondary analysis from a randomised controlled trial", "authors": [ "Poovitha Shruthi P", "Obhuli Chandran M", "Baskaran Chandrasekaran", "Vaishali K.", "Suresh Sugumar", "Rajagopal Kadavigere", "Poovitha Shruthi P", "Obhuli Chandran M", "Baskaran Chandrasekaran", "Vaishali K.", "Suresh Sugumar" ], "abstract": "Background: Alteration in the central vascular hemodynamics is speculated to influence cognitive functions, including executive functions in young adults. Prolonged sitting is associated with compromised central vascular functions, which activity micro-breaks could mitigate. However, the association between the carotid vascular hemodynamic alteration and the executive functions is yet to be explored. Methods: We administered a randomised controlled trial investigating the effects of various intensities' micro-breaks on central vascular and cognitive functions during simulated work conditions for four hours. The carotid artery hemodynamics and cognitive functions were measured by Duplex ultrasound at 0th, 2nd and 4th hour and computer-based Flanker tests at 0th, 1st, 2nd, 3rd and 4th hour of visit days, respectively. From the randomised controlled trial, we extracted the secondary data of carotid artery hemodynamics and cognitive functions change at the 4th hour from the baseline and analysed for any relation. Results: Though we observed linear relation between the carotid artery hemodynamics and the executive functions, the relation was not statistically significant. we found a significant reduction in carotid artery diameter during prolonged sitting (0.03 cm [95%CI 0.01, 0.05]), velocity (10.35 cm/s [95%CI -2.85, 17.86]) and shear rate during interrupted sitting (174.39 [95%CI 65.67, 283.11]) We found increased accuracy during prolonged sitting (12.7% [95%CI 0.66, 24.81]) and sitting with light-intensity activity breaks (6.92% [95%CI 1.39, 12.44]). We did not find any significant relation between the change in central vascular functions (carotid artery diameter, velocity, shear rate and blood flow) and the cognitive functions during three different work conditions. Conclusion: Though a significant relation between carotid artery function and cognitive function could not be established, microbreaks can mitigate the vascular and cognitive risks associated with prolonged sitting.", "keywords": [ "Prolonged sitting", "Central vascular function", "Blood flow", "Velocity", "Doppler", "Micro-breaks", "Cognition" ], "content": "1. Introduction\n\nProfound dynamic changes in the endothelial functions in early adulthood is associated with early atherosclerosis and cardiovascular disease risk in late adulthood.1–3 High sedentary behavior (sitting activities with low energy expenditure less than 1.5 metabolic equivalents) is now identified to be the independent risk factor for the early atherogenesis and cardio-metabolic disease risk.4,5 However, high sedentary behavior is evident and continue to rise globally and in contextual settings such as workplace and schools.6–8 Hence it is imperative to address contextual sedentary behavior through administering movement based micro-breaks.9,10 Empirical evidence elucidating the efficacy of advocating activity breaks during the prolonged sitting time on cardiometabolic disease risk and cognitive decline remains mixed.11–13\n\nMechanistic plausible mechanisms have linked central vascular functions and resulting cortical perfusion to cognitive functions such as memory, attention, visuospatial skills and cognitive control.10,14,15 Executive functions and working memory influences common work-related skills: decision making and problem-solving, resulting in better work productivity. The alteration in the vascular function and the resulting cognitive functions are viewed as plausible mechanistic links to poor problem-solving skills and low work productivity. Few epidemiological evidence and acute laboratory studies have attempted to elucidate the above possible association between vascular endothelial functions, cognitive functions, and work productivity however, it remains inconclusive.16\n\nWe attempted to explore the possible association between the central vascular functions and the executive functions in simulated sedentary and active work conditions. We hypothesised that the subtle association between central vascular functions and executive functions may foster occupational health experts to design appropriate public health and behavioral strategies to culminate the adverse effects of work conditions on central vascular and cognitive functions, which may improve work productivity.\n\n\n2. Methods\n\nThe present findings are the results of the secondary analysis of our ongoing randomised controlled trial. Kasturba Hospitals Institutional Ethics Committee (IEC 383-2021) approved the study and was prospectively registered in India's Clinical Registry (CTRI/2021/09/036496). The study was conducted and conforms to the research principles of the Declaration of Helsinki.17\n\nThe findings presented in the study is based on the results of a randomised cross over the trial, which explores the impact of passive and active work conditions on central vascular functions and cognitive control in young adults. The study was conducted in the ultrasound testing room, department of radiodiagnosis and imaging of a multidisciplinary teaching hospital. The study was conducted between September 2021 – December 2021. Potential participants were randomised to one sedentary and two active work conditions for four hours, with each study visit was separated by a wash-out period of at least six days. The whole study design is depicted in Figure 1. The present study explored the relation between the dynamic carotid vascular changes (diameter, velocity, shear rate and blood flow) and executive functions. We explored the possible association of cognitive functions and the dynamic carotid artery functions with the lifestyle factors such as physical activity, smoking, alcoholism and body composition.\n\nThe participants were randomised to the three different behavioral interventions in simulated work conditions for four hours: (1) SIT (uninterrupted sitting for four hours with bathroom breaks only); (2) LIT (sitting interrupted with light intensity walking breaks for three minutes every one hour for four hours of the study period; MIT (sitting interrupted moderate-intensity stair climbing breaks for three minutes every one hour for four hours of the study period). Doppler ultrasound-mediated carotid, superficial femoral artery diameter and velocity were measured every two hours of each visit period, and computer-based executive functions were measured every hour of each visit period.\n\nYoung adults of age 25 – 35 years of both genders belonging to a single university were invited to the study through the official Exchange student emails, brochures in college and hostel noticeboards. Due to cultural barriers for Doppler ultrasound measurement, only male students volunteered for the study. To be eligible, the potential participants should be physically inactive (self-reported physical activity levels of less than 600 METmin/week), optimum levels of visual acuity (> 5/6) for operating the computer-based cognitive tests with adequate lower limb strength to walk or climb stairs for three minutes. Participants with self-reported cardiometabolic diseases, recent musculoskeletal trauma < three weeks or self-reported depressive disorders affecting physical activity or cognitive measurement were excluded from the study. Further, the volunteers willing to dedicate at least six weekday hours were included in the study.\n\n2.3.1 Vascular functions\n\nThe vascular functions using Doppler ultrasound was measured as stated and administered in the earlier studies.9,18–23 Dynamic central (right carotid artery) and peripheral vascular (Superficial Femoral Artery) functions [diameter, velocity] were measured using Duplex ultrasound (GE Voluson Swift, Germany) at a pulsed frequency of 50 MHz using the probe insonated at an angle of 60° were used. The diameter and the velocity were automatically measured using inbuilt edge-detection software, and the captured images were analysed using B Mode images and confirmed with the carotid artery’s diameter and velocity. Shear rate was calculated using the formula: 4 × [mean blood velocity/arterial diameter]. The maximal blood flow was calculated from continuous diameter and mean blood velocity recordings using the following equation: 3.14(diameter/2)2 mean blood velocity 60.24\n\n2.3.2 Executive functions\n\nExecutive functions or cognitive control was assessed using the computer-based Response Inhibition test, Eriksen Flanker paradigm (Milliseconds, Inquist). The participants were presented with the visual stimuli on a laptop using Inquist 6.0 software (Millisecond Software, Seattle, WA, USA).\n\nThe participants were shown a line with five alphabets H, K, S &C with the central alphabet as the target and flankers on the sides. The participants were instructed to focus on the central alphabet and press either Q or P based on the H or K, and S or C displayed on the left and right sides of the computer screen, respectively. The task had two types of trials: congruent (noise) and incongruent (no noise) trials. All the alphabets are the same in congruent trials, while the flanker and target alphabets were different in the incongruent trials. A total of 120 trials (60 congruent, 60 incongruent) were presented to the participants, which were randomly sampled. Each trial lasted for 3000 ms, with an interstimulus interval of 1500 ms. The participants were given a one min break after every 40 trials. The data were automatically stored in the inquisit software and retrieved as csv files later for analysis.\n\nWe administered activity interruptions during sitting at two different intensities: (1) Light Intensity Task (LIT): The participants were asked to walk in the 30-meter laboratory hallway at their comfortable pace (perceived exertion less than 11 in original Borg’s scale) for three minutes every hour during this intervention visit; (2) Moderate Intensity Task (MIT): The participants were asked to climb laboratory stairs of 20 cm with a self-selected stepping rate (perceived exertion of 13-15 corresponding to in original Borg’s scale) for three minutes every hour during this intervention visit.\n\nIn the present study, the participants had visited the laboratory four times, of which one was a familiarisation session, and the other three were interventional visits. On the first study visit, the participants were familiarised with the standardised procedures of vascular and executive functions measurement along with the familiarisation of hallway walk (LIT) and stair climbing (MIT). Further, the intervention order (SIT, LIT and MIT) was randomised using computer randomisation (www.randomiser.org). The participants were asked to pick the concealed envelopes of the random generated treatment orders, and the order was followed for the subsequent visits. On the second visit, the patient arrived between 8:00 AM-9:00 AM to reduce the effect of the diurnal variation on the vascular and cognitive function. The patients were instructed to refrain from smoking, alcohol and any vigorous activity for at least 48 hours prior to the second, third and fourth study visits. The potential participants were given an asleep food diary log and ensured adequate sleep for at least 8 hours, and the previous dinner was at least separated by 12 hours from the study visit. The participants were transported from their location to the lab by means of the motor vehicle to avoid any vigorous activity during the travel. After baseline vascular and cognitive measures, the participants were given a standard breakfast (idly with dhal kichadi on participants preference) which ensured 33% of the daily calorie consumption based on the food log during the familiarisation visit. The study visits, including measurement and interventions, took place in the temperature and humidity-controlled laboratory (26°C and 84% humidity).\n\nBased on the order of the randomisation, the participants underwent SIT or LIT or MIT interventions. During the SIT intervention visit, the participants were instructed to perform their day work (read, write or watch non-stimulant videos of their preference) for the next four hours (9:00 – 1:00 PM) in the uninterrupted sitting position with minimal lower limb movements. If the participant wished to use the bathroom in the middle of the study visit, the participants were passively transferred to the western toilet using a wheelchair. A researcher monitored and ensured to avoid the unpurposeful movements in the participants during all three study visits. The participants followed a similar work simulation during LIT intervention, except they interrupted their sitting time by self-paced walking for three minutes every hour in the laboratory hallway. During the MIT intervention visit day, the participants interrupted their sitting time by three minutes of stair climbing every one hour at a self-selected stair climbing velocity. The participants were instructed to select a climbing velocity that may induce a moderate-intensity effort (exertion level of 13 and above).\n\nThe central (right common carotid artery) and peripheral (right superficial femoral artery) vascular functions were measured at baseline, 2nd hour, and 4th hour, whereas the computer-based executive functions were measured every one hour (0th, 1st, 2nd, 3rd, 4th hour).\n\nThe present study results are part of secondary analysis from a randomised controlled trial. We have presented the baseline demographics, cerebral vascular and cognitive functions as mean and standard deviation after log-transformed the non-normal data. The normalisation was assessed using the Shapiro Wilk test, and in the case of non-normality, the variables were log-transformed. The change in the central vascular and executive functions before and after 4 hours of the three study visits was calculated using excel 2016. The mean change in the central vascular and executive functions at the 4th hour from the baseline using paired t-tests and effect size using Cohen d. The relation between the mean change in the central vascular functions (diameter, velocity and shear rate) and the executive functions (reaction times and accuracy) before and after four hours were analysed using the Pearson correlation and multiple linear regression model with the executive function as the dependant variables and the covariates as central vascular function controlling for baseline demographic variables. All the statistical treatments were analysed using statistical software JASP version 0.14.0 (University of Amsterdam, Netherlands).\n\n2.6.1 Power calculation\n\nAs the presented data is a secondary analysis of a randomised controlled trial, the presented sample size was also calculated for the randomised controlled trial. For the randomised controlled trial, we have estimated our sample size as 14 participants to have at least a difference in blood flow velocity of 0.45 ml/min with the moderate effect (Cohen d = 0.45) between the SIT and LIT interventions at 95% level of significance and 80% power. With an assumed drop of 20% of the sample for the three study visits, we have included 17 participants. The sample size was calculated using a software program (GPower version 3.1.9.6, Universitat Kiel, Germany).25\n\n\n3. Results\n\nSeventeen males volunteered for the study, and all of them completed all three study visits that were six-seven days apart. Only male participants participated in the study as the females were reluctant for the lower limb vascular function study. Of 22 participants volunteered for the study, 17 participants were found to be eligible due to potential reasons displayed in Figure 2. All the 17 participants completed the 4 day experimental visits with no missing data. Figure 2 shows the inclusion of the participants and the secondary data extracted from the cross over trial.\n\nThe majority of the participants (n = 16; 94%) had a normal BMI, whereas one volunteer was found to be obese with a mean BMI of 24.88 ± 3.50. Many of the participants (n = 10; 55.85%) were found to have at least one lifestyle risk factor, such as smoking or alcohol. The majority of the participants (n = 14; 82.35%) were found to be physically inactive. We did not find any significant differences among the carotid artery variables or executive function variables during all the active and passive work conditions from baseline except the reaction times. Table 1 demonstrates the baseline characteristics (demographic, central vascular and executive functions) of the included study participants.\n\n* Differences among SIT, LIT, MIT variables are assessed using analysis of variance.\n\n** p = 0.001.\n\nWhen the central vascular functions and cognitive functions change were compared at the fourth hour with the baseline, we found a significant reduction in carotid artery diameter during SIT (0.03 cm [95%CI 0.01, 0.05], Cohen’s d = 0.677), velocity (10.35 cm/s [95%CI -2.85, 17.86], Cohen’s d = 0.709) and shear rate during MIT (174.39 [95%CI 65.67, 283.11], Cohen’s d = 0.825), reaction times during MIT (54.10 ms [95%CI 15.06, 93.22], Cohen’s d = 0.8712), accuracy during SIT (12.7% [95%CI 0.66, 24.81], Cohen’s d = 0.542) and LIT (6.92% [95%CI 1.39, 12.44], Cohen’s d = 0.644). However we found a significant increase in carotid artery shear stress during SIT (-129.30 [95%CI -255.61, -2.98], Cohen’s d = -0.526 and accuracy during MIT conditions (-3% [95%CI -7.38, 2.03], Cohen’s d = -0.292). We did not find significant variation in other central vascular and executive function variables among three different working conditions. Table 2 illustrates the mean change of the cognitive and central vascular functions at the fourth hour from the baseline among the three different working conditions of SIT, LIT and MIT.\n\n¶ = values calculated from the paired t test,\n\n* = p < 0.05,\n\n** = p < 0.01, * &** - denotes level of significance.\n\nWe did not find any significant relation between the change in central vascular functions (carotid artery diameter, velocity, shear rate and blood flow) and the cognitive functions during three different work conditions. Table 3 revealed no significant correlation among the central vascular and cognitive functions change between the 0th hour and 4th hour during different work postures. Multiple linear regression also revealed no significant association between the change central vascular and cognitive functions within the conditions (Figure 3A, 3B and 3C)\n\nThough changes in reaction times and accuracy were found to be associated positively with change in carotid artery diameter (a, d), carotid artery velocity (b, e) and negatively associated with change in carotid artery shear rate (c, f), the associations were not statistically significant.\n\nThough changes in reaction times and accuracy were found to be associated positively with change in carotid artery diameter (a, d), carotid artery shear rate (c, f) and negatively associated with change in carotid artery velocity (b, e), the associations were not statistically significant.\n\nThough accuracy was found to be associated negatively with change in carotid artery diameter (d), carotid artery shear rate (f) and positively associated with change in carotid artery velocity (e), the associations were not statistically significant. We observed non-linear and non-significant relation between reaction times and the central vascular functions (a, b, c) when compared 0th and 4th hour within conditions.\n\n\n4. Discussion\n\nOur present study aimed to investigate whether the change in the central vascular functions is associated with any change in the executive functions during the different active and passive work conditions. We found no significant relation exists between the change in carotid artery endothelial functions and the cognitive functions during the work conditions with or without interruption between varied intensities of physical activities.\n\nAltered central vascular hemodynamics, especially carotid artery stiffness and sclerosis, is a long recognised risk for cognitive decline in the elderly.26,27 Epidemiological studies have observed plausible mechanistic links for the altered carotid artery hemodynamics and cognition: narrowing of carotid artery due to atherosclerotic plaques and low shear stress reducing the bioavailability of nitric oxide and the prostaglandins, which in turn reduces the cortical perfusion to frontal, temporal, limbic systems and increased risk of cognitive and neurodegenerative disorders such as stroke and dementia.28,29 Though the existing evidence has confirmed the positive association between central vascular functions and cognitive decline in the elderly, the association remains uncertain in young adults. As central vascular hemodynamic changes occur at an early, relatively younger age, the problem should be addressed at a younger age to mitigate the cognitive decline at an older age. However, our study failed to find a positive relation between the central vascular and cognitive functions in the young adults, probably due to homogeneity in the baseline characteristics (age, gender, diet and physical activity) with the simulated work conditions with or without physical activity interventions. Our study findings are contrary with the existing observational studies that have established the linear relation between the cognitive impairment and central vascular diameters30 flow velocity,28,31 shear stress32 and blood flow. The findings of non-significant relation between the central vascular functions and the executive functions in our study probably due to the less age, gender bias, the nature of the working conditions (low stimulus, boredom) and unstandardized tasks not relevant to the participants routine work.21,33 Further evidence to explore the association between cognitive functions and central vascular functions is warranted.\n\nWe found a 4.68% reduction in the carotid artery diameter after four hours of uninterrupted sitting. Our study findings concur with the recent experimental trials that have observed the reduction in central and peripheral artery diameter, reactivity and stiffness with uninterrupted sitting.21,23,34 Further, our findings demonstrated an 8.68% increased shear stress in the carotid artery after four hours of prolonged sitting which is contrary to the existing hypothesis that prolonged sitting reduces stroke volume and increased shear stress in central and peripheral vasculature.24,34–37 Nevertheless, our findings concurs with the previous findings that prolonged sitting reduces the accuracy by 13%, whereas interrupting sedentary time with three minutes of stair climbing (MIT) every hour may improve accuracy by 3%. Even light-intensity walk breaks (LIT) could not mitigate the risk of inaccuracy associated with prolonged sitting. We could find a significant reduction (8-10%) in the carotid artery velocity and shear rate and reaction times when the prolonged sitting was with stair climbing (MIT). Our findings add to the existing evidence that demonstrated the short term effects of interrupting prolonged sitting to improve central vascular and cognitive functions.18,21,38–40 However, we could not appreciate the association between central vascular and cognitive functions changes during various working postures and conditions.\n\n(1) Our findings are retrieved as a secondary analysis from a randomised controlled trial, and the sample size was based on the same. The readers should interpret the findings with caution due to the low sample and poor causal effect41; (2) Our study findings did not adapt postural changes (sitting to supine) for vascular function measurements, unlike earlier studies which might have influenced the results. We wanted to extrapolate the findings to the real-world work environment, and hence we have not altered the assigned position (sitting) during the carotid artery measurement42; (3) we have included only males for the convenience in central and peripheral vascular functions that inherently introduced a gender bias in our study.42,43 Future studies should investigate the vascular effects of interrupting sitting among both genders for real-world generalisation.\n\nTo conclude, our study found no association between the change in the central vascular and cognitive functions during sitting with or without interruption. The negative effects in central vascular and cognitive functions associated with uninterrupted sitting can be well mitigated by a brief period of stair climbing hourly.\n\n\nData availability\n\nHarvard Dataverse. Alteration in carotid artery physiology and cognitive function during simulated work conditions in males. https://doi.org/10.7910/DVN/IP33PI.44\n\nThis project contains the following underlying data:\n\n- Alteration in the central vascular hemodynamics is speculated to influence cognitive functions, including executive functions in young adults. Prolonged sitting is associated with compromised central vascular functions, which activity micro-breaks could mitigate. However, the association between the carotid vascular hemodynamic alteration and the executive functions is yet to be explored. We administered a randomised controlled trial investigating the effects of various intensities' micro-breaks on central vascular and cognitive functions during simulated work conditions for four hours. The carotid artery hemodynamics and cognitive functions were measured by Duplex ultrasound at 0th, 2nd and 4th hour and computer-based Flanker tests at 0th, 1st, 2nd, 3rd and 4th hour of visit days, respectively. From the randomised controlled trial, we extracted the secondary data of carotid artery hemodynamics and cognitive functions change at the 4th hour from the baseline and analysed for any relation. Though we observed linear relation between the carotid artery hemodynamics and the executive functions, the relation was not statistically significant. we found a significant reduction in carotid artery diameter during prolonged sitting (0.03 cm [95%CI 0.01, 0.05]), velocity (10.35 cm/s [95%CI -2.85, 17.86]) and shear rate during interrupted sitting (174.39 [95%CI 65.67, 283.11]) We found increased accuracy during prolonged sitting (12.7% [95%CI 0.66, 24.81]) and sitting with light-intensity activity breaks (6.92% [95%CI 1.39, 12.44]). Though a significant relation between carotid artery function and cognitive function could not be established, micro-breaks can mitigate the vascular and cognitive risks associated with prolonged sitting.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC BY 4.0 Public domain dedication).", "appendix": "References\n\nGooding HC, Gidding SS, Moran AE, et al.: Challenges and Opportunities for the Prevention and Treatment of Cardiovascular Disease Among Young Adults: Report From a National Heart, Lung, and Blood Institute Working Group. J. Am. Heart Assoc. 2020; 9(19): e016115. PubMed Abstract \| Publisher Full Text\n\nUrbina EM, Kimball TR, Khoury PR, et al.: Increased arterial stiffness is found in adolescents with obesity or obesity-related type 2 diabetes mellitus. J. Hypertens. 2010; 28(8): 1692–1698. 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PubMed Abstract \| Publisher Full Text\n\nElias MF, Torres RV, Davey A: Carotid Artery Blood Flow Velocities and Cognitive Performance: Forecasting Cognitive Decline. Am. J. Hypertens. 2019; 32(3): 237–239. Publisher Full Text\n\nZhang H, Liu H, Dong Y, et al.: Low carotid wall shear stress independently accelerates the progression of cognitive impairment and white matter lesions in the elderly. Oncotarget. 2018; 9(13): 11402–11413. PubMed Abstract \| Publisher Full Text\n\nCredeur DP, Miller SM, Jones R, et al.: Impact of Prolonged Sitting on Peripheral and Central Vascular Health. Am. J. Cardiol. 2019; 123(2): 260–266. PubMed Abstract \| Publisher Full Text\n\nMcManus AM, Ainslie PN, Green DJ, et al.: Impact of prolonged sitting on vascular function in young girls. Exp. Physiol. 2015; 100(11): 1379–1387. PubMed Abstract \| Publisher Full Text\n\nRestaino RM, Walsh LK, Morishima T, et al.: Endothelial dysfunction following prolonged sitting is mediated by a reduction in shear stress. Am. J. Physiol. Heart Circ. Physiol. 2016; 310(5): H648–H653. PubMed Abstract \| Publisher Full Text\n\nRestaino RM, Holwerda SW, Credeur DP, et al.: Impact of prolonged sitting on lower and upper limb micro- and macrovascular dilator function. Exp. Physiol. 2015; 100(7): 829–838. PubMed Abstract \| Publisher Full Text\n\nMorishima T, Restaino RM, Walsh LK, et al.: Prolonged sitting-induced leg endothelial dysfunction is prevented by fidgeting. Am. J. Physiol. Heart Circ. Physiol. 2016; 311(1): H177–H182. PubMed Abstract \| Publisher Full Text\n\nWennberg P, Boraxbekk CJ, Wheeler M, et al.: Acute effects of breaking up prolonged sitting on fatigue and cognition: a pilot study. BMJ Open. 2016; 6(2): e009630. PubMed Abstract \| Publisher Full Text\n\nCarter SE, Draijer R, Holder SM, et al.: Effect of different walking break strategies on superficial femoral artery endothelial function. Physiol. Rep. 2019; 7(16): e14190. PubMed Abstract \| Publisher Full Text\n\nGibbs BB, Kowalsky RJ, Perdomo SJ, et al.: Effect of alternating standing and sitting on blood pressure and pulse wave velocity during a simulated workday in adults with overweight/obesity. J. Hypertens. 2017; 35(12): 2411–2418. PubMed Abstract \| Publisher Full Text\n\nZiyatdinov A, Kim J, Prokopenko D, et al.: Estimating the effective sample size in association studies of quantitative traits. G3 (Bethesda). 2021; 11. PubMed Abstract \| Publisher Full Text\n\nPatel K, Rössler A, Lackner HK, et al.: Effect of postural changes on cardiovascular parameters across gender. Medicine (Baltimore). 2016; 95(28): e4149. PubMed Abstract \| Publisher Full Text\n\nLevenson J, Pessana F, Gariepy J, et al.: Gender differences in wall shear-mediated brachial artery vasoconstriction and vasodilation. J. Am. Coll. Cardiol. 2001; 38(6): 1668–1674. PubMed Abstract \| Publisher Full Text\n\nSukumar S: Alteration in central vascular and cognitive functions during simulated work conditions in males – a secondary analysis from a randomised controlled trial.2022. Harvard Dataverse, V1, UNF:6:I8KqlavhS35wrCHVTOZjrQ== [fileUNF].Publisher Full Text" }	[ { "id": "183409", "date": "17 Jul 2023", "name": "Edward Bliss", "expertise": [ "Reviewer Expertise Cerebrovascular function", "cognition", "cardoivascular and neuroscience." ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have aimed to describe and find an association between the change in the central vascular and cognitive function during sitting with or without interruption. However, there are significant limitations in the study design, with the first being that central vascular (i.e. cerebrovascular) measurements were not technically performed as the right common carotid artery is an extracranial vessel and not an intracranial vessel and, as such, is not reflective of central vascular function. Simple pre and post differences (i.e. t-tests) have been performed instead of comparing changes amongst groups (i.e. repeated measures ANOVA). There is also no discussion around the dynamic values (modelling) associated with the response of the blood vessel used in testing, as given the choice of the blood vessel, this may not be reflective of endothelial function. There is also no clear indication of the actual physical activity performed by the participants and key baseline characteristics are missing, such as blood pressure, thus making the conclusions drawn difficult to clearly ascertain. There are also other challenges associated with determining the outcomes of the study such as no details being provided about how the right common carotid artery was actually insonated (e.g. depth).\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [] }, { "id": "206855", "date": "16 Nov 2023", "name": "Watson Arulsingh D.R", "expertise": [ "Reviewer Expertise Sports/ Orthopedic Physiotherapy" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntroduction\nTo reframe the following sentence However, high sedentary behavior is evident and continue to rise globally and in contextual settings such as workplace and schools.\nAdd reference for the following sentences Executive functions and working memory influences common work-related skills: decision making and problem-solving, resulting in better work productivity. The alteration in the vascular function and the resulting cognitive functions are viewed as plausible mechanistic links to poor problem-solving skills and low work productivity.\nAdd suitable references for the following statement Few epidemiological evidence and acute laboratory studies have attempted to elucidate the above possible association between vascular endothelial functions, cognitive functions, and work productivity however, it remains inconclusive\nDefine executive function:\nStudy design Please re- frame the following sentence The findings presented in the study is based on the results of a randomized cross over the trial,\n2.2 Participants How did you administer the procedure mentioned below? To be eligible, the potential participants should be physically inactive (self-reported physical activity levels of less than 600 METmin/week)\nDiscussion Reference should be cross verified for the following statement Altered central vascular hemodynamic, especially carotid artery stiffness and sclerosis, is a long recognised risk for cognitive decline in the elderly. (26,27)\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] } ]	2	https://f1000research.com/articles/11-397
https://f1000research.com/articles/13-611/v1	10 Jun 24	{ "type": "Research Article", "title": "Understanding the Dynamics of consumer behaviour and purchase intentions for Green Cosmetic Products in North India: A Gender-Neutral Approach", "authors": [ "Neha Singh", "Babita Rawat", "Dhani Shanker Chaubey", "Ambica Prakash Mani", "Aditi Singh", "Babita Rawat", "Dhani Shanker Chaubey", "Ambica Prakash Mani", "Aditi Singh" ], "abstract": "Background The increasing popularity of green cosmetic products among consumers who prioritize skin health, quality, and beauty has driven the production of these products. Growing awareness of harmful toxins in traditional cosmetics is leading consumers to prefer natural alternatives. This study aimed to identify the factors influencing Indian consumers' buying behaviour and purchase intentions toward green cosmetics, focusing on both male and female consumers.\n\nMethods To achieve this, a thorough evaluation of the literature from Scopus-indexed journals was conducted, employing the theory of planned behavior as the theoretical framework. The study used Smart PLS 3.0’s structural equation modeling to analyze data and performed a multi-group analysis to explore variations in purchasing intentions and actions between male and female consumers.\n\nResults The research indicated an increasing demand for green cosmetics among males in North India. Findings revealed that subjective norms significantly influenced both purchase behaviour and purchase intention. Additionally, perceived behavioural control and subjective norms positively impacted purchase intention, which in turn indirectly affected purchase behaviour. Interestingly, environmental concerns did not influence consumers' actual purchasing intentions or behaviour. The analysis also demonstrated no significant differences between male and female consumers regarding the impact of various factors on their purchase intentions and behaviours.\n\nConclusion These findings provide valuable insights for policymakers and marketing managers aiming to promote green cosmetic product purchase behaviour. Recognizing that subjective norms and perceived behavioural control are crucial drivers of purchase intention and behaviour can help in devising effective marketing strategies. Despite the absence of significant gender differences in the factors influencing purchase behaviour, the increasing interest in green cosmetics, especially among males, highlights a broader market potential for these products. This research underscores the importance of focusing on social and behavioural influences to encourage the adoption of green cosmetics", "keywords": [ "Green cosmetic products", "Purchase behavior", "Purchase intention", "TPB", "organic skin care", "multi-group analysis", "Environment Concern" ], "content": "1. Introduction\n\nOver the last few decades, more people have been opting for natural and eco-friendly products as they change their habits when it comes to choosing everyday items. This trend extends to cosmetics, which a large portion of consumers use as part of their daily routine (Yu & Lee, 2019). As of late, customers have become more conscious of their purchasing decisions regarding their health and the environment (Chin et al., 2018). This has led to a preference for green cosmetic products (Seinfeld & Pandis, 2016). Different terms have been used in previous studies to describe the concept of ‘green’, including “environmentally friendly”, “environmentally responsible activities”, \"pro-environmental consumer behavior”, “pro-environmental consumption behaviour” and “sustainable” (S. H. Kim & Seock, 2019; Sadiq & Adil, 2021; Taufique et al., 2017). Green products have been defined by (Saxena & Khandelwal, 2008) as products that are durable, chemical free, and sometimes made from recycled materials, and minimally packaged, while (Peattie, 2010) describes green products as having significantly improved environmental and social performance in production, use and disposal as compared to chemical or competitive product offered in the market. These cosmetics may include hair dye, lipstick, lotion, sunscreen, hair gel, shampoo, conditioner, toothpaste, and deodorant. Many people now consider these products to be essential items (Sahota, 2014). As given in the Drugs and Cosmetics Act of 1940 in India, a “cosmetic\" is defined as any product that is meant to be applied or introduced to the human body, or any part of it, for cleansing, enhancing beauty, improving attractiveness, or changing appearance. This includes any item that is intended to be used as a component of a cosmetic. It appears that cosmetology was first developed in ancient Egypt and India. (Patkar, 2008) The use of cosmetics dates to the Indus Valley civilization (2500-1500 B.C). In the past, cosmetics made through traditional methods included microplastics and other harmful chemicals that had detrimental effects on both people and the environment (Andrady, 2011);(Seinfeld & Pandis, 2016). However, consumers are now more conscious of how their choices impact their health and the planet. As a result, they are becoming more cautious and selective in their consumption pattern and purchase behaviour. Products like hair colour, lipsticks, colour cosmetics, face creams, deodorants, soaps, hand wash, body wash, dental care items, shampoos, UV filters, detergents, sunscreens, and fragrances can have harmful effects on the environment when washed off of people's bodies and into bodies of water like lakes, rivers, and oceans (Klaschka, 2015).\n\nScholars have noted that green products can be effective in promoting environment safety throughout their complete life cycle (Maniatis, 2016) and can help to reduce the damage caused to nature and Mother Earth (Tomasin et al., 2013). To gain insight into consumer behaviour, it is crucial to understand why individuals purchase green cosmetics and how frequently they do so. It's important to keep in mind that just because someone is aware of environmental concerns and the impact of their cosmetic choices does not always mean they will purchase green products.\n\nResearch has indicated that consumer views on green marketing and consumption vary; some may have favourable intentions and perceptions, while others may have bad experiences and favourable conventional methods of consumption (Lim et al., 2013). Companies must comprehend these divergent viewpoints to sell their green products properly. Therefore, to boost demand for eco-friendly cosmetics, it is imperative to research several aspects impacting consumers' purchase intentions. (Paul et al., 2016; Hsu et al., 2017) authors also presented in their studies that the successful development of green products is crucial for business growth with eco-friendly strategies. There is a growing trend in India, where men increasingly use cosmetics for various purposes. Both male and female consumers in India choose eco-friendly and natural cosmetic products, resulting in a sales increase of around USD 1.2 billion in 2023. While past studies have mostly focused on female consumers and their purchasing behaviour, the current market scenario demands a study on men's cosmetic usage and their preference for natural cosmetics. There is a growing trend of guys using makeup for various objectives in India. In India, eco-friendly and natural cosmetics are preferred by both male and female consumers, leading to a projected 1.2 billion USD increase in sales by 2023. Previous research has predominantly examined female consumers and their purchase behaviour; however, given the state of the market, a study must be conducted on the cosmetic consumption of males and their inclination towards natural cosmetics (Amberg & Fogarassy, 2019).\n\nThis research paper delves into how customers view green-beauty items' worth and the elements that sway their buying choices. The investigation employs a method with a survey to understand consumer actions and motives regarding green cosmetics. It also examines how environmental and health worries affect the connection between the desire to purchase eco cosmetics and the factors that lead to consumer reluctance. The study helps marketers and producers of green cosmetic products manufacture, distribute, and advertise the advantages of green cosmetics to customers by providing an understanding of this issue. Furthermore, the study divides the cosmetics business into gender-specific divisions and offers separate findings for customers who identify as male or female.\n\n\n2. Literature review\n\nBehaviors are shaped by our intentions, which are developed based on our attitudes how we perceive norms, and the level of control we believe we have over our actions (Ajzen, 2002). Attitude refers to a person's evaluation of behaviour, while subjective norms involve social pressures that support or discourage behaviour, perceived behavioural control reflects how easy or difficult it is to perform a behaviour based on past experiences and anticipated obstacles and Purchase intention ultimately leads to actual purchasing behaviour, with environmentally conscious consumers willing to pay a premium for natural products (Ajzen, 1991). Purchase behaviour refers to the consumer's decision-making process and evaluation of products or services (Gera & Jain, 2020). Although there has been a lot of research on the topic, prior studies have not explored the precise reasons that underlie the attitude-behavior gap for green cosmetic goods (Kumar et al., 2019). To comprehend customer behavior and buying intentions, the TPB model is frequently employed. In this study, TPB was used to analyze the purchasing behaviour of men and women toward natural cosmetics (Sparks et al., 1992).\n\nWhen shopping for goods, customers tend to compare factors such as quality, price, and utility before making a purchase decision (Peattie, 2010). This is especially true for shopping for goods, which requires more effort from consumers to seek information and understand the product. Green cosmetic products come under the category of these goods. This rational approach to product information means that consumers are less likely to refuse to buy green products based solely on their attitudes (Quester & Lin Lim, 2003). However, convenience goods, which are low-value and frequently purchased, may be subject to attitude bias or brand loyalty when it comes to choosing green alternatives. Researchers have studied the influence of product knowledge regarding green cosmetic products on environmental concerns to understand consumer purchase behaviour. The hypothesis is set accordingly, and a multi-group analysis is done among male and female consumers.\n\nConsumers' product knowledge and its influence on environmental concern is gender neutral.\n\nWhen it comes to personal care (Gadema & Oglethorpe, 2011) and cosmetic products (Richter, 2010), many consumers prioritize green and environmentally-friendly options. However, implementing a green purchasing lifestyle can be difficult. One factor affecting consumer behaviour is perceived behavioural control (PBC), which refers to the belief that one has the necessary resources and sufficient opportunities to positively carry out a desired purchase behaviour (Ajzen, 1991). PBC emphasizes situational constraints, similar to self-efficacy and barriers (Ajzen, 2002). Unfortunately, many studies do not specify the constraints or barriers that hinder consumers from making green choices. Instead, respondents are often asked direct questions regarding the ease or difficulty of performing a certain action, leaving room for interpretation. In this context, we believe that perceived behavioral control is closely related to consumer purchasing behaviour. Therefore, we suggest hypotheses 3 and 4.\n\nPerceived Behavioural Control (PBC) and its influence on purchase behaviour is gender neutral\n\nThe growing concern for the environment has led to a rise in demand for green cosmetics. These products are preferred for their natural ingredients, green buying behaviour, and positive impact on the environment (Bamberg, 2003). Researchers argue that the consumers who prioritise green cosmetics are conscious of environmental issues and seek to understand the origin of raw materials used in the products they purchase (Balderjahn, 1988; Chenery, 2004; Oyewole, 2001). Consumers opt for those cosmetic products that do not contribute to pollution and have fewer carbon footprints (Bamberg, 2003). The ingredients of a cosmetic product play a significant role in determining its popularity among environmentally aware consumers; this trend is commonly referred to as environmental awareness (S. Kim & Seock, 2009).\n\nConsumer Environmental concern and its influence on purchase intention is gender neutral\n\nPurchase intentions refer to an individual consumer’s willingness to be involved in buying behaviour, which reflects their concern for the product and its quality. This is considered to be a significant factor that influences their behaviour. Many researchers say purchase intentions for green cosmetic products are affected by consumers' likelihood of purchasing other green cosmetic products (Chen & Chang, 2012). On the other hand, he argues that it reflects the consumer's desire to protect or preserve the environment by purchasing green products (Rojšek, 2001). (Fraj & Martinez, 2007) suggests that green cosmetic product purchase intentions can be measured by considering purchasing green products, switching to green brands, and choosing a green product version. However, researchers have not reached a consensus on how product knowledge affects green purchase intentions.\n\nConsumer purchase intention and its effect on purchase behaviour are gender neutral\n\nSubjective norm is the pressure that an individual consumer perceives from society to perform a specific behaviour. When consumers believe that others highly regard organic skin care products, they are more likely to intend to purchase these items. Research has demonstrated that subjective norm significantly impacts the intention to manage skin effectively (Hillhouse et al., 2000). Moreover, studies on green consumer behaviour have revealed a strong correlation between subjective norms and the purchase intention of consumers (Bamberg, 2003; Kalafatis et al., 1999).\n\nSubjective norm and its influence on purchase intention of cosmetics are gender neutral\n\nTheoretical framework\n\nUsing a gender-neutral approach, a comprehensive theoretical framework is required to understand the dynamics of consumer behaviour and purchase intents for green cosmetic items in North India. The Theory of Planned Behavior (Ajzen, 1991) serves as the foundation for this study, which looks into how people's intentions to buy green cosmetics are shaped by their views toward the products, social factors, and perception of their control over the purchasing process. The theory behind this research is that attitudes, subjective norms, and perceived behavioral control influence intentions and subsequent behavior. This study tries to examine how gender-neutral marketing and messaging techniques may lessen gender biases in the context of green cosmetics use. This is achieved by incorporating insights from the Gender Schema Theory (Fornell & Larcker, 1981), which clarifies how societal gender norms and schemas influence individuals' perceptions and behaviors. Moreover, in light of the increasing significance of sustainability and environmental awareness in consumer choice, ideas from the literature on green marketing (Peattie, 2010) and will be utilized to analyze how eco-friendly or green attributes, labelling, and messaging influence the consumers' perceptions and preferences for green cosmetic products. This theoretical framework integrates psychological, sociological, and marketing perspectives to offer a holistic understanding of the factors driving consumer behaviour and purchase intentions for green cosmetics in North India while accounting for gender-neutral considerations.\n\n\nMethods\n\nThis study utilised primary and secondary data with a descriptive research design to investigate factors influencing the purchase behaviour and intentions of male and female consumers in India towards green cosmetic products. Figure 1 displays the research objectives and methodology. A self-administered questionnaire with a five-point Likert scale and 29 items were distributed among consumers in Delhi, Dehradun, Faridabad, Sonipat, and Meerut in Oct 2023. Table 1 shows the studies supporting the factors selected for the study, and further measurement variables were developed. Independent variables included environmental concern, product knowledge, perceived behavioural control, and subjective norms; dependent variables were purchase intention and purchase behaviour. The Reliability test was conducted with the help of SPSS software and found to be 0.950, well above the threshold of 0.70. After assuring the reliability, a full-scale survey was carried out. Research has received 545 responses. After editing, 505 responses were found fit, leaving 40 insincerity-filled responses. Respondents' demographics are detailed in Table 2.\n\nSource: Author’s Data analysis.\n\n\nResults\n\nOne of the more advanced modelling techniques, partial least squares structural equation modelling (PLS-SEM), is frequently required to properly comprehend the intricate and multifaceted elements influencing consumers' purchasing intention and conduct. Using this technique, researchers can investigate the intricate relationships that exist between several factors, such as perceived value, product attributes, social impact and brand image. With PLS-SEM, researchers can determine the direct and indirect effects of these attributes on customers' actual purchasing behaviour and intentions. These findings provide significant insights that organizations can use to improve customer satisfaction and marketing tactics. These models provide an advanced understanding of the dynamic mechanisms affecting consumer decisions in the modern economy. The model's initial output is called the measurement model.\n\nUsing SPPS 23, an EFA was carried out to lower the construct's variable count prior to SEM analysis. The author used varimax rotation and set the latent root criterion to 1.0 for including factors. The author also set a cut-off of 0.70 for factor inclusion and factor loading. Table 2 confirms that all factor loading values in the proposed model were above the recommended minimum of 0.7, meaning the items in the construct had high loading. These results show that the model was a suitable explanation for the dimensionality (Vinodkumar & Bhasi, 2009;Shook et al., 2004). All the constructs' Cronbach Alpha levels were significant (>0.70), indicating that the model is reliable (Shook et al., 2004;Chin et al., 2018). According to Table 2, it is confirmed that all six factors have sufficient convergent validity since each latent variable has a CR above 0.70 and an AVE above 0.50, which surpasses the required cut-off criteria for both CR and AVE values (Chin et al., 2018;Chin et al., 2018). In each case, the AVE of each latent variable was larger than the squared correlation coefficient that corresponded with it. This demonstrates that the constructs are distinct and explained well by their measurement scales. As a result, authors have ensured convergence and discriminant validity, which is suitable for our measurement scale (Fornell & Larcker, 1981;Yu & Lee, 2019).\n\nDiscriminant validity Analysis\n\nThe Discriminant validity of the EC, PBC, PKN, and SN in relation to PB and PI in the measurement scale implies that each construct is perceived differently and does not have high correlations. This means that respondents react differently to each construct. Table 3 shows values less than 0.8, which indicates that the HTMT criterion supports the existence of discriminant validity in the responses received for the measurement scale. Furthermore, the Discriminant validity of the present measurement scale, which measures the PB and PI of consumers for green cosmetic products, is evaluated using the Fornell Larcker criteria. This involves comparing the square root of the AVE of each construct with its correlation with all other constructs in the measurement model. The square root of the AVE is displayed on the main diagonal of the table, and the correlation between the constructs is displayed in the remaining cells. The result reveals that the square root of the AVE of individual constructs is more than its relationship with the other construct in the present measurement model. This confirms the presence of discriminant validity of the present measurement model.\n\nTo assess variations based on the gender of the consumers, a Multi-Group Analysis was conducted. A non-parametric test was also performed to understand and study the changes in the relationship between the models specifically based on the gender features of the respondents. Table 4 presents the path values of two groups of male and female consumers, along with the differences within the group and their respective p-values, as suggested by (Henseler & Ringle, 2009). The PMGA (Private Multi-Group Aggregation) displays the significance of group differences from PLS-SEM using p-values, shown in Table 5.\n\nBased on the sample collected from the male and female respondents, it was seen in the results that the two groups had a notable difference in the connection between the perceived behavioural control and purchase intentions of female and male consumers. Additionally, there is a significant difference in the purchase behaviour and intentions between female and male respondents. However, gender did not impact the correlation between environment concerns, subjective norms, perceived behaviour control and product knowledge to purchase green cosmetic products. Table 6 displays the results.\n\nThe study's first objective involved identifying variables from the systematic literature review related to the constructs present in the TPB. All the articles referred to in the study were from Scopus-listed journals, web of Science, Research Gate, Emerald Insight and Google Scholar and a gap was identified among them. As part of the second objective, we utilized the TPB and SEM (Figure 2) to understand the connection between the variables that affected the purchase intentions and purchasing behaviour of consumers toward green cosmetic products specific to the respondents' gender. SEM was used to test relevant hypotheses in Smart PLS 3.0 to determine if the relationships between variables were significant. The final model to understand the purchase intentions of male and female consumers was created based on hypothesis testing. Environment Concerns did not significantly impact purchase intention, while product knowledge, subjective norms, and perceived behavioural control positively impacted purchase intention for green cosmetics. The study found that knowledge about a green product directly impacted a person's environmental concern, but it did not influence their intention to purchase green cosmetics. However, it was found that having an intention to purchase green cosmetic products had a significant and positive impact on the actual purchase behaviour of the individuals.\n\nSource: Author’s Data analysis.\n\nAbout the third objective, it can be noted that perceived behavioural control and subjective norms have a positive and significant influence on the purchase behaviour towards green cosmetic products for both males and females. However, it was found that environmental concerns do not significantly impact consumers' purchase intentions toward green cosmetic products. Therefore, it can be inferred that there are no substantial differences between males and females concerning their purchase intentions and the factors that influence them. The last objective was to develop the purchase intentions of the consumers and their purchase behaviour model towards green cosmetic products. Modelling details are presented in Figure 2, and Table 7 explains the relationship between variables.\n\nResearch reveals several significant elements that impact the purchasing decisions of both male and female consumers regarding green cosmetic goods. Particularly for male consumers, it was discovered that their opinions on green cosmetics, product knowledge, and subjective standards were all favourably correlated with their purchase intentions. Remarkably, their inclinations to purchase were not significantly influenced positively by environmental concerns.\n\nOur study found that female customers' inclinations to buy green cosmetics were positively connected with attitudes, subjective norms and product knowledge. Similar to their male colleagues, their purchasing intentions were unaffected directly by environmental concerns. However, product knowledge was crucial in predicting how they felt about environmental issues, similar to the findings for male consumers. These studies demonstrate the significance of factors such as attitudes, subjective norms, and product knowledge in affecting the purchase intentions of both male and female consumers. It is argued that societal norms and product-related factors have a substantial impact even when they do not directly influence purchasing decisions. When it came to green cosmetics, there were no appreciable differences between male and female consumers' intentions or buying habits.\n\n\nDiscussions\n\nThe research revealed no statistically significant variations in India's purchase behaviour or intentions with regard to eco-friendly cosmetics based on gender. According to the study, both male and female customers' purchase intentions for green cosmetics are positively impacted by subjective standards. Moreover, a significant element influencing how customers behave when making purchases is their intention to buy.\n\nThe factors that influence purchase intentions tend to shape the purchasing behaviour of male and female consumers toward green cosmetic products in India (Vinod Kumar & Bhasi, 2009). Additionally, the study found that perceived behavioural control also positively influences consumers' purchase behaviour towards green cosmetic products. According to the Theory of Planned Behavior, perceived behavioural control affects both consumers' purchase behaviour and purchase intention.\n\nIt can be concluded that PBC (Perceived Behavioral Control) significantly impacted purchase behavior, both directly and indirectly. However, product knowledge of green cosmetic products only impacts consumers' environmental concerns without affecting their purchase intentions for these products. Therefore, we can conclude that knowledge regarding green products can raise consumers' awareness of environmental issues, but this knowledge does not influence their purchase intentions. So we could say that among all the variables, environmental concern was the only factor that was not influencing the purchase intentions and purchase behaviour of male and female consumers toward green cosmetic products.\n\nWe have found that consumer behavior is a result of a combination of factors. Some belong to the wider consumer environment, such as culture, social context, and family, which comes under subjective norms. Others belong to specific individuals, such as perceived behavioral control, product knowledge, and environmental concern.\n\nThe results of the study can provide guidance to organizations regarding the factors that affect consumer behavior and their intention to buy environmentally friendly cosmetic products. As a result, the company can implement an effective green strategy that enables it to achieve better segmentation and positioning compared to conventional cosmetic products.\n\nSignificant theoretical ramifications flow from the study's findings, which provide a gender-neutral perspective on the dynamics of consumer behaviour and purchase intentions for green cosmetic items in North India. By applying the Theory of Planned Behaviour (TPB) and Structural Equation Modelling (SEM), the research elucidates the complex interrelationships among diverse factors that impact purchasing intentions, with a particular focus on gender-specific subtleties. Subjective norms, perceived behavioural control, product knowledge, and environmental concerns did not significantly influence purchase intention; nevertheless, they were key factors. Notably, product knowledge did not directly influence purchase intentions, even though it favourably increased environmental concerns. This highlights the intricate relationship between the creation of intentions and knowledge acquisition. The study also shows that intention to buy green cosmetics influences actual purchase behaviour in a considerable way, closing the gap between intention and behaviour. These results highlight intention's critical role in behaviour prediction and shed light on the varying effects of variables on buying intentions across genders, which helps to improve theoretical frameworks like TPB.\n\nFrom a management perspective, the report provides useful information to businesses involved in North India's green cosmetics industry. Through the identification of the variables impacting consumer behaviour and purchase intents, companies can create more specialised marketing campaigns. The significant positive influence of subjective standards and perceived behavioural control on purchasing decisions suggests the significance of social influences and personal empowerment. The study also demonstrates that purchasing intentions are not significantly influenced by environmental concerns. This means that businesses should focus on enhancing consumer awareness of their products and fostering favourable perceptions of green cosmetics to boost demand. This demonstrates how critical it is to start public awareness campaigns and educational initiatives to raise consumer understanding of environmental challenges and the benefits of eco-friendly products. By including these insights in their strategy, companies can strengthen their competitiveness and market positioning in the expanding green cosmetics industry. This will help promote environmentally responsible behaviour and sustainable consumption patterns.\n\n\nConclusions\n\nAfter conducting research and discussing the findings, the study concludes that environmental concern is not significantly correlated with the purchase intentions of male and female consumers in India regarding green cosmetic products. This suggests that even if a consumer has a high level of environmental awareness, they may not necessarily feel a strong desire to purchase green cosmetic products as they may not believe such an act would significantly contribute to preserving the environment.\n\nIt has been observed that there is a significant correlation between consumers' knowledge about a product and their concern for the environment. In other words, if consumers possess sufficient knowledge about a product, it will undoubtedly affect their perception of the product's features that help in environmental safety. But ultimately it does not influence their decision to purchase the product.\n\nThe study also discovered that subjective norms significantly impact the purchase intentions of both male and female consumers when it comes to green cosmetic products. This means that individuals who receive positive feedback from their close friends or relatives are likelier to have a favourable attitude towards such products. Additionally, social media advertisements play a role in encouraging potential buyers to see the benefits of these cosmetic products, eventually leading to their purchase. It's important to note that a person's decision to use and purchase green cosmetics should come from within rather than being influenced by others if we want it to continue for a longer period. Research shows that perceived behavioural control, as a dependent variable, has a significant positive relationship with purchase intentions and purchase behaviour of both male and female Indian consumers towards green cosmetic products. With this, we can understand that if someone gets the right opportunity and a sufficient amount of money and time, then it will drive the consumer toward the green cosmetic product. This will help create a need, desire and demand for the consumer for the green cosmetic product in India.\n\nBased on the research findings, it is recommended that companies should have a strong grip on marketing strategies to attract more male consumers towards green cosmetic products. Presently, limited advertisements are targeting male consumers for cosmetic products, which are easily noticeable. Companies should also try to be more responsible toward the environment and start producing cosmetic products which are environment friendly as well as good for the skin of the consumers. For future research, the author wants to suggest that the transgender community should also be explored. We need to see if these factors also influence the transgender in the same way, and we also need to explore the needs of the transgender in terms of cosmetic products and their purchase behaviour toward them.\n\nLimitations of the study\n\nWhile this study provided valuable insights into the dynamics of consumer behaviour and purchase intentions towards green cosmetic products in North India, several limitations should be acknowledged. Firstly, the research focused solely on North India, limiting the generalizability of findings to other regions. Additionally, the study employed a cross-sectional design, which may not capture changes in consumer behaviour over time. In addition, the use of self-reported data raises the possibility of social desirability bias, which could affect response accuracy. Future research should consider longitudinal methodologies and a broader geographic scope to improve the generalizability of outcomes.\n\nFurther research should investigate several paths to gain a deeper understanding of consumer behaviour regarding green cosmetic goods, building on the findings of this study. First, it might be insightful to look into how cultural influences affect how consumers feel and act toward eco-friendly items. A fuller understanding of the sustainability trends in the cosmetics business could be obtained by using longitudinal research to monitor changes in consumer preferences and behaviours over time. Also, qualitative research techniques like focus groups and interviews may offer a more in-depth understanding of the underlying motives influencing consumer decisions. Future studies can deepen our understanding of how consumers behave toward eco-friendly cosmetics and provide guidance for sustainable marketing and product development tactics by exploring these pathways.\n\n\nEthical statement\n\nThis research was conducted under the guidelines of the Research Ethics Board (REB) of Uttaranchal University. The Research Ethics Board was approved on March 4, 2023, and the approval number is UU/DRI/EC/2023/003.\n\n\nInformed consent\n\nAll the participants involved in the study have given consent. A self-explanatory written statement was attached to the questionnaire for the participants, and a similar questionnaire has been submitted to the university research board (REB).", "appendix": "Data availability statement\n\nThe underlying data related to the paper is available in Figshare with the following citations and DOI:\n\nFigshare: Singh, neha (2024). research paper data set.xls. Figshare. Dataset. https://doi.org/10.6084/m9.figshare.25498282.v1\n\nUnderstanding the Dynamics of Consumer Behaviour and Purchase Intentions for Green Cosmetic Products in North India: A Gender-Neutral Approach © 2024 by Neha Singh is licensed under CC BY 4.0. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.\n\nAll the data was collected from the respondents by filling out the questionnaire and can be made public in SPSS file format if required. Data can be provided by the author if it is very important, as the same data has been used for thesis analysis.\n\n\nReferences\n\nAagerup U, Nilsson J: Green consumer behavior: being good or seeming good? J. Prod. Brand. Manag. 2016; 25(3): 274–284. Publisher Full Text\n\nAjzen I: The theory of planned behavior. Organ. Behav. Hum. Decis. Process. 1991; 50(2): 179–211. Publisher Full Text\n\nAjzen I: Perceived behavioral control, self-efficacy, locus of control, and the theory of planned behavior 1. J. Appl. Soc. 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Publisher Full Text" }	[ { "id": "295409", "date": "11 Jul 2024", "name": "Ishani Patharia Chopra", "expertise": [ "Reviewer Expertise Marketing", "Consumer /behaviour", "Sustainability" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper is well designed and adds to the green purchase literature but there are some issues that can be resolved: 1. An English editing would be helpful to improve presentation. 2. Many of the seminal papers using similar model and factors are missing. For example:\n\n(i) Patharia, I., Rastogi, S., Vinayek, R., & Malik, S. (2020). A fresh look at environment friendly customer's profile: Evidence from India. International journal of economics and business research, 20(3), 310-321.\n\n(ii)\n\nPatharia, I., Rastogi, S., Vinayek, R. (2022). Determining Green Purchase Behaviour Towards Electronic Products in an Emerging Economy: Theory and Evidence. In: Nguyen, N., Nguyen, H.V., D'Souza, C., Strong, C. (eds) Environmental Sustainability in Emerging Markets. Approaches to Global Sustainability, Markets, and Governance. Springer, Singapore. https://doi.org/10.1007/978-981-19-2408-8_4 (iii) Sharma, K., Aswal, C., & Paul, J. (2023). Factors affecting green purchase behavior: A systematic literature review. Business Strategy and the Environment, 32(4), 2078-2092. (iv) Yusoff, N., Alias, M., & Ismail, N. (2023). Drivers of green purchasing behaviour: a systematic review and a research agenda. F1000Research, 12. Therefore, the authors must include them in the manuscript. 3. The format of citations is inconsistent which needs to checked and improved. 4. The hypotheses are poorly framed and the hypothese for main effects are missing as the current hypotheses focus on moderation effects and not the direct effects. 5. There is no literature review provided for moderation effects. 6. The sequencing of theoretical framework and literature review are incorrect. 7. The discussion on novelty of contributions of this paper need to be elaborated. 8. Please provide the statements used for measuring the constructs. 9. Various model fit indices such as R square, Q square and F suare have not been reported. 10. The managerial implications need to be elaborated especially around moderation effect.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13189", "date": "23 Jan 2025", "name": "Neha Singh", "role": "Author Response", "response": "As per the reviewer's feedback, I will incorporate the references provided to enhance the article's depth and credibility. The language of the article will be revised for clarity and precision. Additionally, the statements used to test the constructs will be included in the article to ensure comprehensiveness and alignment with the reviewer's suggestions. More clarity will be provided for the test used in the article." } ] }, { "id": "334012", "date": "07 Jan 2025", "name": "Adilla Anggraeni", "expertise": [ "Reviewer Expertise Consumer Behaviour", "Retail", "Social Marketing" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe study is interesting and provides insights into green purchase intention. However, it is recommended to provide more details into the justification on the respondent criteria. Should the respondents be customers/consumers of a particular green cosmetic brand? Even though the study was conducted in North India, the study may not have to mention it unless it can provide differences/comparisons of green consumption behaviours of North Indians vs South Indians.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13190", "date": "23 Jan 2025", "name": "Neha Singh", "role": "Author Response", "response": "The language of the article has been clarified and further explanations of the test will be provided within the article." } ] } ]	1	https://f1000research.com/articles/13-611
https://f1000research.com/articles/13-453/v1	07 May 24	{ "type": "Systematic Review", "title": "Efficacy and safety of various drug combinations in treating plaque Psoriasis: A meta-analysis", "authors": [ "Nayak Snehasis", "Sayed Zafar", "Ngabo Herve", "Pendyala Siri", "Karshe Haji Ali", "Ngabo Herve", "Pendyala Siri", "Karshe Haji Ali" ], "abstract": "Background Psoriasis, a chronic inflammatory disease affecting the skin, joints, and nails (2-3% worldwide), significantly affects quality of life. Genetic and environmental factors also play key roles. Topical corticosteroids, calcineurin inhibitors, and oral corticosteroids help to manage plaque psoriasis symptoms, but combination therapies might offer greater effectiveness and improved safety profiles. These combinations could potentially reduce medication dosages and side effects in patients.\n\nObjective To assess the efficacy and safety of various drug combinations over conventional monotherapies in the treatment of moderate to severe plaque psoriasis, which incorporates palmoplantar psoriasis and psoriasis vulgaris, by discovering and utilizing research articles comprising the same or similar variables as PASI 75 and evaluating the information using RevMan v5.4.1.\n\nMethod We reviewed the efficacy and safety of combination therapy vs. monotherapy/placebo for moderate-to-severe plaque psoriasis (palmoplantar and vulgaris) using PASI 75 via RevMan v5.4.1. Risk of bias assessment and funnel plots were employed to assess the heterogeneity of each paper. Inclusion criteria – Publications < 20yrs, RCTs, plaque/palmoplantar/psoriasis vulgaris; exclusion criteria – Guttate/arthritic psoriasis, pediatric and pregnant individuals, publications > 20 yrs.\n\nResults Seventeen studies were analyzed, comprising a total of 2291 patients (n=1147 with combination regimens and n=1144 with control regimen in the analysis). A significant PASI 75- response was observed in the pioglitazone combination subgroup as compared to placebo (OR=4.92,95% CI 2.19-11.05, P = 0.0001); methotrexate combination subgroup as compared to placebo (OR=2.56, 95% CI 1.67-3.94, P< 0.0001) test of subgroup differences showed P= 0.14, I2= 34%. Incidence rate of abnormality in levels of liver enzymes (OR=1.89,9.5% CI 6.69-5.22, P=0.22), nausea (OR=1.28,95% CI 0.77-2.14, P=0.34), headache (OR=1.28,95% CI 0.77-2.14, P=0.58), fatigue (OR=0.89, 95% CI 0.41-1.90, P=0.45).]\n\nConclusion This study showed that combination therapy is very effective for plaque psoriasis, with promising combinations of pioglitazone. While safety seems similar between the groups, larger studies are needed to determine the long-term effects. These findings suggest that personalized treatment plans could improve outcomes; however, confirmation through larger trials is crucial before wider use. This opens doors to research on optimal combinations for individual patients.", "keywords": [ "PASI 75%", "RoB2", "Pioglitazone", "Combination therapy" ], "content": "1. Introduction\n\nPsoriasis is a chronic, inflammatory, and multisystemic disease that can cause considerable morbidity and adversely affect quality of life.1,2 It affects 2-3% of the global population and is commonly seen in genetically predisposed individuals triggered by environmental factors that mainly affect the skin, nails, and joints.3\n\nThe precise cause of plaque psoriasis is unknown; however, it is thought to be a combination of hereditary and environmental factors. The immune system incorrectly assesses healthy skin cells, resulting in an overabundance of skin cells and inflammation, which results in distinctive plaques.\n\nPlaque psoriasis pathogenesis involves a complicated interplay between the immune system, genetics, and environmental variables. The immune system plays an important role in plaque psoriasis development. T cells, which are white blood cells, are activated and concentrated in the skin causing inflammation.4\n\nInterleukin-17 (IL-17), tumor necrosis factor-alpha (TNF-alpha), and interleukin-23 (IL-23) are cytokines that play a role in the inflammatory response. These cytokines increase keratinocyte proliferation and differentiation, resulting in psoriatic plaque production.5 Genetics also plays a role in the development of plaque psoriasis. Many genes have been found to contribute to the development of the disease, including HLA-Cw6, which has been linked to an elevated risk of psoriasis. Other immune response genes such as interleukin-12 (IL-12) and Interleukin-23 (IL-23) have also been implicated.6,7\n\nEnvironmental variables, such as stress, infection, and drugs, can cause or worsen plaque psoriasis. Streptococcal infections have been linked to the onset of psoriasis in some patients. Lithium, beta-blockers, and antimalarial have also been associated with the development of psoriasis.8\n\nCurrent monotherapy options for moderate-to-severe plaque psoriasis often have limitations, including partial response, safety concerns, and the development of resistance.8 Combination therapy for plaque psoriasis has emerged as a promising approach to overcome the limitations of monotherapy, aiming to improve efficacy, reduce side effects, and potentially delay resistance.9\n\nIn this study, we intended to compare the efficacy utilizing PASI 75 score which is a binary outcome that indicates 75% or greater improvement in PASI from baseline25 and safety of some of the drug combinations statistically used in the treatment of disease-focused (i.e., plaque psoriasis, psoriasis vulgaris, palmoplantar psoriasis) using a few manuscripts in the databases that talked about random trial techniques where the drug combinations were compared with the results of placebo; thus, we used the software, RevMan v5.4.1, a freely available software, initially built to ease the planning of protocols, the writing of reviews, and the storing of information within the Cochrane organization.\n\nReviews can be systematic or nonsystematic. In our systematic review, we aimed to incorporate quantitative analysis method, such as meta-analysis; RevMan v5.4.1, which helped us do the job and additionally produced some interesting graphical outputs of the data entered. It offered a variety of statistical features and methods, such as effect size calculations, heterogeneity tests, subgroup analyses, risk of bias summary and risk of bias graph, and publication bias. This enabled us to synthesize data from various studies, visualize data using forest and funnel plots, and produce more accurate and reliable estimations of treatment effects.\n\nReducing inflammation, itchiness, and redness is the main goal of psoriasis treatment.10 Classes of drugs, such as topical corticosteroids, topical retinoids, topical calcineurin inhibitors, and oral medications, such as methotrexate, cyclosporine, and acitretin, are being used.11,12\n\nAlthough several systematic reviews provide a summary of studies that report combination therapy with systemic agents,9,13,14 risk of bias assessments were only found in one throughout our search.1\n\nIn this study, we combined drugs such as pioglitazone, methotrexate, apremilast, etanercept, calcipotriol, betamethasone, cyclosporine, clobetasol propionate, acitretin, fumarate, and cetirizine using RevMan v5.4.1, additionally Forest plots were used for better visualization and analysis of the efficacy and safety results by comparing the odds ratio. For papers with graphical representations,15 extra software such as web plot digitizer and Python plot were used to extract PASI 75 values.\n\n\n2. Method\n\nWe performed a systematic literature study using Mendeley software to identify randomized controlled trials that compared the efficacy and safety of different drug combinations for plaque psoriasis and searched several stand-alone databases, including Google Scholar, PubMed, Pub Chem, Wiley library, MEDLINE, JDD Library, and the Cochrane Library. Considering the rapid evolution of knowledge and methodological standards in psoriasis research, particularly over the past two decades, we chose to limit our search to studies published after 2004. This ensures that our analysis reflects the most recent and methodologically sound evidence relevant to the current clinical practice.\n\nTreatment regimens between the time period of 8 and 24 weeks were chosen based on the understanding that studies conducted over shorter durations (<8 weeks) may not capture the full spectrum of treatment effects, potentially leading to biased conclusions. Conversely, long-term studies (>24 weeks) may introduce confounding variables or dropout rates, thereby compromising the reliability of the findings. Additionally, by encompassing a moderate timeframe, research within the 8–24-week range enables a balanced evaluation of both short-term and intermediate-term outcomes. This timeframe minimizes bias and ensures a comprehensive understanding of the drug’s efficacy and safety profile over a meaningful treatment period.\n\nSome of the keywords included meta-analysis, safety, PASI 75, (psoriasis OR plaque psoriasis) AND (combination therapy OR drug combination OR poly-therapy) AND (randomized controlled trial OR clinical trial OR randomized trial).\n\nAs per the protocol, the reference lists of relevant articles and their reviews were thoroughly analysed and shortlisted for additional studies. Duplicates were eliminated using the Mendeley method.\n\nDesktop v1.19.8 and screening the titles and abstracts of the remaining records for eligibility.\n\nThe PICO framework was used to formulate the research question and define the inclusion and exclusion criteria for the studies. The PICO elements were:\n\n• Population: Patients with moderate to severe plaque psoriasis/Palmo-plantar and psoriatic vulgaris\n\n• Intervention: Drug combinations\n\n• Comparison: Placebo or monotherapy\n\n• Outcome: The proportion of patients who achieved at least 75% improvement in the Psoriasis Area and Severity Index (PASI 75) and incidence of adverse events.\n\nThe years of publication were less than 20 years. Plaque Psoriasis (which also includes Palmo-planter psoriasis and psoriasis vulgaris), randomized controlled trials, parallel group, 8-24 weeks treatment regimes, and combination drugs. Articles written in English. Body surface involvement was ≥5%. We included studies that reported the proportion of patients who achieved at least 75% improvement in the Psoriasis Area and Severity Index (PASI 75) and the incidence of adverse events; studies with comparable baseline characteristics were included.16\n\nAbstract/title with psoriatic arthritis, guttate arthritis, erythrodermic psoriasis, non-randomized controlled trial papers (observational studies, retrospective studies, case reports, and review articles), >24 weeks treatment regimes, involvement of paediatric patients, non-English articles, studies that did not compare drug combinations with placebo or monotherapy.\n\nWe excluded studies that did not report the proportion of patients who achieved at least 75% improvement in the Psoriasis Area and Severity Index (PASI 75), studies without comparable baseline characteristics, large sample sizes leading to heterogeneity, and trials that included patients with ongoing previous treatment regimens.\n\nIndirect comparisons were performed to compare the efficacy and safety of different drug combinations for plaque psoriasis because there were insufficient trials that directly compared them with placebo. We used trials that evaluated the combination of drugs A and B versus drug B monotherapy as a surrogate for drug A combination versus placebo. The following assumptions were made for indirect comparisons:\n\n(1) The effect of the drug A and drug B combination was equal to the sum of the effects of drugs A and B alone.\n\n(2) The effect of drug B monotherapy was comparable to that of placebo.\n\n(3) The effect of drug A was homogeneous across different combinations.\n\nFive reviewers independently extracted data from the included studies using a standardized form. We extracted the following information: study characteristics (authors, year, country, design, duration, and sample size), intervention details (drugs, doses, frequency, and route of administration), and outcome measures (PASI 75, adverse events). The Cochrane risk of bias tool (RoB 2) was used to evaluate the methodological quality of the studies. Any discrepancies were resolved by discussion or consultation with other reviewers. We mailed the authors of the original studies for missing or unclear data.\n\nWe used WebPlotDigitizer v4.7 and Python Plotly v5.18.0 to extract the PASI 75 data from the Morita paper, which did not report the exact data numbers. We calculated the odds ratio (OR) and 95% confidence interval (CI) for each study by using the extracted data. We performed a meta-analysis using a random-effects model to estimate the pooled OR and 95% CI for the comparison of drug combinations with placebo or monotherapy. We assessed heterogeneity across studies using the I2 statistic and the chi-square test.\n\nWe explored the potential sources of heterogeneity using subgroup analyses, based on the following variables: disease severity, including indices such as PASI 75, and risk of bias inherent in the studies under review. To evaluate the safety profile of the medications, we gathered data on adverse events (AE), including the prevalence of common side effects, such as abnormal liver enzymes, nausea, headache, and fatigue among the patient cohorts.\n\nPublication bias was assessed using funnel plots. RevMan v5.4.1 , was used for all statistical analyses. We followed the PRISMA guidelines for reporting systematic reviews and meta-analyses by creating the PRISMA checklist.\n\n\n3. Results\n\nA total of 154 records were initially identified through a comprehensive search across the following databases: PubMed (n = 15), JDD (n = 40), Cochrane Library (n = 20), Wiley Online Library (n = 30), and Google Scholar (n = 49). After removal of duplicates, 100 unique records were screened, leading to the exclusion of 69 articles for reasons such as not being randomized controlled trials (RCTs), didn’t utilize PASI as a way to measure efficacy,17,18 lacking relevance to psoriasis, or focusing on drugs not covered in this review. Subsequently, 27 articles were included in the full-text review, of which 17 met our inclusion criteria and were consequently incorporated into this meta-analysis (refer Figure 1). The details of the materials are listed in Table 1.\n\nIn most areas, most ITT trials had a low risk of bias, indicating a high level of scientific rigor. Nonetheless, a few issues were observed in terms of deviations from the intended interventions, indicating potential areas for future investigations. The fact that no domain was predominantly related to a considerable risk of bias demonstrated the overall reliability of the included RCTs. Furthermore, one study that used PPS reported a low likelihood of bias. Because of the prevalence of open-label and single-blinded trials, the randomization domain may be more prone to bias than the others. However, because meta-analyses are intrinsically heterogeneous,19 they emphasize the importance of carefully assessing diversity because they do not automatically imply biased conclusions (refer Figures 2, 3, 4 and 5).\n\nOur funnel plot analysis revealed a symmetric distribution along the x-axis, indicating that the studies were evenly distributed across the range of standard errors (SE) of the logarithm of the odds ratio (log [OR]). However, upon closer examination, we found that the studies were grouped together and had higher SE (log [OR]) values. The observed clustering suggests heterogeneity among the included studies or variability due to differences in sample size (refer Figure 6).\n\nOur analysis used the Mantel-Haenszel random-effects model, which we considered well suited for achieving dichotomous outcomes, as well as better adjusting for study size, data stratification, and generalization across diverse populations. As is well known, the PASI 75 response was regularly used to assess the severity and prognosis of psoriasis patients, and it fulfilled therapeutic expectations in the vast majority of these cases. Therefore, PASI 75 was utilized in this meta-analysis to evaluate the therapeutic efficacy of pharmaceutical combinations.\n\nOur investigation found that combination therapy significantly increased the likelihood of positive outcomes by 2.53 times compared with controls (OR = 2.53, 95% CI: 1.94-3.30, p < 0.00001), refer Figure 7. The test for subgroup differences revealed no statistically significant variations in treatment effects (p = 0.14). However, the I-squared value (34%) indicated some heterogeneity across subgroups, necessitating further investigation using larger datasets.\n\nPioglitazone emerged as the frontrunner among the tested medication combinations, with an impressive odds ratio of 4.92 (95% CI: 2.19-11.05) and a very significant p-value of 0.0001. This study revealed a strong link between pioglitazone combination drugs and better outcomes compared with controls.\n\nSeveral additional drug combinations showed promising results, with odds ratios of > 2 for methotrexate, cyclosporine, clobetasol propionate, and fumarate. These findings require further examination to confirm their potential benefits owing to data-size constraints.\n\nData availability for Acitretin and Cetirizine combinations was limited, with only a single study examining each. Although their respective odds ratios (0.98 and 1.00) did not reach statistical significance, drawing definitive conclusions based on single studies would be premature. This underscores the need for further research with larger sample sizes to assess their efficacy comprehensively.\n\nForest plots and subgroup analysis findings for the efficacy results are provided for easy reference.\n\nIn our study exploring different drug combinations, we closely examined the side effects they might cause, such as abnormal liver enzymes, headaches, nausea, and fatigue.\n\n3.5.1 Abnormal liver enzyme findings\n\nIn our meta-analysis, we found that the overall odds ratio (OR) was 1.89 (95% CI: 0.69-5.22), indicating a nearly two-fold increase in risk; however, when we looked at the overall effect of the drug combinations on abnormal liver enzyme findings, the results were not statistically significant (P = 0.22). This suggests that based on the available evidence, we cannot definitively conclude that the drug combinations had a significant impact on abnormal liver enzyme readings. However, there was significant heterogeneity between trials (I2 = 60%, P = 0.03), which could be related to variations in the study techniques, patient demographics, or treatment durations. It is also worth mentioning that20 this study found the highest OR of 6.16, indicating a six-fold increase in ALE risk among patients receiving combination drugs (refer Figure 8).\n\n3.5.2 Nausea findings\n\nIn our investigation, we found that the experimental group had a slightly higher incidence of nausea (6.9%, 46 of 667 patients) than the control group (5.0%, 33 of 653). However, the odds ratio of 1.28, with a 95% confidence interval of 0.77 to 2.14, and a p-value greater than 0.05, which is above the customary threshold of 0.05 for statistical significance, indicate that this difference is not statistically significant. As a result, our findings are insufficient to establish that the incidence of nausea differed considerably between the two treatment groups. This data highlights the need for more research to identify whether experimental treatment is related to a higher incidence of nausea than control treatment (refer Figure 9).\n\n3.5.3 Headache findings\n\nThe incidence of headache appeared to be equivalent between the experimental and control groups. In the experimental group of 746 patients, 7.4% (n = 55) complained of headaches, whereas in the control group of 741 patients, 8.1% (n = 60) reported comparable events. Overall, there appeared to be no statistically significant difference in the frequency of headaches between the combination therapy and control groups (refer Figure 10). This is seen by the overall odds ratio (OR) of 0.90 (95% CI: 0.60, 1.33), which is very near to 1.0. Furthermore, the p-value for the test of the overall effect is 0.58, which is significantly higher than the widely accepted significance level of 0.05. Furthermore, the heterogeneity statistic was noteworthy at (I2 = 0%).\n\n3.5.4 Fatigue findings\n\nOur study included eight trials that examined the incidence of fatigue with different medication combinations for the treatment of plaque psoriasis. The results revealed that the experimental group experienced considerably less fatigue than the control group did. The odds ratio for fatigue was 0.89 (95% confidence interval, 0.41 to 1.90), indicating that patients in the experimental group were 11% less likely to feel weariness than patients in the control group. This difference was not statistically significant (P = 0.75). There was no significant heterogeneity among the studies (I2 = 0%), indicating consistent results across all the investigations (refer Figure 11).\n\n\n4. Discussions\n\nTo study the efficacy and safety of combination therapy for plaque psoriasis in comparison with controls and other combination medications, we used a network meta-analysis approach. The lack of research articles directly comparing different combination therapies to placebo or to each other has led to the selection of this approach. According to prior systematic reviews and meta-analyses, combination therapies are either more effective than control groups or as effective.21 Subjects aged 18 years or older were included in the study. Pregnant women and those with other genetic abnormalities were excluded. Only three large-scale, carefully planned clinical trials been conducted in the field of combination therapy have,8,20,22 despite the fact that several RCTs involving patients have been conducted. Combination therapy showed a substantial improvement in PASI 75 response when compared to controls (OR: 2.53, P < 0.00001). Combination therapy that included pioglitazone showed the best correlation with beneficial outcomes (OR, 4.92; P = 0.0001).There was a substantial PASI 75 response also noted here, in the pioglitazone combination subgroup when compared with the placebo (OR = 4.64, 95% CI 2.03–10.60, P < .00001).23 Therefore these results were consistent with their findings. Similar findings were obtained in24 a study examining the effects of insulin sensitizers (metformin and pioglitazone) in patients with metabolic syndrome and psoriasis. Both the metformin and pioglitazone cohorts showed a significant improvement in Psoriasis Area and Severity Index (PASI) scores compared to the placebo group. Our subgroup analysis indicated substantial heterogeneity (I2 = 34%); however, no significant differences were observed, indicating the need for more research with larger datasets. Promising trends were also observed for combinations such as methotrexate (OR, 2.56; 95% CI 1.67 – 3.94, P < 0.0001). A few additional combinations also produced good results, but the available data were insufficient to investigate them further, and this warrants further research with larger datasets. We assessed the frequency of particular adverse events (AEs) associated with the therapies under study to conduct a safety analysis. Trials that reported headache, nausea, exhaustion, and elevated or abnormal liver enzyme values were included. The proportion of individuals in a treatment arm who experienced each adverse event (AE) was our definition of “incidence.” Results are as follows: increase/abnormal levels of liver enzymes (OR: 1.89, 95% CI 0.69-5.22, P = 0.22), nausea (OR: 1.28, 95% CI 0.77-2.14, P = 0.34), fatigue (OR: O.89, 95% CI 0.41-1.90, P = 0.75), headache (OR: 0.90, 95% CI 0.60-1.33, P = 0.58). According to our investigation, there were no discernible differences in the occurrence of headaches, nausea, or abnormal liver enzyme levels between the groups. With 7% of the participants in the combination group and 8% in the control group, fatigue data indicated a possible lower risk in the combination group; however, this difference was not statistically significant. The incidence of SAEs was extremely low, and the overall safety profiles for combination regimes appeared manageable in the near term. Our study provides compelling evidence that treating plaque psoriasis with a combination of medications may be more successful than using them separately. This suggests that the effectiveness of various medication combinations for the treatment of plaque psoriasis may vary. Our findings may have implications in clinical practice. The observed variations in the safety and efficacy profiles across combination treatments indicate the potential for customized treatment regimens based on unique patient responses and features. However, before it can be widely used in clinical settings, further investigation is required to validate these results in more extensive, long-term investigations. It is critical to recognize some of the limitations of our meta-analysis. First, because there are few publications that directly compare therapies to a placebo, we used a network meta-analysis methodology in our approach. Compared with direct head-to-head comparisons, this approach naturally adds a degree of uncertainty, even though it permits indirect comparisons between treatments. Second, sample sizes varied among the included studies. A few studies have provided information from smaller sample sizes, which might have affected the reliability and applicability of our conclusions. Therefore, further investigation is required to validate these results for particular combinations and to fully evaluate safety profiles using larger datasets.\n\n\n5. Conclusion\n\nIn summary, this network meta-analysis presents strong evidence that combination therapy is a potentially more effective treatment than monotherapy for plaque psoriasis. Although the pioglitazone combination seems to work well, more research is required to fully understand the potential of different combinations. The observed differences in the safety and efficacy profiles indicate the potential for individualized treatment plans based on the requirements of each patient. Further large-scale, long-term studies that directly compare various combination medications are essential to verify these results and to enhance patients’ treatment plans for plaque psoriasis.", "appendix": "Data availability\n\nNo Data are associated with this article.\n\n\n\n• Figshare: Efficacy and safety of various drug combinations of various drug combinations in treating plaque psoriasis: A meta analysis - Figures (Forest plots, flowcharts, RoB2). https://doi.org/10.6084/m9.figshare.25656471.v1 26\n\n• Supplementary material 1, Figshare: String operations employed in Efficacy and safety of various drug combinations in treating plaque psoriasis: A meta-analysis. https://doi.org/10.6084/m9.figshare.25656465.v1 27\n\n• Supplementary material 2, Figshare: Risk of bias excel tool with MACROS for included studies in ‘Efficacy and safety of various drug combinations in treating plaque psoriasis: A meta-analysis’. https://doi.org/10.6084/m9.figshare.25656411.v2 28\n\n• Supplementary material 3, Figshare: intervalidation META ANALYSIS.xlsx. https://doi.org/10.6084/m9. figshare.25656405.v2 29\n\nData are available under the terms of the Creative Commons Attribution 4.0 International (CC-BY 4.0).\n\nFigshare: PRISMA CHECKLIST v2020 for ‘Efficacy and safety of various drug combinations in treating plaque psoriasis: A meta-analysis’. https://doi.org/10.6084/m9.figshare.25656444.v3 30\n\nData are available under the terms of the Creative Commons Attribution 4.0 International (CC-BY 4.0).\n\n\nAcknowledgement\n\nWe would like to express our appreciation to Dr. Rene N. Argenal and Dr. Nino Ismael Pastor for their valuable support with this meta-analysis.\n\n\nReferences\n\nChang G, Wang J, Song J, et al.: Efficacy and safety of pioglitazone for treatment of plaque psoriasis: a systematic review and meta-analysis of randomized controlled trials. J. Dermatolog. Treat. 2020 Oct 2; 31(7): 680–686. PubMed Abstract \| Publisher Full Text\n\nBalak DMW: ADVANCING PSORIASIS TREATMENT Clinical drug evaluation of fumaric acid esters and TLR-antagonists.2018.\n\nAbidi A, Rizvi D, Saxena K, et al.: The evaluation of efficacy and safety of methotrexate and pioglitazone in psoriasis patients: A randomized, open-labeled, active-controlled clinical trial. Indian J. Pharm. 2020 Jan; 52(1): 16–22. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nGisondi P, Del Giglio M, Cotena C, et al.: Combining etanercept and acitretin in the therapy of chronic plaque psoriasis: A 24-week, randomized, controlled, investigator-blinded pilot trial. Br. J. Dermatol. 2008 Jun; 158(6): 1345–1349. PubMed Abstract \| Publisher Full Text\n\nHassanandani T, Panda M, Jena AK, et al.: Methotrexate monotherapy versus methotrexate and apremilast combination therapy in the treatment of palmoplantar psoriasis: A prospective, randomised, assessor-blinded, comparative study. Indian J. Dermatol. Venereol. Leprol. 2022; 89(2): 213–220. PubMed Abstract \| Publisher Full Text\n\nLajevardi V, Hallaji Z, Daklan S, et al.: The efficacy of methotrexate plus pioglitazone vs. methotrexate alone in the management of patients with plaque-type psoriasis: a single-blinded randomized controlled trial.Reference Source\n\nGhiasi M, Ebrahimi S, Lajevardi V, et al.: Efficacy and safety of pioglitazone plus phototherapy versus phototherapy in patients with plaque type psoriasis: a Double Blinded Randomized Controlled Trial. J. Dermatolog. Treat. 2019; 30(7): 664–667. PubMed Abstract \| Publisher Full Text\n\nGottlieb AB, et al.: A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis. Br. J. Dermatol. 2012 Sep; 167(3): 649–657. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nFerence EH: Combination Treatments for Psoriasis. Arch. Dermatol. 2012 Apr; 148(4): 511. Publisher Full Text\n\nVena GA, Galluccio A, Pezza M, et al.: Combined treatment with low-dose cyclosporine and calcipotriol/betamethasone dipropionate ointment for moderate-to-severe plaque psoriasis: A randomized controlled open-label study. J. Dermatolog. Treat. 2012 Aug; 23(4): 255–260. PubMed Abstract \| Publisher Full Text\n\nMahajan R, Kaur I, Kanwar A: Methotrexate/narrowband UVB phototherapy combination vs. narrowband UVB phototherapy in the treatment of chronic plaque-type psoriasis - A randomized single-blinded placebo-controlled study. J. Eur. Acad. Dermatol. Venereol. 2010; 24(5): 595–600. PubMed Abstract \| Publisher Full Text\n\nSingh SK, Singnarpi SR: Safety and efficacy of methotrexate (0.3 mg/kg/week) versus a combination of methotrexate (0.15 mg/kg/week) with cyclosporine (2.5 mg/kg/day) in chronic plaque psoriasis: A randomised non-blinded controlled trial. Indian J. Dermatol. Venereol. Leprol. 2021 Mar; 87(2): 214–222. PubMed Abstract \| Publisher Full Text\n\nJensen P, Skov L, Zachariae C: Systemic Combination Treatment for Psoriasis: A Review. Acta Derm. Venereol. 2010; 90(4): 341–349. Publisher Full Text\n\nGustafson CJ, Watkins C, Hix E, et al.: Combination Therapy in Psoriasis. Am. J. Clin. Dermatol. 2013 Feb; 14(1): 9–25. Publisher Full Text\n\nMorita A, et al.: Efficacy and safety of apremilast and phototherapy versus phototherapy only in psoriasis vulgaris. J. Dermatol. 2022 Dec; 49(12): 1211–1220. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nGupta MC, Aggarwal K, Nayak K: Evaluation of Role of Add on Anti Hyperglycaemic Drugs Metformin and Pioglitazone in Patients of Psoriasis with Metabolic Syndrome.2020. Reference Source\n\nRodgers M, Epstein D, Bojke L, et al.Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis: a systematic review and economic evaluation.2011. Reference Source\n\nGold LS, Lebwohl MG, Sugarman JL, et al.: Safety and efficacy of a fixed combination of halobetasol and tazarotene in the treatment of moderate-to-severe plaque psoriasis: Results of 2 phase 3 randomized controlled trials. J. Am. Acad. Dermatol. 2018 Feb; 79(2): 287–293. PubMed Abstract \| Publisher Full Text\n\nHiggins JPT, et al.: Measuring inconsistency in meta-analyses.2003.\n\nLiu LF, et al.: Etanercept biosimilar (recombinant human tumor necrosis factor-α receptor II: IgG Fc fusion protein) and methotrexate combination therapy in Chinese patients with moderate-to-severe plaque psoriasis: a multicentre, randomized, double-blind, placebo-controlled trial. Arch. Dermatol. Res. 2020 Aug; 312(6): 437–445. PubMed Abstract \| Publisher Full Text\n\nBusard C, Zweegers J, Limpens J, et al.: Combined Use of Systemic Agents for Psoriasis. JAMA Dermatol. 2014 Nov; 150(11): 1213. Publisher Full Text\n\nLebwohl MG, et al.: A randomized study to evaluate the efficacy and safety of adding topical therapy to etanercept in patients with moderate to severe plaque psoriasis. J. Am. Acad. Dermatol. 2013 Sep; 69(3): 385–392. PubMed Abstract \| Publisher Full Text\n\nChang G, Wang J, Song J, et al.: Efficacy and safety of pioglitazone for treatment of plaque psoriasis: a systematic review and meta-analysis of randomized controlled trials. J. Dermatolog. Treat. 2020 Oct 2; 31(7): 680–686. PubMed Abstract \| Publisher Full Text\n\nSingh S, Bhansali A: Randomized placebo control study of insulin sensitizers (Metformin and Pioglitazone) in psoriasis patients with metabolic syndrome (Topical Treatment Cohort). BMC Dermatol. 2016 Aug; 16(1): 12. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nGuenther L, Cambazard F, Van De Kerkhof PCM, et al.: Efficacy and safety of a new combination of calcipotriol and betamethasone dipropionate (once or twice daily) compared to calcipotriol (twice daily) in the treatment of psoriasis vulgaris: a randomized, double-blind, vehicle-controlled clinical trial. Br. J. Dermatol. 2002 Aug; 147(2): 316–323. PubMed Abstract \| Publisher Full Text\n\nNayak S, Zafar S, Siri P, et al.: Efficacy and safety of various drug combinations of various drug combinations in treating plaque psoriasis: A meta analysis - Figures(Forest plots, flowcharts, RoB2). figshare. 2024 [cited 2024Apr20]. Publisher Full Text Reference Source\n\nNayak S: String operations employed in Efficacy and safety of various drug combinations in treating plaque psoriasis: A meta analysis. figshare. 2024 [cited 2024 Apr 20]. Publisher Full Text Reference Source\n\nNayak S: Risk of bias excel tool with MACROS for included studies in ‘Efficacy and safety of various drug combinations in treating plaque psoriasis: A meta analysis’. figshare. 024 [cited 2024 Apr 24]. 2. Publisher Full Text Reference Source\n\nNayak S, Zafar Sintervalidation META ANALYSIS.xlsx. figshare. 2024 [cited 2024 Apr 24]. Publisher Full Text Reference Source\n\nNayak SPRISMA CHECKLIST v2020 for ‘Efficacy and safety of various drug combinations in treating plaque psoriasis: A meta analysis’. figshare. 2024 [cited 2024 Apr 24]. Publisher Full Text Reference Source" }	[ { "id": "275508", "date": "14 May 2024", "name": "Naoko Kanda", "expertise": [ "Reviewer Expertise Cutaneous immunology", "atopic dermatitis", "psoriasis" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n1.The term ‘ combination therapy’ appears to mean the combination of more than one systemic treatments, and does not appear to include combination of systemic and topical treatments. However, the combination of topical and systemic treatments is included in this study. Such analysis is rather queer since such combination is ordinarily done in real-world clinical practice. 2.The choice of drugs is also very much biased: pioglitazone, methotrexate, apremilast, etanercept, calcipotriol, betamethasone, cyclosporine, clobetasol propionate, acitretin, fumarate, and cetirizine. Among these, calcipotriol, betamethasone, clobetasol propionate are topical treatments and should be deleted from this review. Cetilizine is a second-generation antihistamine while pioglitazone is an anti-diabetic medication. The reasons for choosing these agents for psoriasis are unknown. Etenercept is the only biologic among the agents, and thus dealing with this drug in parallel to other small molecule systemic agents should be avoided. 3.The definition of palmoplantar psoriasis is ambiguous. Is that palmo-plantar pustulosis or psoriasis appearing on palmoplantar areas?\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Partly\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Partly\n\nIs the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required.\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable", "responses": [ { "c_id": "11564", "date": "28 May 2024", "name": "Snehasis Nayak", "role": "Author Response", "response": "Firstly, thank you ma'am for your valuable insight about our paper. We do appreciate your patience and time for reviewing our article. But I would like to address certain points of comment on my article. Comment 1 - We acknowledge that the term can sometimes be interpreted more narrowly to refer solely to systemic combinations. However, in this study, we deliberately adopted a broader definition of combination therapy to encompass all possible treatment combinations, including those that involve both systemic and topical medications. This approach aligns with real-world clinical practice, where dermatologists frequently combine topical and systemic therapies to achieve optimal results for patients with plaque psoriasis. This includes the synergistic effects of combining topical and systemic therapies, which is a common and effective approach in real-world clinical practice. While there is extensive study on the efficacy and safety of combination therapies compared to placebo or monotherapy, a comparative analysis between various combination therapies remains relatively unexplored in recent times. We aimed to address this specific gap by investigating the relative efficacy and safety profiles of different combination regimens for plaque psoriasis. Comment 2 - It's important to clarify that our choice of drugs was not biased, but rather based on established evidence from several randomized controlled trials (RCTs) regarding their efficacy in treating plaque psoriasis. Pioglitazone, for instance, has been studied extensively in the context of psoriasis treatment, with numerous RCTs such as Ghiasi 2020, VG Hafiz 2015, and Lajevardi 2015 demonstrating its effectiveness. Moreover, our study is a meta-analysis, meaning that we synthesized data from existing literature rather than arbitrarily selecting treatments. We included a range of systemic and topical treatments to provide a comprehensive overview of available options for psoriasis management. Therefore, the inclusion of calcipotriol, betamethasone, and clobetasol propionate, which are topical treatments, is justified as they are commonly used in clinical practice. Comparing biologics with small molecule treatments is crucial for understanding their relative efficacy and safety. This comparison helps clinicians make informed choices about integrating biologics into treatment regimens. Including a biologic like etanercept ensures our study covers all major classes of psoriasis treatments, providing a complete picture of therapeutic options. We have also emphasized on the need of further research into these areas as well. We have not stated that these could be used as definitive treatment regimes but instead as possible treatment regimes. Thus, our approach was systematic and evidence-based, aiming to provide clinicians with comprehensive information to guide treatment decisions for psoriasis patient. Furthermore, it's important to acknowledge that this study utilized a network meta-analysis approach, allowing for indirect comparisons between treatments. We have highlighted the limitations of this methodology in our paper to ensure transparency and help readers interpret the findings appropriately Comment 3 - I see where the confusion might arise. While palmoplantar psoriasis shares similarities with plaque psoriasis in terms of its underlying condition, it's essential to differentiate them as palmoplantar psoriasis specifically. I would make the necessary correction related to that. We hope these points clarify the rationale behind our study design and drug selection; and we appreciate your consideration of our perspective. Best regards, Snehasis Nayak" } ] }, { "id": "281705", "date": "17 Jun 2024", "name": "Romana Čeović", "expertise": [ "Reviewer Expertise Psoriasis and erithematosquamous dermatosis", "dermatological oncology." ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article is nicely written and educational as it provides detailed information on the safety and effectiveness of various combination therapies used in the treatment of psoriasis. Statistical processing accurately displays the data that is most important in daily praxis. Although the pioglitazone combination seems to work well, more research is required to fully understand the potential of different combinations. Further large-scale, long-term studies that directly compare various combination medications are essential to verify these results and to enhance patients’ treatment plans for plaque psoriasis.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes", "responses": [] } ]	1	https://f1000research.com/articles/13-453
https://f1000research.com/articles/13-224/v1	27 Mar 24	{ "type": "Research Article", "title": "Using Health Claims to Teach Evidence-Based Practice to Healthcare Students: A Mixed Methods Study", "authors": [ "Ida-Kristin Orjasaeter Elvsaas", "Hilde Tinderholt Myrhaug", "Lisa Garnweidner-Holme", "Jürgen Kasper", "Astrid Dahlgren", "Marianne Molin", "Hilde Tinderholt Myrhaug", "Lisa Garnweidner-Holme", "Jürgen Kasper", "Astrid Dahlgren", "Marianne Molin" ], "abstract": "Background A multifaceted and interactive teaching approach is recommended for achieving proficiency in evidence-based practice, with critical thinking considered vital for connecting theory and practice. In this context, we advocate the strategic use of health claims in media to promote critical thinking and provide an accessible entry point to evidence-based practice for early-stage university healthcare students.\n\nMethod We conducted a convergent mixed methods study, including a cross-sectional survey with structured and open-ended questions as well as focus group interviews, at the Faculty of Health Sciences, Oslo Metropolitan University, during the 2020-2021 academic year. Participants were bachelor’s students in bioengineering, physiotherapy, social education, and occupational therapy. We employed a blended learning approach, combining digital learning resources, teaching in critical assessment of health claims and evidence-based practice, and a concurrent group exam assignment centered around health news. The outcome measures included students’ experiences integrating health claims into evidence-based practice teaching and their experiences with teaching approaches, including the group exam.\n\nResults Out of 446 participants, 136 (30.5%) responded to the structured questions in the survey. In response to the open-ended questions within the survey, 109 (80.1%) of the respondents shared positive experiences about the course, while 98 (72%) suggested improvements. Additionally, 25 students participated in focus group interviews. Synthesizing the results, we found that students viewed the inclusion of health claim assessment as a useful entry point for learning evidence-based practice. In addition, both the blended learning design and the group exam were identified as contributors to a positive perception of learning outcomes from the course.\n\nConclusions Integrating critical reflection on media health claims into evidence-based practice education, alongside a blended learning approach and a group exam, may be beneficial for educating bachelor’s healthcare students. However, further rigorous study designs are needed to assess the effect of the course on learning outcomes.\n\nRegistration DOI 10.5281/zenodo.6985449", "keywords": [ "Evidence-Based Practice", "Evidence-Based Healthcare", "Critical Thinking", "Health Literacy", "Health Education", "Professional Education", "Mixed Method Design" ], "content": "Background\n\nEvidence-based practice (EBP) is essential for enhancing healthcare quality and safety.1–3 Educational programs in healthcare professions should incorporate EBP to ensure that graduates can deliver high-quality, evidence-based care.4,5 In Norway, higher education institutions are legally obligated to equip health and welfare science students with EBP competencies.6\n\nWhile the core components of EBP are generally agreed upon,3,4,7 successful teaching and learning in EBP require interactive and multifaceted approaches integrated with clinical practice.5 These teaching strategies should incorporate various assessment methods to gauge students’ progress and comprehension.5 In addition, cultivating critical thinking skills is considered essential for bridging the gap between theory and practice, allowing students to understand the relevance of evidence in their future professional roles.8 To address this issue, we propose using health claims in the media to promote critical thinking and provide an entry point for EBP for university healthcare students9 in the early stages of their education and lack of clinical practice experience. Health claims found in news articles, social media posts, and advertisements are easily identifiable and hold relevance to students’ daily lives,9 as well as their future professional practice when faced with health claims from patients and caregivers.10,11 Previous studies have shown this approach to be successful at teaching the public to think critically about health claims.12,13 Consequently, there is potential for applying this strategy in professional education, fostering similar skills during training, and enhancing comprehension of the practical implementation of EBP.\n\nDuring the academic year 2020 to 2021, Oslo Metropolitan University (OsloMet) adopted a blended learning approach to deliver a newly developed three-week course on evidence-based practice in healthcare (hereafter called the EBHC course). The EBHC course was designed to align with the common learning outcomes for bachelor’s students in health and social services education, thereby becoming a mandatory course for first- or second-year students at the Faculty of Health Sciences. In addition, the course incorporated a module with elements from a previous learning design called “Behind the Headlines”,9 serving as a stepping-stone to EBP. The “Behind the Headlines” section builds on the Informed Health Choices (IHC) Key Concept Framework and focuses on assessing treatment claims.14 In this context, treatment claims refer to actions or products used to maintain or improve health. The initial implementation of the EBHC course encompassed four study disciplines: bioengineering, physiotherapy, social education, and occupational therapy.\n\nThis study aimed to explore healthcare students’ experiences during the first year of implementing our EBHC course that incorporated media health claims. The outcome measures encompassed their experiences integrating health claims into EBP teaching, as well as their experiences with teaching approaches, including the group exam.\n\n\nMethods\n\nWe employed a convergent mixed methods research design,15 which included a cross-sectional survey and focus group (FG) interviews. The convergent design is a single-phase approach that involves the collection of quantitative and qualitative data, followed by separate analyses, culminating in an integrated analysis.15,16 The combination of structured and open-ended questions in the questionnaire, along with FG interviews, was used to comprehensively understand participants’ experiences. Our goal was to extract fresh insights that surpass the results obtained from separate analyses of the quantitative and qualitative data.16\n\nThe reporting of the study was guided by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement,17 the Consolidated Criteria for Reporting Qualitative Research (COREQ),18 and the Mixed Methods Appraisal Tool (MMAT), Version 2018.19\n\nThis study evaluates healthcare education. Although OsloMet does not have an Ethics Review Board to approve projects, researchers are committed to adhering to ethical standards following applicable national regulations, institutional guidelines, and the principles of the Declaration of Helsinki (as revised in 2013).20\n\nThe data in the study were collected anonymously, without personal or indirect personal information, or health and illness data. Therefore, according to the guidelines of the Norwegian Agency for Shared Services in Education and Research, no approval from them was necessary. Before participating in the study, all participants provided written informed consent for the collection and use of data for research purposes.\n\nWe included bachelor’s students who participated in the EBHC course from 2020 to 2021. The eligible participants were 446 first- and second-year bachelor students enrolled in bioengineering, physiotherapy, social education, and occupational therapy programs at the Faculty of Health Sciences at OsloMet. Separate courses were conducted for each study program.\n\nTo collect survey data, announcements were posted on “Canvas,” the learning management system utilized by OsloMet, toward the end of the courses. A reminder was posted 4 to 7 days later. Participation in the survey was voluntary and anonymous, although respondents who completed the survey had the opportunity to enter a lucky draw to win NOK 500 gift cards. However, to participate in the draw, respondents needed to express their interest by emailing one of the lecturers. There was no connection between the submitted answers and participants’ email addresses to ensure anonymity.\n\nToward the end of the EBHC courses, an invitation to participate in the FG interviews was issued through “Canvas,” with participants selected based on convenience sampling. Each participant in the FG interviews was offered a gift card worth NOK 300.\n\nThe three-week EBHC course (Figure 1) comprised digital learning materials, lectures, and student activities in “Behind the Headlines” and EBP,4 with concurrent student collaboration on a group exam assignment. For the course generic timetable, see Extended data.21\n\nAt the beginning of the course and before each new topic, students were encouraged to use digital learning materials covering the EBHC curriculum. These materials were accessed via the learning management system (“Canvas”) and consisted of textual content as well as links to videos and other multimedia resources.\n\nIn the “Behind the Headlines” module, students were asked to critically reflect on the reliability of health claims made by the media regarding treatment effects. This was achieved through an assessment of the basis for these health claims using five key concepts (Table 1) from the IHC Key Concept Framework.14\n\nThe students were taught EBP in six sequential steps (Figure 1). This involved reflecting on information needs (Step 1), formulating questions using the PICO framework (Step 2), conducting literature searches (Step 3), critically appraising research studies (Step 4), gaining insight into implementing (Step 5), and evaluating (Step 6) EBP in clinical settings.\n\nExam assignment\n\nIn the course’s first week, a group exam assignment was distributed, requiring students to critically assess the basis of one (out of several) provided health news articles using the five IHC Key Concepts (Table 1). This process also prompted them to reflect and identify information needs, followed by formulating a research question using the PICO framework and conducting targeted literature searches. Additionally, they were required to provide a relevant checklist for appraising the methodological quality of the selected research article. Finally, the students discussed whether the health claim made in the news article was supported by the selected research article and explored the potential relevance of these findings for patients or the Norwegian health service.\n\nEvaluation survey\n\nThe data were collected anonymously through a questionnaire created using nettskjema.no, a survey solution developed and hosted by the University of Oslo. The questionnaire21 included several sections, starting with background information such as gender, age, and study program. Furthermore, there was a course evaluation section featuring Likert scale questions and open-ended questions.\n\nTwo of the Likert scale questions in the questionnaire focused on course information (“To what extent did the information provided by the course managers effectively serve its purpose in informing you about the course?”) and overall learning outcomes (“Please rate your learning outcomes in the course”). The respondents were asked to rate these items from one (very good) to four (not good at all). The learning outcomes were further explored through eight questions, where students indicated their level of agreement on a scale from 1 (completely agree) to 6 (completely disagree), with an additional option for “do not know.” In addition, there was a section for participants to provide other comments.\n\nIn the open-ended questions, students were allowed to provide feedback on the EBHC course by answering the following questions: “Please share any positive aspects you found in the course, such as the content, teaching methods, organization, work style, assessment, etc.” and “Do you have any suggestions for improving the course, such as the content, teaching methods, organization, work style, assessment, etc.?”.\n\nDescriptive statistics were used to analyze the respondents’ characteristics, and frequencies were employed to analyze the responses to each Likert scale evaluation question. In addition, the responses related to the detailed learning outcomes were collapsed and categorized into “agree” (ratings of 1, 2, and 3 on the 6-point scale), “disagree” (ratings of 4, 5, and 6 on the 6-point scale) and “do not know”. The data were analyzed using IBM SPSS Statistics version 27 software.22\n\nThe answers to the open-ended questions were analyzed using the systematic text condensation strategy as follows: 1) obtaining an overall impression; 2) identifying and organizing meaningful units; 3) condensing the information; and 4) synthesizing the condensed material.23 The analytical steps were carried out independently by two researchers. Subsequently, the researchers engaged in discussions to achieve a common understanding of the findings.\n\nFocus group interviews\n\nWe utilized Rosenbaum’s honeycomb framework24 as the basis for developing the FG interview guide.21 This framework encompasses various problem aspects and differentiates between multiple facets of user experience. The FG interviews were conducted via Zoom following OsloMet’s privacy policy for Zoom interviews (https://ansatt.oslomet.no/en/rutine-zoom-forskningsintervjuer) and lasted for approximately one hour. The FG interviews were not audio recorded. One researcher was the moderator while two other researchers took notes during the interviews. All the participating researchers then cross-checked these notes. Any discrepancies or differences of opinion among the researchers were resolved through consensus. The student participants did not provide feedback on the notes.\n\nThe notes obtained from the FG interviews were analyzed using the systematic text condensation strategy,23 following the same analytical approach applied to the responses to the open-ended questions in the evaluation survey.\n\nMixed methods approach\n\nTo facilitate the synthesis of results from the structured and open-ended questions in the survey and focus group interviews, we initially analyzed similarities and differences in the datasets, considering their respective purposes and the responses they generated. Furthermore, to gain insights beyond what can be derived from the separate analysis of the quantitative and qualitative datasets, we synthesized and presented the findings in a joint display,16 visually integrating the data.\n\nIn qualitative research, which also encompasses a mixed-methods approach, researchers play an integral role in the research process, and our prior experiences, assumptions, and beliefs will therefore inevitably shape its trajectory and outcomes.25 The authors of the study have diverse backgrounds, and experience in conducting systematic reviews, EBP teaching and research, and clinical and academic areas. The team collaborated to ensure investigator triangulation.\n\nTwo of the co-authors (HTM and MM) actively participated in the development of the course and the teaching process and conducted the FG interviews. However, the remaining co-authors were not involved in either the teaching or the FG interviews. To address potential biases in the analysis of the qualitative data, two researchers (HTM and IKOE) independently conducted the data analysis before reaching a shared understanding. This methodological approach, together with the extensive use of quotations from open-ended questions and FG interviews, was used to strengthen the credibility of the study findings.26\n\n\nResults\n\nTo ensure transparency, the underlying quantitative and qualitative data are made publicly available.21\n\nOur survey included 136 out of 446 eligible participants, representing a response rate of 30.5% (Table 2). There were no missing values.21 Most of the study participants were women, accounting for 79.4% of the sample, and a substantial proportion were younger than the age of 26 (78.0%). All the various fields of study were represented, with the highest representation from physiotherapy (32.4%) and the lowest from occupational therapy (19.1%).\n\nApproximately 76% of the students rated the course information as either “good” or “very good,” while 90.5% reported a positive perception of their overall learning outcome, indicating that it was either “good” or “very good”.\n\nThe overall learning outcome was further investigated through eight questions related to different educational methods implemented in the EBHC course. When analyzing these subcategories, students exhibited the highest satisfaction within the collaborative exam group, with 50.4% completely agreeing with the statement “I have experienced positive learning outcomes from working in the exam group.” The subcategories related to experienced learning outcomes for other resources or teaching methods displayed variability. However, upon categorizing the results of the subcategories of learning outcomes as “agree,” “disagree,” and “do not know,” it became evident that these learning outcome measures leaned toward agreement, as indicated in Table 3.\n\nIn total, 80.1% (109/136) of the students answered what they regarded as positive about the course and 72.1% (98/136) suggested improvements. See Underlying data21 for the distribution of responses to the open-ended questions in the evaluation survey.\n\nPositive feedback about the course\n\nAnalysis of the positive feedback about the course was divided into topics about (1) digital learning resources, (2) student learning activities, (3) group exam collaboration, and (4) the usefulness of the course. Additional quotes supporting the topics can be found in Extended data.21\n\nThe availability of comprehensive digital learning resources both before and after the lessons was appreciated by many. For instance, as one physiotherapy student wrote, “The organization of self-learning through Canvas etc … was fantastic and easy to follow along.”\n\nThe students held a positive perception of the student learning activities, expressing the lecturers’ proficiency in facilitating diverse learning activities such as quizzes, group discussions, seminar presentations, and peer reviews. An occupational therapy student commented, “Exciting content, committed lecturers, fun with collaborative tasks/discussion in plenary.”\n\nThe incorporation of the group exam early in the course and thus ample time for reflection received positive feedback. A bioengineering student noted, “You got so much more out of the course when you worked in groups. Then you could discuss with each other and generally hear what others think. You could be good together.”\n\nAdditionally, the students expressed appreciation for the acquisition of critical assessment skills regarding health claims in the media, familiarity with the evidence pyramid, and the ability to critically appraise scientific research papers, considering these components relevant to their future professional endeavors. A physiotherapy student wrote, “I think being able to be critical of health claims on the internet was incredibly good.” Furthermore, an occupational therapy student wrote, “Everything about this course has been educational and useful. It is very relevant for future assignments and bachelor’s thesis.”\n\nSuggestions for improvement\n\nThe analysis of the open questions about suggestions for improvements was distributed among the topics of (1) digital learning resources, (2) education, and (3) the group exam. Additional quotes supporting the topics can be found in Extended data.21\n\nSome students expressed concerns about the organization of the learning management system (“Canvas”) and the presence of two similar platforms from different universities, one affiliated with OsloMet in English and the other with the Western Norway University of Applied Sciences in Norwegian. A physiotherapy student who articulated this concern serves as an example, writing “Difficult to find the right information, as there were several Canvas rooms and a bit “messy” with information in both English and Norwegian.” As a suggestion for improvement, a bioengineering student wrote, “As for the organization inside Canvas, I think this was very good when I first understood it, but there should perhaps have been a little clearer information about how to find and use Canvas, this learning platform is new and unfamiliar to many so early in the studies.”\n\nConcerns were raised about the efficacy of breakout rooms, as many students either did not actively participate or were unprepared, resulting in a lack of meaningful discussion. For instance, a physiotherapy student wrote, “Many digital lectures had almost only breakout rooms, with very little academic content. I felt there was no point in discussing something I didn’t know with someone who also didn’t know [the academic content].” This perspective was echoed by others, for example, an occupational therapy student who wrote, “There were a lot of breakout rooms/seminars which were a bit of a waste. That there was unnecessary time spent in breakout rooms.”\n\nAlthough the group exam was generally successful, some concerns arose regarding the possibility of free riders and the appropriate approach to managing such situations. A physiotherapy student commented, “The group project method – having to do the exam in a group – will always be challenging when some contribute a lot and are very engaged and interested, while others are checked out and unmotivated.” A possible solution to the free rider problem was expressed by a social education student, writing “In the case of further online group work, I think [there should be] a requirement to log attendance so that everyone contributes and that it is not difficult for the students to report if someone wandered off.”\n\nOut of 29 interested students, 25 from the various programs participated in the FG interviews. The first FG interview included five bioengineering students, the second involved eight physiotherapy students, the third comprised five social education students, and the fourth consisted of seven occupational therapy students. Details regarding participation and drop-outs are provided in Extended data,21 although no reasons were given for the dropouts.\n\nThe analysis of the FG interviews covered the following topics: (1) digital learning resources, (2) course comprehension, (3) the relevance of health claims, (4) group collaboration, and (5) the course’s usefulness. Several pertinent quotations corroborating the topics are available in Extended data.21\n\nThe students acknowledged the presence of diverse information within the learning management system (\"Canvas\"), as exemplified by one comment from a physiotherapy student in FG interview 2, \"[…] good [learning] resources in Canvas.\" However, some initially perceived its layout to be disorganized. As they became more familiar with the system, they found navigation to be effortless. One bioengineering student in FG interview 1 expressed that “[It was] easy to find [the information] once you became familiar [with Canvas].”\n\nAt the outset of the course, most students showed limited familiarity with the concept of evidence-based practice and the course content. However, they appreciated the course’s well-structured progression and the clarity of the learning materials, making the content easily understandable, aided by the logical steps in EBP teaching. One occupational therapy student expressed in FG interview 4, “Well structured, easy to follow. Everything was clear.”\n\nHealth claims, introduced through the “Behind the Headlines” module, were acknowledged as a useful entry point for EBP, as expressed by one occupational therapy student in FG interview 4, “Behind the headlines and EBP are connected. EBP is sort of next step …”. This could be attributed to their direct relevance to everyday experiences. One physiotherapy student expressed in FG interview 2 “I think it would have been much duller if you had removed [the health claims]. That’s how [the course] becomes relevant for us.” Another physiotherapy student in the same FG interview further emphasized the significance of health claims for their future profession, stating, “You can get patients who base their knowledge on [health claims]. [We] must be able to refute them sensitively.”\n\nSeveral students emphasized the importance of group collaboration as a catalyst for fostering critical reflection. An occupational therapy student in FG interview 4 expressed, “It is important to have a group when we are going to be critical, several points of view emerge.” A social education student echoed a similar sentiment in FG interview 3, expressing an appreciation for the collaborative learning approach, “I liked that it was group work. It makes it easier to learn when you are in a team. Easier to discuss.”\n\nThe students perceived the course as highly beneficial, serving multiple purposes. These included enhancing their ability to write their bachelor’s thesis, critically assessing health claims encountered in their everyday lives, and preparing themselves for their forthcoming roles as updated healthcare practitioners, informed by best practices. One occupational therapy student expressed in FG interview 4, “I have already started searching the Health Library (“Helsebiblioteket”) to prepare for practice, [I have] never done [that] before.”\n\nAll the students articulated that the course provided them with the necessary skills to critically assess media claims. One social education student expressed in FG interview 3 that “Being critical of sources is useful. [Behind the Headlines] was like an ABC.” Moreover, the students reported the acquisition of skills in locating trustworthy research and the ability to autonomously appraise its validity. One bioengineering student highlighted in FG interview 1 that “[I have] learned to be critical of research - learned good ways to be critical - a proper recipe.” Furthermore, the students acknowledged the universal significance of this knowledge, emphasizing its potential benefits for a broader audience.\n\nOur datasets served distinct purposes and provided diverse insights. The structured questions in the survey primarily evaluated learning outcomes, lacking inquiries about, for example, the usefulness of “Behind the Headlines” for understanding the concept of EBP. Students provided open-ended responses in the survey concerning content, teaching methods, organization, work style, and the exam. The primary concerns centered around how teaching methods, organization, and work style prepared them for the exam, with some offering feedback on the practical applicability of course content. The FG interviews provided an in-depth understanding of students’ experiences with the EBHC course, including the integration of health claims as a fundamental aspect of the educational process.\n\nWe identified three main outcomes addressing our study objective through the synthesis of results obtained from our datasets, as presented in Table 4. First, we found that critical reflection on health claims introduced through the “Behind the Headlines” module was a useful entry point for EBP. Second, the blended learning design had a positive influence on the students’ perceived learning outcomes. Finally, the collaborative exam assignment promoted both critical reflection and positively impacted perceived learning outcomes.\n\n* Most of the quotes are directly translated from Norwegian to English using Google Translate. Therefore, the wording and sentence structure may be somewhat unfamiliar to an English-speaking audience. N/A=not assessed.\n\n\nDiscussion\n\nWe designed an EBHC course that integrated the assessment of media health claims, along with the use of a blended learning approach and a group exam. Our study aimed to explore healthcare students’ experiences with this course. To our knowledge, this is the first study to examine the experiences of bachelor healthcare students in which the use of health claims for critical thinking is employed as an entry point to EBP.\n\nWe found that engaging in critical reflection on the reliability of health claims presented in the “Behind the Headlines” module helped introduce healthcare students to the concept of EBP. The implementation of blended learning, which combined online and in-person components, proved beneficial for students’ perceived learning outcomes. In addition, the collaborative exam assignment succeeded not only in promoting critical reflection but also in enhancing students’ perceived learning outcomes. The following sections provide a detailed elaboration of our findings.\n\nOur study revealed that health claims, introduced through the “Behind the Headlines” module, served as a helpful entry point for EBP. Five IHC Key Concepts,14 most of which align with the “0.2 Recognize the rationale for EBP” section of Albarqouni et al.’s EBP framework,4 were introduced via this module to foster an understanding of the role of reliable research in informing practical application. Students’ perception of the interrelationship between the “Behind the Headlines” module and EBP was likely influenced by the use of health claims in the initial module, acting as a bridge to the broader context of the EBP course.27\n\nOur results further indicate that students found health claims advantageous for multiple purposes. Rather than starting directly with scientific articles, they found this approach useful for facilitating critical evaluation of health claims in everyday life and preparing for their future roles as healthcare professionals. The ability to critically assess health claims, an aspect of critical health literacy,27,28 plays a role in protecting individuals against misleading treatment claims and enabling them to make informed decisions regarding their health.14 With the growing prevalence of health claims in various media channels29 and an emphasis on shared decision-making,30,31 future healthcare professionals are likely to encounter health claims from patients sourced from the media.11 However, the ability to assess health claims remains limited among various individuals, including healthcare professionals.32,33 Thus, interventions aimed at promoting critical thinking in this domain hold value. Several initiatives, including the strategy described in our current study, as well as other relevant approaches,12,13,34,35 have the potential to facilitate this process. We believe that the integration of health claims into EBP teaching will empower future healthcare professionals to skillfully navigate the vast media landscape. This empowerment may enable healthcare professionals to assist patients in making informed decisions about their health through shared decision-making. Consequently, this approach can result in improved health outcomes, enhanced quality of life, and better access to suitable and cost-effective treatments,36 making it a valuable contribution to evidence-based healthcare.\n\nOur EBHC course employed a blended learning strategy37 with elements from a flipped classroom approach.38 This approach involved utilizing digital learning resources for pre-class preparation and in-class sessions, which included lectures and collaborative problem-solving activities. We found that students appreciated the extensive digital learning resources available both before and after the lectures. Furthermore, the students expressed their appreciation for the wide range of learning activities incorporated during the lectures, such as quizzes, seminars, and peer assessments. For instance, 73.5% of the students agreed that they had experienced positive learning outcomes from problem-solving seminars with teachers. This finding is consistent with the findings of Bala et al.’s systematic review, which emphasized the importance of interactive and multifaceted approaches in EBP education.5 However, students’ experience with breakout rooms revealed that many students were unprepared, leading to frustration during lecture sessions that involved multiple breakout room activities. This finding aligns with findings in a review that identified the drawbacks of a flipped classroom approach, which highlighted the frequent occurrence of insufficient student preparation before in-class sessions.39\n\nØdegaard et al.40 found, in their systematic review, that various digital learning designs, including blended learning and flipped classrooms, in physiotherapy education demonstrated comparable or superior effects to traditional classroom teaching in terms of knowledge and practical skills acquisition. In addition, Akçayır and Akçayır39 reported that the most common benefit associated with a flipped classroom approach was the enhancement of student learning performance. These findings align with the results of Naing et al.,41 who also concluded that the implementation of flipped classrooms has the potential to improve academic achievement and enhance student satisfaction across various health professional programs. Although our study did not specifically assess students’ learning performance in terms of EBP knowledge, skills, and attitudes, most participants (90.5%) reported a positive perception of the overall learning outcome on the Likert scale in the evaluation survey.\n\nOur findings indicate that implementing the active engagement approach through a blended learning design in the EBHC course contributed to a positive perception of the students’ learning achievements. In previous studies, active engagement has consistently demonstrated positive associations with learning outcomes.5,42 The alignment of our findings with existing research underscores the potential effect of the active engagement approach, as found in blended learning, in promoting favorable learning outcomes for students.\n\nA core element of our EBHC course was the collaborative exam assignment, which was designed to promote critical reflection and student engagement, enhance learning outcomes, and assess students’ grasp of EBP principles. The students recognized group collaboration as vital for promoting critical thinking43 and experienced the benefits of collaborative efforts in critically assessing a health claim and discussing the research evidence. Engaging with peers in the group setting probably encouraged them to challenge assumptions, consider alternative viewpoints, and arrive at well-informed conclusions.44\n\nA substantial 78% of participants acknowledged that engaging in exam groups contributed to increased learning outcomes. The FG interviews additionally underscored the students’ recognition of the benefits of group work in enhancing learning outcomes, emphasizing that discussing and learning in a collaborative group setting was beneficial. The interactive exam group discussions and seminars facilitated a collaborative learning environment, encouraging active participation and the exchange of ideas.45 In the open-ended feedback, an emphasis was placed on the advantages of working in groups during the course. This was attributed to the ability to engage in discussions and gain exposure to diverse viewpoints, fostering a deeper understanding of the assignment. Furthermore, feedback from peers was noted to contribute to enhanced insights. This highlights how collaboration among students likely fostered an environment conducive to questioning, seeking clarity, giving constructive feedback, and cultivating a sense of responsibility for meaningful contributions to their group’s advancement. However, the issue of potential free riders emerged as a concern. This aligns with the findings of Donelan and Kear’s systematic review of challenges in online group projects in higher education, which highlighted key issues, including low and uneven student participation.46 Improving the collaborative learning experience can likely be achieved by implementing strategies to solve the free rider problem, such as logging participation in group work, as suggested in the open-ended response. Other strategies for addressing online group project challenges include clear student guidance and preparation, and ongoing practical and emotional support to boost confidence and engagement.46\n\nThe incorporation of group collaboration in the course aligns with educational theories that emphasize the value of social interaction in learning.47 Collaborative learning models have been shown to promote critical thinking, problem-solving skills, and communication abilities,45,48 all of which are integral to EBP.5 The positive outcomes from the collaborative learning experience within the group exam task in our study confirm its relevance and applicability as a strategic component of EBP education and as a useful method for assessing students’ understanding of EBP principles.\n\nOur study has several limitations. Surveys are susceptible to limitations in representing the sample population, such as potential non-response issues.49 In our study, the response rate was relatively low, as we were able to recruit approximately 30% of the students who were enrolled in the EBHC course. This low response rate introduces the possibility of sampling bias, as the characteristics of the respondents may differ systematically from those of the non-responders.50 Consequently, there is an increased risk that the obtained results may not accurately represent the entire study population.51 However, among the respondents, 80.1% (109/136) provided positive feedback about the course, and 72.0% (98/136) provided constructive suggestions for improvement. These response rates demonstrate a high level of engagement and participation from the individuals surveyed.\n\nParticipants from the various courses were included in the FG interviews, ensuring representation across the board. Nevertheless, the presence of lecturers as both moderators and note-takers during the interviews may have introduced social desirability bias,52 leading participants to provide responses that align with researchers’ expectations. It is noteworthy, however, that the findings derived from the FG interviews were consistent with the anonymous responses obtained through open-ended questions in the evaluation survey. This alignment of results suggested that the responses were not susceptible to the influence of social desirability bias.\n\nThe primary objective of this study was to assess the experiences of health students in the EBHC course, with a specific emphasis on the integration of health claims. However, this study is part of a broader feasibility project.53 Therefore, some findings that are not included in this paper, will contribute to the refinement of the course structure, ultimately facilitating a comprehensive evaluation.\n\n\nConclusion\n\nIncorporating critical reflection on media health claims into EBP education, along with a blended learning approach and a group exam, showed promise as a useful approach for educating bachelor healthcare students in this study. However, further research employing more robust study designs will be necessary to assess the effect of our pedagogical design on learning outcomes.", "appendix": "Data availability\n\nZenodo: Supplements and underlying data for the study: Using Health Claims to Teach Evidence-Based Practice to Healthcare Students: A Mixed Methods Study, https://doi.org/10.5281/zenodo.10532808. 21\n\nThis project contains the following underlying data:\n\n• Quantitative data. 2_All quantitative data_English translation.xlsx\n\n• Qualitative data (open-ended questions). 3_All open questions_English translation.docx\n\n• Qualitative data (FG interviews). 4_All FG interviews_English translation.docx\n\nZenodo: Supplements and underlying data for the study: Using Health Claims to Teach Evidence-Based Practice to Healthcare Students: A Mixed Methods Study, https://doi.org/10.5281/zenodo.10532808. 21\n\nThis project contains the following extended data:\n\n• 1_Supplements_.docx\n\n• STROBE_checklist_BHinEBP.docx\n\n• Consolidated criteria for reporting qualitative studies.docx\n\n• Mixed Methods Approach checklist.docx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nThe authors thank all the students who participated in the study. The authors also thank Matt Oxman and Gro Røkholt for their assistance in conducting the FG interviews. Matt Oxman is a Ph.D. candidate at OsloMet and Gro Røkholt is an associate professor at OsloMet.\n\n\nReferences\n\nLehane E, et al.: Evidence-based practice education for healthcare professions: an expert view. BMJ Evid. Based Med. 2019; 24(3): 103–108. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSackett DL, et al.: Evidence based medicine: what it is and what it isn’t. BMJ. 1996; 312(7023): 71–72. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nDawes M, et al.: Sicily statement on evidence-based practice. BMC Med. Educ. 2005; 5(1): 1. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAlbarqouni L, et al.: Core Competencies in Evidence-Based Practice for Health Professionals: Consensus Statement Based on a Systematic Review and Delphi Survey. JAMA Netw. Open. 2018; 1(2): e180281. 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PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBoutron I, et al.: Three randomized controlled trials evaluating the impact of “spin” in health news stories reporting studies of pharmacologic treatments on patients’/caregivers’ interpretation of treatment benefit. BMC Med. 2019; 17(1): 105. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nvan Bekkum JE , Hilton S: Primary care nurses’ experiences of how the mass media influence frontline healthcare in the UK. BMC Fam. Pract. 2013; 14: 178. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nNsangi A, et al.: Effects of the Informed Health Choices primary school intervention on the ability of children in Uganda to assess the reliability of claims about treatment effects: a cluster-randomised controlled trial. Lancet. 2017; 390(10092): 374–388. PubMed Abstract \| Publisher Full Text\n\nSemakula D, et al.: Effects of the Informed Health Choices podcast on the ability of parents of primary school children in Uganda to assess claims about treatment effects: a randomised controlled trial. Lancet. 2017; 390(10092): 389–398. PubMed Abstract \| Publisher Full Text\n\nOxman AD, Chalmers I, Dahlgren A: Key Concepts for assessing claims about treatment effects and making well-informed treatment choices (Version 2022) IHC Working Paper.2022.\n\nCreswell JW, Creswell JD: Research design: Qualitative, Quantitative & Mixed Methods Approaches. 5th ed.SAGE Publications; 2018.\n\nGuetterman TC, Fetters MD, Creswell JW: Integrating Quantitative and Qualitative Results in Health Science Mixed Methods Research Through Joint Displays. Ann. Fam. Med. 2015; 13(6): 554–561. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nvon Elm E , et al.: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. PLoS Med. 2007; 4(10): e296. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nTong A, Sainsbury P, Craig J: Consolidated criteria for reporting qualitative research (COREQ): a 32-item checklist for interviews and focus groups. Int. J. Qual. Health Care. 2007; 19(6): 349–357. PubMed Abstract \| Publisher Full Text\n\nHong QN, et al.: Mixed methods appraisal tool (MMAT), version 2018. Registration of copyright. 2018; 1148552(10).\n\nWorld Medical Association: World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. JAMA. 2013; 310(20): 2191–2194. Publisher Full Text\n\nElvsaas I-KO, et al.: Supplements and underlying data for the study: Using Health Claims to Teach Evidence-Based Practice to Healthcare Students: A Mixed Methods Study. Zenodo. 2024.\n\nIBM Corp: IBM SPSS Statistics for Windows. Armonk, NY: IBM Corp; 2020.\n\nMalterud K: Systematic text condensation: A strategy for qualitative analysis. Scand. J. Public Health. 2012; 40(8): 795–805. Publisher Full Text\n\nRosenbaum S: Improving the user experience of evidence: a design approach to evidence-informed health care.Oslo: Oslo School of Architecture and Design; 2010.\n\nDodgson JE: Reflexivity in Qualitative Research. J. Hum. Lact. 2019; 35(2): 220–222. Publisher Full Text\n\nGraneheim UH, Lundman B: Qualitative content analysis in nursing research: concepts, procedures and measures to achieve trustworthiness. Nurse Educ. Today. 2004; 24(2): 105–112. PubMed Abstract \| Publisher Full Text\n\nOxman AD, García LM: Comparison of the Informed Health Choices Key Concepts Framework to other frameworks relevant to teaching and learning how to think critically about health claims and choices: a systematic review. F1000Res. 2020; 9: 164–164. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nChinn D: Critical health literacy: a review and critical analysis. Soc. Sci. Med. 2011; 73(1): 60–67. Publisher Full Text\n\nSuarez-Lledo V, Alvarez-Galvez J: Prevalence of Health Misinformation on Social Media: Systematic Review. J. Med. Internet Res. 2021; 23(1): e17187. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLancet T: Taking shared decision making more seriously. Lancet. 2011; 377(9768): 784. PubMed Abstract \| Publisher Full Text\n\nHoffmann TC, Montori VM, Del Mar C: The Connection Between Evidence-Based Medicine and Shared Decision Making. JAMA. 2014; 312(13): 1295–1296. Publisher Full Text\n\nAustvoll-Dahlgren A, et al.: The Norwegian public’s ability to assess treatment claims: results of a cross-sectional study of critical health literacy [version 2; peer review: 1 approved, 1 approved with reservations]. F1000Res. 2021; 9(179). Publisher Full Text\n\nOxman A, et al.: Understanding of key concepts relevant to assessing claims about treatment effects: a survey of Norwegian adults, in IHC Working Paper.Oslo: 2017.\n\nNsangi A, et al.: Effects of the Informed Health Choices primary school intervention on the ability of children in Uganda to assess the reliability of claims about treatment effects, 1-year follow-up: a cluster-randomised trial. Trials. 2020; 21(1): 27. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nElvsaas I-KO, et al.: Development and Evaluation of a Serious Game Application to Engage University Students in Critical Thinking About Health Claims: Mixed Methods Study. JMIR Form. Res. 2023; 7: e44831. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nVahdat S, et al.: Patient involvement in health care decision making: a review. Iran Red. Crescent Med. J. 2014; 16(1): e12454. PubMed Abstract \| Publisher Full Text\n\nBoelens R, et al.: Blended learning in adult education: towards a definition of blended learning.2015.\n\nAbeysekera L, Dawson P: Motivation and cognitive load in the flipped classroom: definition, rationale and a call for research. High. Educ. Res. Dev. 2015; 34(1): 1–14. Publisher Full Text\n\nAkçayır G, Akçayır M: The flipped classroom: A review of its advantages and challenges. Comput. Educ. 2018; 126: 334–345. Publisher Full Text\n\nØdegaard NB, et al.: Digital learning designs in physiotherapy education: a systematic review and meta-analysis. BMC Med. Educ. 2021; 21(1): 48. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nNaing C, et al.: The effects of flipped classrooms to improve learning outcomes in undergraduate health professional education: A systematic review. Campbell Syst. Rev. 2023; 19(3): e1339. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPrince M: Does Active Learning Work? A Review of the Research. J. Eng. Educ. 2004; 93(3): 223–231. Publisher Full Text\n\nLai ER: Critical thinking: A literature review. Pearson’s Research Reports. 2011; 6(1): 40–41.\n\nGokhale AA: Collaborative learning enhances critical thinking.(fall 1995), 1995; 7(1).\n\nLaal M, Laal M: Collaborative learning: what is it? Procedia. Soc. Behav. Sci. 2012; 31: 491–495. Publisher Full Text\n\nDonelan H, Kear K: Online group projects in higher education: persistent challenges and implications for practice. J. Comput. High. Educ. 2023; 1–34. Publisher Full Text\n\nOkita SY: Social Interactions and Learning, in Encyclopedia of the Sciences of Learning. Seel NM, editor. Boston, MA: Springer US; 2012; pp. 3104–3107.\n\nVoogt J, Roblin NP: A comparative analysis of international frameworks for 21st century competences: Implications for national curriculum policies. J. Curric. Stud. 2012; 44(3): 299–321. Publisher Full Text\n\nCouper MP: Issues of Representation in eHealth Research (with a Focus on Web Surveys). Am. J. Prev. Med. 2007; 32(5, Supplement): S83–S89. PubMed Abstract \| Publisher Full Text\n\nTurk A, Heneghan C, Nunan D: Non-response bias. Catalogue of Bias Collaboration; 2019.\n\nPartin MR, et al.: The impact of survey nonresponse bias on conclusions drawn from a mammography intervention trial. J. Clin. Epidemiol. 2003; 56(9): 867–873. PubMed Abstract \| Publisher Full Text\n\nGrimm P: Social desirability bias. Wiley international encyclopedia of marketing; 2010.\n\nElvsaas I, et al.: Ability to assess claims about treatment effects among bachelor students in health sciences: a protocol for feasibility testing a course in Evidence-Based Health Care. Zenodo. 2022." }	[ { "id": "260812", "date": "26 Apr 2024", "name": "Wendy Romney", "expertise": [ "Reviewer Expertise Physical Therapy", "Evidence Based Practice", "Education" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article highlights a novel teaching approach to evidence based practice using media health claims. It uses mixed methods to evaluate the teaching approach from a variety of students who completed the course. It is well written and clear.\nIn terms of citations: consider other EBP research in physiotherapy:\n1. Kaplan S et al, 2016 [Ref 1]\n2.Chen Y et al, 2023 [Ref 2]\nMinor recommendations:\nConsider naming, add “media” health claims in the title and define it by providing an example right away.\n\nProvide a “behind the headlines” example so it is clear what health claims means. The reader is left to guess what this could mean until they click on a link. I thought about insurance claims. A worked example would also provide the reader with the ability to reproduce the course. Please also describe the course. 3 weeks, how many hours? Was the course split between blending learning and flipped classroom? A general outline would be helpful.\nIs it possible to compare the sample that consented to the sex of students in each of the classes? Also compare the sizes of the program in general to the response rate? For example, of the 446 eligible, what % were from each program? Was the response rate comparable across program types?\n\nTable 1. Please provide all 5 of the IHC Key Concepts that were used versus just 3.\n\nThe reader is left to click on the link to find the 49 key concept.\nUnder data collection: please describe 'the learning outcomes were further explored through eight questions'- what are these eight questions? Suggestion summarizing eight questions as ‘other learning strategies used’ or refer to table 3.\n\nMethods: Is it possible to see if there were any differences in quantitative data between program type? Separate courses were conducted for each program and focus groups were conducted by program type, yet the quantitative analysis isn’t separated. Even though the shell was the same, some course instructors may have been different in delivery and could explain some of the findings. Or not, but then the discussion could include information on that as support for the flipped classroom style.\nPlease write out IHC the first time and describe the IHC key concept framework for those who are not familiar with it. It appears to just be published. How were 5 key concepts were selected from the 49? Are the 5 key concepts the lower rows on table 1? Details of this are needed. Please update citation on the IHC key concepts: https://f1000research.com/articles/11-890\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "12390", "date": "17 Sep 2024", "name": "Ida-Kristin Orjasaeter Elvsaas", "role": "Author Response", "response": "Dear Dr. Romney, We are grateful for your insightful feedback on our article regarding students' experiences with our EBHC course. We have thoroughly considered your suggestions and addressed your comments in the subsequent responses. We sincerely apologize for the delay in our response and greatly appreciate your patience. We hope that you will find the modifications we have made to the article and the explanations provided below satisfactory. Reviewers comment: In terms of citations: consider other EBP research in physiotherapy: 1. Kaplan S et al, 2016 [Ref 1] 2.Chen Y et al, 2023 [Ref 2] Response: We appreciate your input on the literature. However, we find that these references may not be entirely relevant to our study, which encompasses healthcare students more broadly. In the revised version, we have introduced multiple clarifications about our learning design, hoping to shed more light on the structure of our EBHC course. Elaboration: In our enthusiasm to disseminate the students' experiences with our course, we may have inadvertently overlooked the inclusion of sufficient detail about the specific Norwegian context within which EBP is taught. In Norway, we have spent considerable time developing an approach to EBP education based on the Norwegian adaption of the CASP model (detailed (in Norwegian) in: Tuntland H, Nordheim L. Teaching and learning in evidence-based practice. Presentation of the CASP-model, Ergoterapauten. 2009;9), which has been adopted by most Norwegian institutions teaching EBP. Our unique contribution to this learning design involves the consistent integration of health claims, the encouragement of active student learning through a blended learning approach, and the application of a group exam to assess the course's learning outcomes. Our main objective was to explore students' experiences with these added components. We hope that our revisions provide a more detailed understanding of our study. Despite being set in a Norwegian context, we believe this study may capture the interest of those looking to integrate similar elements into their own EBP context. Reviewers comment: Consider naming, add “media” health claims in the title and define it by providing an example right away. Provide a “behind the headlines” example so it is clear what health claims means. The reader is left to guess what this could mean until they click on a link. I thought about insurance claims. A worked example would also provide the reader with the ability to reproduce the course. Please also describe the course. 3 weeks, how many hours? Was the course split between blending learning and flipped classroom? A general outline would be helpful. Response: We have updated the title to include the term \"media health claims\" and have emphasized that this study focuses on students' experiences with our course. We have also added generic examples of health claims in the Background section and real examples from exam assignments in the section about the exam paper. Our initial plan was to employ a flipped classroom approach. However, the course implementation leaned towards a broader blended learning approach, which included elements from the flipped classroom approach. We have added a general course description to the article, while details (the course's general timetable) can be found in the extended data file. Reviewers comment: Is it possible to compare the sample that consented to the sex of students in each of the classes? Also compare the sizes of the program in general to the response rate? For example, of the 446 eligible, what % were from each program? Was the response rate comparable across program types? Response: During the revision process, an error was identified in the count of eligible participants for the EBHC course. The corrected total of participants is 465, including 70 eligible bioengineering students, 159 eligible physiotherapy students, 161 eligible social education students, and 75 eligible occupational therapy students. Consequently, the overall response rate, following the correction of the total number of eligible students, is 29.2%. The response rate, relative to the number of students in each study program, was as follows: bioengineering (48.6%), physiotherapy (27.7%), social education (19.9%), and occupational therapy (34.7%). There could be several factors influencing a student's decision to respond to our voluntary evaluation questions. Still, the differences in response rates between the study programs are not deemed relevant to our overall aim with the study. The quantitative portion serves as one of three sources for gaining insights about the general experiences of healthcare students with our course. This point has been emphasized by extending the Limitations section of the article. Reviewers comment: Table 1. Please provide all 5 of the IHC Key Concepts that were used versus just 3. The reader is left to click on the link to find the 49 key concept. Response: A new table that better captures the five key concepts taught in \"Behind the Headlines\" is included in the revised article. Reviewers comment: Under data collection: please describe 'the learning outcomes were further explored through eight questions'- what are these eight questions? Suggestion summarizing eight questions as ‘other learning strategies used’ or refer to table 3. Response: We have restructured this sentence to enhance its readability and comprehension. Reviewers comment: Methods: Is it possible to see if there were any differences in quantitative data between program type? Separate courses were conducted for each program and focus groups were conducted by program type, yet the quantitative analysis isn’t separated. Even though the shell was the same, some course instructors may have been different in delivery and could explain some of the findings. Or not, but then the discussion could include information on that as support for the flipped classroom style. Response: The quantitative and qualitative data were independently collected for each study program. However, all datasets were collectively analyzed across disciplines during the analysis phase, separate and in a joint display. Our approach was informed by our primary objective of gathering experiences from students across various healthcare disciplines, rather than investigating the differences between these fields. While the quotations drawn from the qualitative datasets are presented with their associated study specializations, this method was implemented primarily due to its customary application in qualitative research. We endeavored to select quotes from diverse fields of study, underscoring the universality of these perceptions across all disciplines. However, to prevent an emphasis on study specializations, we have now omitted the students' study affiliation associated with their quotes in the revised article. Furthermore, the article has been updated with a new section to describe the learning activity structure, which was comparable across disciplines. Reviewers comment: Please write out IHC the first time and describe the IHC key concept framework for those who are not familiar with it. It appears to just be published. How were 5 key concepts were selected from the 49? Are the 5 key concepts the lower rows on table 1? Details of this are needed. Please update citation on the IHC key concepts: https://f1000research.com/articles/11-890 Response: The present study is partly part of a broader \"Behind the Headlines\" project at OsloMet, which commenced in 2018. During the initial stages of this project, lectures at OsloMet, external researchers, and students collaborated to identify IHC Key Concepts deemed essential for assessing health claims, resulting in the inclusion of five concepts. This initial phase of the project is detailed in Oxman M, Habib L, Jamtvedt G, Kalsnes B, Molin M. Using claims in the media to teach essential concepts for evidence-based healthcare. BMJ Evidence-Based Medicine. 2021;26(5):234-6. We have updated our article with a brief description of the original “Behind the Headlines” learning design, which was implemented in a condensed form in our EBHC course. Additionally, the five key concepts included in the EBHC course are those presented in the lower rows of Table 1. However, in the revised version of the article, we have provided an alternative overview of the key concepts used. The citation is also updated. Once again, we would like to express our gratitude for your insightful comments and valuable suggestions, which have greatly contributed to enhancing the quality of our article." } ] }, { "id": "285772", "date": "04 Jul 2024", "name": "Conor Gilligan", "expertise": [ "Reviewer Expertise Medical Education", "Public Health", "Social Sciences", "Healthcare Communication" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper is well written and clear. The limitation of the evaluation to very low-level outcomes (student perceptions) needs to be acknowledged.\nThe paper is set up (though title and abstract) as focussing on the health claims aspect but in fact the evaluation and results focus more on the course as a whole including the groupwork approaches and learning management system. The authors could focus the presented results and discussion more on the health claims aspect to make the paper more concise and aligned with their research question.\nPlease also consider:\nThe demographics of participants is provided but to what extent are participants representative of those enrolled in the course?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "12391", "date": "17 Sep 2024", "name": "Ida-Kristin Orjasaeter Elvsaas", "role": "Author Response", "response": "Dear Dr. Gilligan, We appreciate the insightful feedback on our article about students' experiences with our EBHC course. We have carefully considered your feedback and addressed your comments in the responses that follow. We hope that the revisions and clarifications will meet your expectations. Reviewers feedback: The limitation of the evaluation to very low-level outcomes (student perceptions) needs to be acknowledged. Response: We have revised the title, abstract, and main body of the article to reflect that this study reports student experiences with our course and that no causal inference can be drawn based on our findings. Reviewers feedback: The paper is set up (though title and abstract) as focussing on the health claims aspect but in fact the evaluation and results focus more on the course as a whole including the groupwork approaches and learning management system. The authors could focus the presented results and discussion more on the health claims aspect to make the paper more concise and aligned with their research question. Response: We recognize that our article is comprehensive and could have potentially been condensed. However, media health claims are intricately incorporated throughout the course. We regret our inability to explicitly state that health claims formed a crucial part of our learning design. The article has been revised to indicate that this study evaluated the full EBHC course, wherein health claims were consistently used to achieve learning outcomes through both the learning activities and the group exam assignment. Reviewers feedback: Please also consider: The demographics of participants is provided but to what extent are participants representative of those enrolled in the course? Response: Most of the study participants were women, constituting 79.4% of the sample. The included sample broadly mirrors the overall gender distribution of students enrolled in the EBHC course, with women constituting about 78% of the enrolled student body. The Limitations section of the article has been updated with this information. Once again, we would like to express our gratitude for your constructive feedback and valuable suggestions, which have helped to improve the quality of our article." } ] } ]	1	https://f1000research.com/articles/13-224
https://f1000research.com/articles/13-1511/v1	09 Dec 24	{ "type": "Research Article", "title": "Out-of-Pocket Expenditure (OOPE) on Selected Surgeries in the Obstetrics and Gynaecology Department incurred by Ayushman Bharat Pradhan Mantri Jan Arogya Yojana (AB-PMJAY), Private Health Insurance and Uninsured Patients in a Tertiary Care Teaching Hospital in Karnataka state of India.", "authors": [ "Sagarika Kamath", "Siddhartha Sankar Acharya", "Helmut Brand", "Prajwal Salins", "Reena Verma", "Dr. Kumar Sumit", "Dr. Vidya Prabhu", "rajesh kamath", "Sagarika Kamath", "Siddhartha Sankar Acharya", "Helmut Brand", "Prajwal Salins", "Reena Verma", "Dr. Kumar Sumit" ], "abstract": "Introduction OOPE for healthcare services is a major concern within the Indian healthcare system. 30% of the population remains uninsured despite increasing health insurance coverage. For obstetrics and gynaecology (OBG) patients financial obstacles like OOPE can delay access to health care, evaluating spending patterns can inform policies to enhance accessibility, affordability and equitable health.\n\nMethodology A retrospective study was conducted at a tertiary care teaching hospital in Karnataka state of India to analyze OOPE for 905 OBG patients who underwent Cesarean Section(C-Section), Laparoscopic Hysterectomy, Laparoscopic Cystectomy, Laparoscopic Myomectomy and Laparoscopic Assisted Vaginal Hysterectomy (LAVH). These were the top five most performed obstetrics and gynecology surgeries in the tertiary care teaching hospital between January 2023 and July 2023. Data was collected across AB-PMJAY, private health insurance, uninsured patients and analyzed using descriptive statistics (mean, median) and the Shapiro-Wilk test for data normality.\n\nResults The study analyzed OOPE across 905 OBG patients. Findings show AB-PMJAY provided full coverage with zero OOPE for all surgeries. Though private health insurance reduced OOPE compared to uninsured patients under private health insurance still faced significant financial burden. Variations existed in minimum and maximum OOPE and percentage of OOPE across different private insurances. All the uninsured patients incurred 100% OOPE, with a median OOPE of Rs. 33,257 (405.67 USD) to Rs. 57,053 (695.76 USD) and a mean OOPE of Rs. 39,848 (485.95 USD) to Rs. 60,687 (740 USD) across the surgeries.\n\nDiscussion Findings of the study show that AB-PMJAY is highly effective in reducing OOPE and enhancing financial risk protection for OBG patients. Patients covered by private health insurance incurred less OOPE, yet the burden remained considerable. High OOPE rates for uninsured patients (100%) and private health insurance (38.15%) compared to 0% OOPE in AB-PMJAY emphasizes the need for the continued expansion of AB-PMJAY.", "keywords": [ "Out-of Pocket Expenditure", "AB-PMJAY", "Ayushman Bharat", "Health Insurance", "Maternal Mortality Rate", "Maternal Health", "Obstetrics and Gynaecology", "Universal Health Coverage" ], "content": "Introduction\n\nOut-of-pocket expenditure (OOPE) associated with healthcare services have become a significant global concern, including in India. The healthcare sector in India has experienced a significant rise in private-sector participation in recent years. According to National Sample Survey Organization (NSSO) in the fiscal year 2017-18, it was found that private healthcare facilities constituted 55.3% of total hospitalizations.1\n\nThe private healthcare sector in India exhibits high OOPE, which leads to a diminished level of financial protection for patients. Although there has been a decrease in the proportion of OOPE in relation to total healthcare expenditure (THE), from 62.6% (Rs. 3,02,520 crore or 39.08 Billion USD) in 2014-15 to 47.1% (Rs. 2,80,923 crore or 34.25 Billion USD) in 2019-20, the burden of OOPE still remains significant.1 In Karnataka, THE for the fiscal year 2019-20 amounted to Rs. 35,761crores (4.36 Billion USD) and OOPE accounted for 31.8%, which is equivalent to Rs. 11,368 crores (1.38 Billion USD).2\n\nThe aggregate size of the health insurance market, as measured by the total premium collected, experienced a significant increase from Rs. 44,873 crores (5.47 Billion USD) in the fiscal year 2018-19 to Rs. 73,052 crores (8.90 Billion USD) in the fiscal year 2021-22.3 The Private Health Insurance market has experienced significant growth in terms of premium collection, increasing from Rs. 10,655 crore (1.29 Billion USD) in the fiscal year 2018-19 to Rs. 20,107 crore (2.45 Billion USD) in the fiscal year 2021-22.3 Despite the considerable growth, private health insurance continues to offer limited coverage, reaching only 9% of the total population.4 70% of the Indian population is estimated to be covered under public and private health insurance as shown in Table 1.4,5,6,7 30% of the population (40 crores or 0.4 Billion) does not have any type of health insurance coverage.8\n\nAB-PMJAY was launched in 2018 by the government of India as a direct response to the demand for comprehensive healthcare services serving the vulnerable population of the country. AB-PMJAY is a government-funded healthcare program aimed at providing health insurance coverage to more than 50 crore (500 Million) individuals across India. It is recognized as one of the largest healthcare initiatives of its kind. As of March 19, 2023, e.g. the state of Karnataka has generated more than 1.36 crore or 13.6 Million AB-PMJAY cards. A total of 35,88,000 or 3.58 Million beneficiaries have availed free healthcare services at an expenditure of Rs.2,982 crore.9 One of the vital aspects of AB-PMJAY is the provision of free maternity care, aligning with the objectives of the National Health Policy (NHP) 2017. The primary objective of this policy is to reduce India’s maternal mortality rate (MMR) to below 100 per 100,000 live births by 2020. India has achieved this objective by reducing the MMR to 97 per 100,000 live births in 2020.10\n\nThe United Nations has established Target 3.1 of the Sustainable Development Goals (SDGs) to address the worldwide emphasis on maternal health. The current aim of the SDGs is to achieve a worldwide decrease in MMR to less than 70 per 100,000 live births by the year 2030. To achieve Target 3.1 of the SDGs, it is important to improve interventions in areas where MMR remains high, ensuring adequate access to high-quality maternal healthcare services throughout India.10 There also exist challenges notably evident in the MMR observed in some specific Indian states. Meghalaya demonstrates a significantly high MMR of 197 Assam following closely at 195, Madhya Pradesh at 173, Uttar Pradesh at 167, Chhattisgarh at 137, Odisha at 119, Bihar at 118.11,12\n\nThe disparities in MMR across different Indian states emphasize the urgent need for focused interventions aimed at mitigating disparities in MMR. The disparity in MMR can be attributed to several factors, such as economic status, education, restricted availability of healthcare services, lack of awareness regarding obstetrics and gynaecology that impact individuals’ healthcare-seeking tendencies.13,14 States and Union Territories that have a significant proportion of institutional deliveries, such as Lakshadweep (100%), Tamil Nadu (99.99%), Puducherry (99.98%), Kerala (99.82%) and Karnataka (99.74%) demonstrate a lower MMR. On the other hand, states such as Meghalaya (57.79%), Bihar (81.27%), Uttar Pradesh (85.63%) and Assam (89.88%), which exhibit lower proportions of institutional deliveries, are associated with elevated levels of MMR.15 The correlation between institutional delivery and MMR highlights the importance of institutional deliveries in mitigating MMR.\n\nLaparoscopic Hysterectomy, Laparoscopic Myomectomy, Laparoscopic Cystectomy and LAVH are minimally invasive surgical procedures widely performed for the management of various gynaecological conditions. Laparoscopic Myomectomy is indicated for the removal of uterine fibroids, benign tumors that can cause symptoms such as abnormal uterine bleeding, pelvic pain and infertility. Laparoscopic Cystectomy is performed to remove ovarian cysts or masses, which can be associated with pelvic pain and irregular menstrual cycles. LAVH and Laparoscopic hysterectomy are treatment options for conditions such as uterine prolapse, menorrhagia, uterine fibroids and endometriosis where the uterus is removed through a combination of laparoscopic and vaginal approaches.\n\nIn the year 2016, the total number of hysterectomy in India was estimated to be approximately 10 million among women aged 30-49 years.16 A study in low-income households in Gujarat, India, found nearly two-thirds of rural women who underwent hysterectomies sought care in private hospitals, resulting in a high OOPE.17 A study in Nigeria found that the absence of an effective health insurance scheme led to an increase in OOPE to Laparsocopic Myomectomy, Laparoscopic Cystectomy and LAVH.18\n\nA positive correlation between possession of health insurance and increased utilization of obstetrics and gynaecology healthcare services has been found.19,20,21 The correlation highlights the importance of health insurance in improving the delivery of obstetrics and gynaecology healthcare services. The increase in women’s enrolment in health insurance is recognized as a critical approach to improving the utilization of obstetrics and gynaecology healthcare services.20,12 Obstetrics and gynaecology patients patients from low-income households and marginalized communities encounter financial hardships as a result of OOPE. A study conducted in two villages near Delhi in north India, found that 43% of women who were married to laborers or unemployed individuals gave birth at home.23 A significant association between the place of childbirth and various economic indicators such as the occupation of the spouse, monthly income and socio-economic status have been confirmed.23\n\nObstetrics and gynaecology patients patients from low-income households face financial obstacles that delay their timely access to healthcare facilities, thereby contributing to unfavourable outcomes and influencing MMR.24,25 Understanding and addressing OOPE is highly significant, as they have a substantial influence on MMR, particularly for obstetrics and gynaecology patients patients from socioeconomically disadvantaged groups. OOPE has the potential to result in financial burden on individuals, leading to impoverishment and hindering timely access to healthcare services. Financial limitations and OOPE may also lead to a change in maternal health behaviours such as compromising on dietary intake or skipping necessary prenatal examinations in order to save money. These behaviours have the potential to contribute to health complications which can result in negative outcomes for the mother and can also potentially contribute to MMR.\n\nWhile AB-PMJAY and private health insurance offer potential remedies, their impact on OOPE incurred for obstetrics and gynaecology patient needs further investigation. This study aims to conduct a focused investigation across that directly compare obstetrics and gynaecology patients patients’ OOPE during Cesarian-Section (C-Section), Laparoscopic Hysterectomy, Laparoscopic Assisted Vaginal Hysterectomy (LAVH), Laparoscopic Myomectomy and Laparoscopic Cystectomy conducted within the Obstetrics and Gynaecology department of a tertiary care teaching hospital in coastal Karnataka, India. C-Section, laparoscopic hysterectomy, laparoscopic cystectomy, laparoscopic myomectomy and LAVH were the top five most performed obstetrics and gynecology surgeries in the tertiary care teaching hospital between January 2023 and July 2023 and scrutinizing spending patterns associated with these five surgeries can provide precise insights for refining policies to enhance the accessibility of obstetrics and gynaecology patients and to mitigate the financial burden.\n\n\nMethods\n\nA retrospective study was conducted over a period of three months starting from December 2023 to February 2024 in a tertiary care teaching hospital in Karnataka state of India. The hospital is a 2000 bedded hospital. Every day, the hospital serves about 200 inpatients and 2,500 outpatients. The hospital is a National Accreditation Board for Hospitals and Healthcare Providers (NABH) accredited hospital. Patients who have had a C-section, Laparoscopic Hysterectomy, Laparoscopic Myomectomy, Laparoscopic Cystectomies and Laparoscopic Assisted Vaginal Hysterectomy (LAVH) were considered for the study. These five surgeries were considered for the study as these five surgeries represented the highest number of obstetrics and gynaecology surgeries in the tertiary care teaching hospital with a total of 783 C-Section cases, 44 cases of Laparoscopic Hysterectomy, 30 cases of Laparoscopic Cystectomy, 18 cases of Laparoscopic Myomectomy, and 30 cases of LAVH between January 2023 and July 2023.\n\nRetrospective single centric study.\n\n\n\n▪ Medical record department\n\n▪ IT department\n\n▪ Finance department\n\n\n\n▪ Patients who have undergone C-Section, Laparoscopic Hysterectomy, Laparoscopic Assisted Vaginal Hysterectomy (LAVH), Laparoscopic Myomectomy and Laparoscopic Cystectomy.\n\n▪ Patients who are covered by AB-PMJAY, private health insurance and uninsured patients.\n\n▪ Surgeries performed between January 2023 to July 2023.\n\n\n\n▪ Patients covered by health insurance other than AB-PMJAY and private health insurance.\n\n▪ Multiple pregnancies\n\n▪ Patients who have undergone other types of surgeries within the same department as well as different departments.\n\n▪ Maternal death\n\nData of 905 maternal patients were considered for this study.\n\nA validated proforma was used. The validated proforma is available in the data repository mentioned in the data availability statement below.\n\nDescriptive statistics such as mean, median and the Shapiro-Wilk test to check the normality of the data were used to analyse and compare the levels of variability in OOPE among different patient category such as AB-PMJAY, private health insurance and uninsured patients.\n\nInstitutional Ethics Committee (IEC) approval was granted from the Kasturba Medical College and Kasturba Hospital Institutional Ethics Committee – 2: DHR registration no. EC/NEW/INST/2021/1707 (IEC2:562/2023) on 19-1-24. The first application was made to the IEC on 12/09/2023. The IEC asked for Modifications (# IEC form: Risk is minimal. # Permission from HOD OBG required. # Inter institute research form to be filled) on 01/11/2023. The first IEC Approval was secured on 21/11/2023. An application for an amendment (addition of co-guide) was made on: 28/12/2023. The 2nd IEC approval date is 19/01/2024. The patient data was made anonymous and treated with strict confidentiality for the study. As the study is a retrospective study and did not involve any new treatments or interventions, informed consent was not applicable. Consent was waived by the ethics committee.\n\n\nResults\n\nThe study included 905 obstetrics and gynaecology patients, who underwent C-Section, Laparoscopic Hysterectomy, Laparoscopic Cystectomy, Laparoscopic Myomectomy and LAVH and uninsured or were covered by AB-PMJAY or private health insurance from January 2023 to July 2023.\n\nTable 2 presents the comprehensive distribution of 905 cases across the five surgeries. The table outlines the specific breakdown, comprising 783 C-Section cases, 44 cases of Laparoscopic Hysterectomy, 30 cases of Laparoscopic Cystectomy, 18 cases of Laparoscopic Myomectomy and 30 cases of Laparoscopic Assisted Vaginal Hysterectomy (LAVH). Figure 1 visually depicts this distribution, presenting the representation of each surgical category within the total of 905 surgeries. The corresponding percentages for each category are as follows: 86.51% for C-Section, 4.86% for Laparoscopic Hysterectomy, 3.31% for Laparoscopic Cystectomy, 1.98% for Laparoscopic Myomectomy and 3.31% for LAVH.\n\nFigure 1: Percentage-wise distribution of surgeries across various categories.38\n\nTable 3 presents the number of cases, median and mean billing amount of the selected surgeries. Under AB-PMJAY, total number of cases of C-Section, Laparoscopic Hysterectomy, Laparoscopic Cystectomy, Laparoscopic Myomectomy and LAVH were 51, 11, 7, 6, and 11 respectively. Under private health insurance, total number of cases of C-Section, Laparoscopic Hysterectomy, Laparoscopic Cystectomy, Laparoscopic Myomectomy and LAVH were 201, 11, 11, 3, and 6 respectively. For uninsured patients, total number of cases of C-Section, Laparoscopic Hysterectomy, Laparoscopic Cystectomy, Laparoscopic Myomectomy and LAVH were 531, 22, 12, 9 and 13 respectively. Under AB-PMJAY, the median billing amount for C-Section, Laparoscopic Hysterectomy, Laparoscopic Cystectomy and LAVH was Rs. 9000 (109.75 USD), Rs. 20,000 (244 USD) and Rs. 11,500 (140.24 USD), while the mean billing amount for Laparoscopic Myomectomy was Rs. 15,000 (183 USD). Under private health insurance, the median billing amount for C-Section was Rs. 50,433 (615 USD). The mean billing amount for Laparoscopic Hysterectomy, Laparoscopic Cystectomy, Laparoscopic Myomectomy and LAVH was Rs. 84,994 (1036.5 USD), Rs. 50,991 (623 USD), Rs. 29,604 (361 USD) and Rs. 58,501(713.42 USD) respectively. For uninsured patients, the median billing amount for C-Section, Laparoscopic Hysterectomy and Laparoscopic Cystectomy was Rs. 33,257 (406 USD), Rs. 57,053 (696 USD) and Rs. 35,891 (438 USD) respectively. The mean billing amount for Laparoscopic Myomectomy and LAVH was Rs. 39,848 (485 USD) and Rs. 53,151 (648.25 USD) respectively. OOPE as average percentage of billing amount was zero for AB-PMJAY across the selected surgeries. For private health insurance it ranged from 15.05% to 38.15% across the selected surgeries. For uninsured patients it was 100% across the selected surgeries. For, AB-PMJAY, median and mean OOPE was zero across the selected surgeries. For private health insurance it ranged from Rs. 5,435 (66.28 USD) to Rs. 35,891(438 USD) across the surgeries. For uninsured patients it ranged from Rs. 33,275 (406 USD) to Rs. 57,053 (696 USD).\n\n* Median billing was considered to measure the central tendency for billing amount where p-value in Shapiro-Wilk test was <0.05, indicating significant deviation from a normal distribution. (e.g. C-Section under AB-PMJAY).\n\n Mean billing was considered where p-value was >0.05, indicating normal distribution (e.g. Laparoscopic Hysterectomy under Private Health Insurance).\n\n* Median OOPE was considered to measure the central tendency for billing amount where p-value in Shapiro-Wilk test was <0.05, indicating significant deviation from a normal distribution. (e.g. C-Section under Private Health Insurance).\n\n**** Mean OOPE was considered where p-value was >0.05, indicating normal distribution (e.g. Laparoscopic Myomectomy under Private Health Insurance).\n\nFigure 2 presents the minimum, maximum and median billing amounts for C-section across AB-PMJAY, private health insurance and uninsured patients. AB-PMJAY billing ranged from a minimum of Rs.9,000 (109.75 USD), to a maximum of Rs.25,000 (305 USD), with a median of Rs.9,000 (109.75 USD),. Private health insurance billing had a larger range, from a minimum of Rs.15,340 (187.07 USD) to a maximum of Rs.4,76,481 (5811 USD), with a median billing of Rs.50433 (615.03 USD). Uninsured patients fell in the middle, with a minimum billing of Rs.2,948 (36 USD), maximum of Rs.3,74,774 (4570.41 USD), and median of Rs.33,257 (406 USD). Here median was used as the main statistic for central tendency since the Shapiro-Wilk test yielded a p-value less than 0.05, indicating significant deviation from a normal distribution.\n\nFigure 2: C-Section Billing: Minimum, Maximum and Median.38\n\nThe findings show that billing amounts can vary among AB-PMJAY, private health insurance, and uninsured patients. AB-PMJAY beneficiaries are typically assigned to general wards, while private health insurance offers a limited selection of beds. The choice of bed type affects the total billing amount, nursing charges, and physician consultation fees. While uninsured patients can choose the bed category as per their requirements.\n\nFigure 3 presents the minimum, maximum, median and mean billing amounts for Laparoscopic Hysterectomy across AB-PMJAY, private health insurance and uninsured patients. AB-PMJAY, ranged from a minimum of Rs. 11,500 (140 USD) to a maximum of Rs.55,000 (671 USD), with a median of Rs.20,000 (244 USD). Private insurance ranged from a minimum of Rs.42,600 (520 USD) to a maximum of Rs.1,50,347 (1833 USD) with a mean of Rs.84,994 (1037 USD). Uninsured patients ranged with a minimum billing of Rs.34,801(424 USD) to a maximum of Rs.1,31,541(1604 USD) and median of Rs.57,053 (696 USD). Here median was used as the main statistic to measure the central tendency of AB-PMJAY and uninsured patients as the Shapiro-Wilk test yielded a p-value less than.005, indicating significantly deviation from a normal distribution. While for private health insurance, mean was used as the data was normally distributed (p>0.05).\n\nFigure 3: Laparoscopic Hysterectomy billing: Minimum, Maximum, Median and Mean.38\n\nFigure 4 presents the minimum, maximum and mean of billing amount for Laparoscopic Myomectomy across AB-PMJAY, private health insurance and uninsured patients. AB-PMJAY had a minimum and maximum billing of Rs. 15,000 (183 USD) with a mean of Rs.15,000 (183 USD). Private insurance ranged from a minimum of Rs.27,500 (335 USD) to a maximum of Rs.32,752 (399 USD) with a mean of Rs.29,804 (363 USD). Uninsured patients ranged with a minimum billing of Rs. 19,806 (241.53 USD) to a maximum of Rs. 59,712 (728 USD) and mean of Rs.39,848 (486 USD). Here mean was used as the main statistic to measure the central tendency as the Shapiro-Wilk test yielded a p-value of more than 0.05, indicating normal distribution.\n\nFigure 4: Laparoscopic Myomectomy billing: Minimum, Maximum and Mean.38\n\nFigure 5 presents the minimum, maximum, median and mean of billing amounts for Laparoscopic Cystectomy across AB-PMJAY, private health insurance and uninsured patients. AB-PMJAY had a minimum of Rs. 10,000 (122 USD) and a maximum billing of Rs. 15,000 (183 USD) with a median of Rs.15,000 (183 USD). Private health insurance ranged from a minimum of Rs.23,150 (282 USD) to a maximum of Rs.90,624 (1105 USD) with a mean of Rs.50,991 (623 USD). Uninsured patients ranged with a minimum billing of Rs. 28,612 (349 USD) to a maximum of Rs. 92,635 (1130 USD) and median of Rs.35,891(438 USD). Here median was used as the main statistic to measure the central tendency of AB-PMJAY and uninsured patients as the Shapiro-Wilk test yielded a p-value less than 0.05, indicating significant deviation from a normal distribution. Mean was used as the main statistic to measure the central tendency of private health insurance, as the Shapiro-Wilk test yielded a p-value of more than.005, indicating, normal distribution.\n\nFigure 5: Laparoscopic Cystectomy billing: Minimum, Maximum, Median and Mean.38\n\nFigure 6 presents the minimum, maximum, median and mean of billing amount for LAVH across AB-PMJAY, private health insurance and uninsured patients. AB-PMJAY had a minimum of Rs. 11,500 (140 USD) and a maximum billing of Rs. 20,000 (244 USD) with a median of Rs.11,500 (140 USD). Private health insurance ranged from a minimum of Rs.29,560 (360 USD) to a maximum of Rs.92,318 (1126 USD) with a mean of Rs.58,501 (713.42 USD). Uninsured patients ranged with a minimum billing of Rs. 27,187 (332 USD) to a maximum of Rs. 84,792 (1034 USD) and mean of Rs.53,151 (648 USD). Here mean was used as the main statistic to measure the central tendency of AB-PMJAY and uninsured patients as the Shapiro-Wilk test yielded a p-value of more than .05 for AB-PMJAY and uninsured patients, indicating a normal distribution. While median was used as the main statistic to measure the central tendency of private health insurance, as the Shapiro-Wilk test yielded a p-value less than.05, indicating significant deviation from a normal distribution.\n\nFigure 6: LAVH billing: Minimum, Maximum, Median and Mean.38\n\nTable 4 presents variation in OOPE for C-section across AB-PMJAY, private health insurance and uninsured patients. All the 51 patients covered under AB-PMJAY had zero OOPE, as the scheme provided full coverage. Uninsured patients were most common with 531 cases, uninsured patients had 100% OOPE. The median OOPE for uninsured patients was Rs. 33,257. For patients under private health insurance, OOPE ranged widely depending on the insurance provider. Private health insurance had total 201 cases with a lower 38.15% average OOPE and median OOPE of ₹17,426 (212.51 USD) compared to uninsured patients. Star Health and Allied Insurance Co Ltd, Sampoorna Suraksha, Bajaj Allianz General Insurance Co. Ltd and Care Health Insurance Company Ltd had a average OOPE 68.35 %, 67.88 %, 58.47 % and 50.98 % respectively. While in Future Generali India Insurance Co Ltd, HDFC, GoDigit General Insurance Limited and Safeway TPA Pvt Ltd the average OOPE were 1.44 %, 7.15 %, 7.67 % and 8.53 % respectively. The mean OOPE in Bajaj Allianz General Insurance Co. Ltd, Manipal Foundation and Medicare were Rs. 1,16,559 (1421.45 USD), Rs. 54,651 (666.47 USD) and Rs. 50,695 (618.23 USD) respectively. The median OOPE in Medicare Patient, V Vidal Health TPA Pvt Ltd and Raksha Health Insurance TPA Pvt Ltd and Medi Assist India TPA Private Ltd were Rs. 32,377 (395 USD), Rs. 9678 (118 USD) and Rs. 9510 (116 USD) respectively.\n\n* Median and Mean OOPE in INR\n\n Median OOPE was considered to measure the central tendency when p-value was <0.05 in Shapiro-Wilk test, indicating significant deviation from a normal distribution. (e.g. Uninsured patients, ICICI Lombard).\n\n* Mean OOPE was considered when p-value was >0.05 in Shapiro-Wilk test, indicating normal distribution (e.g. Bajaj Allianz, Care Health Insurance).\n\nFigure 7 presents the variation in the minimum and maximum OOPE across different private health insurances for C-section. The OOPE range was widest for Bajaj Allianz (Rs. 29,690 [362 USD] - Rs. 2,03,428 [2481 USD]) and Medicare (Rs. 20,835 [254 USD] - Rs. 1,30,575 [1592 USD]). ICICI Lombard (Rs. 4,227[51.54 USD] - Rs. 37,175 [453.35 USD]), Paramount Health (Rs. 3,384 [41.26 USD] - Rs. 36,724 [448 USD]) and STAR Health (Rs. 6,908[84.24 USD] - Rs. 61,495[750 USD]) had more moderate range. Narrower OOPE ranges were seen for insurances Care Health (Rs. 2,629[32 USD] - Rs. 8,081[98.54 USD]) and East West Assist (Rs. 6,371[78 USD] - Rs. 6,396[78 USD]). Medi Assist India TPA Private Ltd was the only private health insurance that provided four patients out of 70 patients with zero OOPE.\n\nFigure 7: C-Section Billing: Minimum and Maximum OOPE.38 Minimum and maximum OOPE in INR.\n\nFigure 8 presents the variation in percentage of patients with zero OOPE for C-section across patient category. 100% of AB-PMJAY beneficiaries had zero OOPE. However, only 2% of private insurance patients had zero OOPE. While none of the uninsured patients had zero OOPE.\n\nFigure 8: Percentage of C-Section patients with zero OOPE across patient category.38\n\nTable 5 presents the variation in OOPE for laparoscopic hysterectomy across patient category: AB-PMJAY, private health insurance and uninsured patients. All the 11 patients under AB-PMJAY had zero OOPE. While all the 22 uninsured patients had 100% OOPE with median OOPE of Rs.57,053 (696 USD). For private health insurance patients, average percentage of OOPE varied across insurances, with patients paying 2.09-53.5 % on average. Sampoorna Suraksha and Star Health and Allied Insurance had the highest average percentage of OOPE of 53.5 % and 19.98% and also they had the highest mean OOPE of Rs. 36,605 (446.4 USD) and Rs. 23,709 (289.13 USD). Health Insurance TPA of India Ltd and Medi Assist India TPA Private Ltd had the lowest average percentage of OOPE of 2.09% and 4.91% and also they had lowest mean and median OOPE of Rs. 1,539 (19 USD) and Rs. 2,065 (25.18 USD).\n\n Median and Mean OOPE in INR\n\n Median OOPE was considered to measure the central tendency when p-value in Shapiro-Wilk test was <0.05, indicating significant deviation from a normal distribution. (e.g. uninsured patients, Medi Assist India TPA Private Ltd).\n\n* Mean OOPE was considered p-value was >0.05 in Shapiro-Wilk test, indicating normal distribution (e.g. Sampoorna Suraksha, Health Insurance TPA of India Ltd).\n\nFigure 9 present the variation in the minimum and maximum OOPE across private health insurances for laparoscopic hysterectomy. Sampoorna Suraksha had the widest range from Rs. 7,600 (93 USD) to Rs. 60,857 (742.15 USD). Medicare Patient and Star Health, with only one patient each, had OOPE of Rs. 7,615 (93 USD) and Rs. 23,709 (289.13 USD) respectively. Medi Assist India had a range from Rs. 900 (11 USD) to Rs. 19,035 (232.13 USD). While Health Insurance TPA of India had the narrowest range from Rs. 1,457 (18 USD) to Rs. 1,620 (20 USD).\n\nFigure 9: Minimum and Maximum OOPE for Different Private Health Insurances for Laparoscopic Hysterectomy.38\n\nFigure 10 present the variation in percentage of patients with zero OOPE for laparoscopic hysterectomy across patient category. 100% of AB-PMJAY beneficiaries had zero OOPE. While none of the patients under private health insurance and uninsured patients had zero OOPE for laparoscopic hysterectomy.\n\nFigure 10: Percentage of Laparoscopic Hysterectomy patients with zero OOPE across Patient Category.38\n\nTable 6 presents the variation in OOPE for laparoscopic cystectomy across AB-PMJAY, private health insurance and uninsured patients. All the 7 patients under AB-PMJAY had zero OOPE. While all the 12 uninsured patients had 100% OOPE with median OOPE of Rs.35,891 (438 USD). For private insurance patients, average percentage of OOPE and median OOPE were 23.64% and Rs. 8,241 (100.5 USD). Medi Assist and MDIndia had the lowest average percentage of OOPE of 1.43% and 5.79%. Medicare Patient and Sampoorna Suraksha had high average percentage of OOPE of 36.79% and 29.7%. While Sampoorna Suraksha had the lowest median OOPE of Rs.4,880 (59.51 USD), Medicare Patient and Vidal Health TPA PVT LTD had highest mean OOPE of Rs.24,387 (297.4 USD) and Rs.12,850 (157 USD).\n\n* Average Median and Mean OOPE in INR\n\n Median OOPE was considered to measure the central tendency when Shapiro-Wilk test p-value was <0.05, indicating significant deviation from a normal distribution. (e.g. uninsured patients and Sampoorna Suraksha).\n\n* Mean OOPE was considered when p-value was >0.05, indicating normal distribution (e.g. MDIndia Health Insurance TPA Pvt. Ltd and Medicare).\n\nFigure 11 present the variation in the minimum and maximum OOPE across private health insurances for laparoscopic cystectomy. Medicare Patient had the widest range of OOPE, from Rs.8,241(100.5 USD) to Rs.40,533(494.3 USD). Sampoorna Suraksha had the from Rs.3,150(38.41 USD) to Rs.30,639(374 USD). MDIndia Health Insurance TPA Pvt. Ltd,Medicare, Medi Assist and Vidal Health had a maximum and minimum OOPE of Rs.4,392(53.56 USD), Rs.11,119(135.59 USD), Rs.850(10.36 USD) and Rs.12,850(157 USD) as each of them had only one case.\n\nFigure 11: Minimum and Maximum OOPE for Different Private Health Insurances for Laparoscopic Cystectomy.38\n\nFigure 12 present the variation in percentage of patients with zero OOPE for laparoscopic cystectomy across patient category. 100% of AB-PMJAY beneficiaries had zero OOPE. While none of the patients under private health insurance and uninsured patients had zero OOPE for laparoscopic cystectomy.\n\nFigure 12: Percentage of Laparoscopic cystectomy patients with zero OOPE across patient category.38\n\nTable 7 present the variation in OOPE for laparoscopic myomectomy across AB-PMJAY, private health insurance and uninsured patients. All the 6 patients under AB-PMJAY had zero OOPE. While all the 9 uninsured patients had 100% OOPE with mean OOPE of Rs.39,848 (486 USD). For private health insurance, the average percentage of OOPE was 18.58% with mean OOPE of Rs.5,435(66.28 USD). Sampoorna Suraksha and Medi Assist India TPA Private Ltd had average percentage of OOPE of 16.01% and 19.86% and mean OOPE of Rs.5,245(64 USD) and Rs.5,530(67.43 USD).\n\n* Median and Mean OOPE in INR\n\n** Only Mean OOPE was considered to measure the central tendency as p-value was >0.05 in Shapiro-Wilk test, indicating normal distribution.\n\nFigure 13 present the variation in the minimum and maximum OOPE across private health insurances for laparoscopic myomectomy. Private health insurances ranged from Rs.3,560 (43.41 USD)-Rs.7,500 (91.46 USD) for Sampoorna Suraksha and for Medi Assist India TPA Private Ltd the minimum and maximum OOPE was Rs.5,245(64 USD) as there was only one case of laparoscopic myomectomy.\n\nFigure 13: Variation in average OOPE across different patient category in Laparoscopic Myomectomy.38\n\nFigure 14 present the variation in percentage of patients with zero OOPE for laparoscopic myomectomy across patient category. 100% of AB-PMJAY beneficiaries had zero OOPE. While none of the patients under private health insurance and uninsured patients had zero OOPE for laparoscopic myomectomy.\n\nFigure 14: Percentage of Laparoscopic Myomectomy patients with zero OOPE across patient category.38\n\nTable 8 present the variation in OOPE across AB-PMJAY, private health insurance and uninsured patients. All the 11 patients under AB-PMJAY had zero OOPE. While all the 13 uninsured patients had 100% OOPE with mean OOPE of Rs.53,151(648.18 USD). For private health insurance, the average percentage of OOPE was 15.05% with mean OOPE of Rs.7,230(88.17 USD). Under private health insurances, Sampoorna Suraksha had the highest average percentage of OOPE of 21.6% while Paramount Health Services Insurance TPA Pvt Ltd and Medi Assist India TPA Private Ltd had the lowest average OOPE of 4.39% and 10.28% and mean OOPE of Rs.3,758 (46 USD) and Rs.9,492 (116 USD).\n\n* Median and Mean OOPE in INR\n\n** Only Mean OOPE was considered to measure the central tendency as p-value was >0.05 in Shapiro-Wilk test, indicating normal distribution.\n\nFigure 15 present the variation in the minimum and maximum OOPE across private health insurances for LAVH. Sampoorna Suraksha ranged from Rs.4,560 (56 USD) minimum up to Rs.1,21,000 (1476 USD) maximum. While Paramount Health Services Insurance TPA Pvt Ltd, Medi Assist India TPA Private Ltd and Star Health and Allied Insurance Co Ltd had the minimum and maximum OOPE of Rs.3,758 (46 USD), Rs.4560 (56 USD) and Rs.9,492 (116 USD) as there were only one case of LAVH for each of the insurances.\n\nFigure 15: Minimum and Maximum OOPE for Different Private Health Insurances for LAVH.38\n\nFigure 16 present the variation in percentage of patients with zero OOPE for LAVH across patient category. 100% of AB-PMJAY beneficiaries had zero OOPE. While none of the private health insurance patients and uninsured patients had zero OOPE for LAVH.\n\nFigure 16: Percentage of LAVH patients with zero OOPE by patient category.38\n\nFigure 17 presents the average OOPE in C-Section, Laparoscopic Hysterectomy, Laparoscopic Cystectomy, Laparoscopic Myomectomy and LAVH across AB-PMJAY, Private Health Insurance and uninsured patients. Patients covered under AB-PMJAY incurred zero OOPE for C-Section, Laparoscopic Hysterectomy, Laparoscopic Cystectomy, Laparoscopic Myomectomy and LAVH. Patients under private health insurance had an average OOPE of Rs.27,222 (332 USD), Rs.15,298 (187 USD), Rs.11,852 (144.53 USD), Rs.5,435 (66.28 USD) and Rs.7,229 (88.15 USD) for C-Section, Laparoscopic Hysterectomy, Laparoscopic Cystectomy, Laparoscopic Myomectomy and LAVH. For C-Section, Laparoscopic Hysterectomy, Laparoscopic Cystectomy, Laparoscopic Myomectomy and LAVH patients uninsured patients had higher financial burden, with average OOPE of Rs.44,545 (543.23 USD), Rs.60,687 (740 USD), Rs.40,236 (491 USD), Rs.39,848 (486 USD) and Rs.53,151 (648.18 USD).\n\nFigure 17: Average OOPE for selected surgeries across patient category.38\n\nFigure 18 present the median OOPE in C-Section, Laparoscopic Hysterectomy, Laparoscopic Cystectomy, Laparoscopic Myomectomy and LAVH across AB-PMJAY, Private Health Insurance and uninsured patients. Patients covered under AB-PMJAY had zero OOPE for C-Section, Laparoscopic Hysterectomy, Laparoscopic Cystectomy, Laparoscopic Myomectomy and LAVH. Patients under private health insurance had median OOPE of Rs.17,426 (212.51 USD), Rs.7,600 (93 USD), Rs.8,241(10.04 USD), Rs.5,245(64 USD) and Rs.6,733(82.1 USD) for C-Section, Laparoscopic Hysterectomy, Laparoscopic Cystectomy, Laparoscopic Myomectomy and LAVH. For C-Section, Laparoscopic Hysterectomy, Laparoscopic Cystectomy, Laparoscopic Myomectomy and LAVH patients who were uninsured had higher financial burden, with median OOPE of Rs.33,257 (406 USD), Rs.57,053 (696 USD), Rs.35,891 (438 USD), Rs.37,456 (457 USD) and Rs.49,687 (606 USD)\n\nFigure 18: Median OOPE for selected surgeries across patient category.38\n\n\nDiscussion\n\nThere is little existing peer reviewed literature on OOPE among obstetrics and gynaecology patients. The current study offers valuable insights into the OOPE incurred by obstetrics and gynaecology patients undergoing various surgical procedures (C-section, laparoscopic hysterectomy, laparoscopic cystectomy, laparoscopic myomectomy and LAVH) across AB-PMJAY, private health insurance and uninsured patients. C-Section, laparoscopic hysterectomy, laparoscopic cystectomy, laparoscopic myomectomy and LAVH were the top five most performed obstetrics and gynecology surgeries in the tertiary care teaching hospital between January 2023 and July 2023 with a total of 783 C-Section cases, 44 cases of Laparoscopic Hysterectomy, 30 cases of Laparoscopic Cystectomy, 18 cases of Laparoscopic Myomectomy and 30 cases of LAVH.\n\nThe study demonstrates the effectiveness of AB-PMJAY in reducing OOPE and enhancing financial risk protection for obstetrics and gynaecology patients. 100% of AB-PMJAY beneficiaries incurred zero OOPE across all analyzed surgical procedures. While private health insurance lowered OOPE compared to uninsured patients, patients still faced substantial OOPE burdens. This indicates that private insurance may not adequately cover the complete costs of these surgical procedures for obstetrics and gynaecology patients like government-sponsored health insurance schemes.26,27\n\nFor obstetrics and gynaecology patients OOPE remains a critical barrier to timely and quality healthcare, particularly for disadvantaged socioeconomic groups.28,29 By alleviating OOPE burdens, AB-PMJAY facilitates access to affordable and accessible obstetrics and gynaecology surgeries for such populations. This has the potential to mitigate maternal mortality rates associated with financial constraints preventing access to obstetric care.30,31\n\nAs shown in Table 2, the analysis revealed that the average and median OOPE under AB-PMJAY was zero across all analyzed surgeries. Conversely, uninsured patients had substantial median OOPE, ranging from Rs. 33,257 (406 USD) for C-section to Rs. 57,053 (696 USD) for laparoscopic cystectomy. Such high OOPE can potentially lead to financial strain and adverse health outcomes.32,33 The variation in OOPE across different private health insurance plans suggests differences in bed categories, individualized benefit plans and co-payments. Median OOPE under private insurance was also significant, varying from Rs. 5,245 (64 USD) for laparoscopic myomectomy to Rs. 17,426 (212.5 USD) for C-section. These findings align with previous observations concerning private insurance coverage limitations.34\n\nHigh OOPE presents a significant barrier to achieving universal health coverage and equitable access to quality healthcare services.35 Expanding government-funded insurance initiatives like AB-PMJAY is critical to mitigating inequities in obstetrics and gynaecology healthcare utilization and OOPE reduction.23,36,37 Such efforts can alleviate financial barriers and promote greater participation in the healthcare system.\n\nThe study’s sample size restricted to a single tertiary care teaching hospital limits the generalizability of findings. Future research with larger, diverse samples could provide deeper insights into variations in OOPE based on geographical location, healthcare infrastructure and population demographics.\n\n\nEthical approval and consent\n\nThe study was conducted following the approval of the ethics committee of the study setting. As the study is retrospective in nature, patient consent was not required. No identifiable images or data of individuals were used in the study.\n\n\nEthical consideration\n\nInstitutional Ethics Committee (IEC) approval was granted from the Kasturba Medical College and Kasturba Hospital Institutional Ethics Committee – 2: DHR registration no. EC/NEW/INST/2021/1707 (IEC2:562/2023) on 19-1-24. The patient data was made anonymous and treated with strict confidentiality for the study. As the study is a retrospective study and did not involve any new treatments or interventions, informed consent was not applicable. Consent was waived by the ethics committee.", "appendix": "Data availability statement\n\nFigshare: Out-of-Pocket Expenditure (OOPE) on Selected Surgeries in the Obstetrics and Gynaecology Department incurred by Ayushman Bharat Pradhan Mantri Jan Arogya Yojana (AB-PMJAY), Private Health Insurance and Uninsured Patients in a Tertiary Care Teaching Hospital in Karnataka state of India. https://doi.org/10.6084/m9.figshare.27080365.v3.\n\nThe project contains the following underlying data:\n\n• OOPE_OBG.xlsx (All the billing amounts for patients under the AB-PMJAY scheme, uninsured patients, and those covered by private health insurance are anonymized. No personal identifying information is included in the dataset). and Proforma.pdf (All patient billing details for AB-PMJAY, private health insurance and uninsured patients were collected via this validated proforma).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nFihsare: Out-of-Pocket Expenditure (OOPE) on Selected Surgeries in the Obstetrics and Gynaecology Department incurred by Ayushman Bharat Pradhan Mantri Jan Arogya Yojana (AB-PMJAY), Private Health Insurance and Uninsured Patients in a Tertiary Care Teaching Hospital in Karnataka state of India. https://doi.org/10.6084/m9.figshare.27080365.v3.\n\nThe project contains the following data:\n\n• Proforma.pdf\n\nData is licensed under CC BY 4.0.\n\n\nReferences\n\nPress Information Bureau: The share of Out-of-Pocket expenditure in total health expenditure has reduced from 62.6% to 47.1%.25 APR 2023. Reference Source\n\nMinistry of Health and Family Welfare: NHA Estimates 2019-2020.25 APR 2023. Reference Source\n\nInsurance Regulatory and Development Authority of India (IRDAI): Annual Report 2021-22.8 APR 2022. Reference Source\n\nInsurance Regulatory and Development Authority of India: Annual report 2017-2018 [09 JAN 2019]. Reference Source\n\nNational Health Authority: PMJAY states at a glance.Reference Source\n\nEmployees’ State Insurance Corporation: Annual report 2018-2019.[31 MAR. 2019]. Reference Source\n\nMinistry of Health and Family Welfare: CGHS dashboard.2021. Reference Source\n\nSarwal R, Kumar A: Health Insurance for India’s Missing Middle.2021 Oct 27. Publisher Full Text\n\nPress Information Bureau: Ayushman Bharat: Providing Holistic Healthcare in Karnataka (State Series).20 MAR 2023. Reference Source\n\nPress Information Bureau: Significant Decline in Maternal Mortality in India.14 Dec 2022. Reference Source\n\nSample Registration System (SRS): Special Bulletin On Maternal Mortality In India 2018-20.28 Nov 2022. Reference Source\n\nGovernment of Meghalaya: The Meghalaya Health Policy 2021.2021. Reference Source\n\nHamal M, Dieleman M, De Brouwere V, et al.: Social determinants of maternal health: a scoping review of factors influencing maternal mortality and maternal health service use in India. Public Health Rev. 2020; 41(1): 13. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPaul P, Chouhan P: Socio-demographic factors influencing utilization of maternal health care services in India. Clinical Epidemiology and Global Health. 2020 Sep; 8(3): 666–670. Publisher Full Text\n\nMinistry of Health and Family Welfare (MoHFW): Health and Family Welfare Statistics in India 2019-20.Reference Source\n\nShekhar C, Paswan B, Singh A: Prevalence, sociodemographic determinants and self-reported reasons for hysterectomy in India. Reprod. Health. 2019; 16: 118. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nDesai S, Sinha T, Mahal A: Prevalence of hysterectomy among rural and urban women with and without health insurance in Gujarat, India. Reprod. Health Matters. 2011; 19(37): 42–51. PubMed Abstract \| Publisher Full Text\n\nOnoh RC, Ezeonu PO, Lawani LO, et al.: Experiences and challenges of gynecological endoscopy in a low-resource setting, Southeast Nigeria. Trop. J. Obstet. Gynaecol. 2018; 35: 30–37. Publisher Full Text\n\nComfort AB, Peterson LA, Hatt LE: Effect of health insurance on the use and provision of maternal health services and maternal and neonatal health outcomes: a systematic review. J. Health Popul. Nutr. 2013; 31(4 Suppl 2): S81–S105.\n\nSanogo NA, Yaya S: Wealth Status, Health Insurance, and Maternal Health Care Utilization in Africa: Evidence from Gabon. Biomed. Res. Int. 2020; 2020: 4036812–4036830. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nRashad AS, Sharaf MF, Mansour EI: Does public health insurance increase maternal health care utilization in Egypt? Frankfurt School - Working Paper Series. 2016. No. 223.Reference Source\n\nYaya S, Da F, Wang R, et al.: Maternal healthcare insurance ownership and service utilisation in Ghana: Analysis of Ghana Demographic and Health Survey. PLoS ONE. 2019; 14(4): e0214841. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSahoo J, Singh SV, Gupta VK, et al.: Do socio-demographic factors still predict the choice of place of delivery: A cross-sectional study in rural North India. J Epidemiol Glob Health. 2015; 5(4 Suppl 1): S27–S34. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nOlonade O, Olawande TI, Alabi OJ, et al.: Maternal Mortality and Maternal Health Care in Nigeria: Implications for Socio-Economic Development. Open Access Maced. J. Med. Sci. 2019 Mar 15; 7(5): 849–855. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMiteniece E, Pavlova M, Shengelia L, et al.: Barriers to accessing adequate maternal care in Georgia: a qualitative study. BMC Health Serv. Res. 2018; 18: 631. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSood N, et al.: Government health insurance for people below poverty line in India: quasi-experimental evaluation of insurance and health outcomes. BMJ (Clinical research ed.). 11 Sep. 2014; 349: g5114. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nNandi S, Schneider H, Dixit P: Hospital utilization and out-of-pocket expenditure in public and private sectors under the universal government health insurance scheme in Chhattisgarh State, India: Lessons for universal health coverage. PLOS ONE. 2017 Nov; 12(11): e0187904. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMohanty SK, Srivastava A: Out-of-pocket expenditure on institutional delivery in India. Health Policy Plan. 2013 May; 28(3): 247–262. Publisher Full Text\n\nBonu S: Incidence and correlates of catastrophic out-of-pocket health expenditures in India: evidence from the national sample survey. BMJ. 2009.\n\nOwusu PA, Sarkodie SA, Pedersen PA: Relationship between mortality and health care expenditure: Sustainable assessment of health care system. PLoS ONE. 2021 Feb; 16(2): e0247413. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKumar S: Reducing maternal mortality in India: Policy, equity and quality issues. Indian J. Public Health. 2010; 54: 57–64. PubMed Abstract \| Publisher Full Text\n\nBhojani U, Thriveni BS, Devadasan R, et al.: Out-of-pocket healthcare payments on chronic conditions impoverish urban poor in Bangalore, India. BMC Public Health. 2012 Dec; 12(1): 1–4. Publisher Full Text\n\nGhosh S: Catastrophic payments and impoverishment due to out-of-pocket health spending in India. Econ. Polit. Wkly. 2014.\n\nWu R, Runguo, et al.: The effects of private health insurance on universal health coverage objectives in China: A systematic literature review. Int. J. Environ. Res. Public Health. 2020 Mar 19; 17(6): 2049. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nManthan A: Roadmap for Universal Health Coverage in India. ABDM.Gov.in. 2022 [cited 2024 Jan 24].\n\nLimwattananon S, Tangcharoensathien V, Tisayaticom K, et al.: Why has the Universal Coverage Scheme in Thailand achieved a pro-poor public subsidy for health care?. BMC Public Health. 2012; 12. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPowell-Jackson T, Hanson K: Financial incentives for maternal health: Impact of a national program in Nepal. J. Health Econ. 2012; 31: 271–284. PubMed Abstract \| Publisher Full Text\n\nDr. Kamath S , Dr. Sankar Acharya S , Brand H, et al.: Out-of-Pocket Expenditure (OOPE) on Selected Surgeries in the Obstetrics and Gynaecology Department incurred by Ayushman Bharat Pradhan Mantri Jan Arogya Yojana (AB-PMJAY), Private Health Insurance and Uninsured Patients in a Tertiary Care Teaching Hospital in Karnataka state of India. figshare. Journal contribution. 2024. Publisher Full Text" }	[ { "id": "348062", "date": "24 Dec 2024", "name": "Neha Ahire", "expertise": [ "Reviewer Expertise Health Insurance", "Universal Health Coverage" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nWork presentation and Literature review Timely and Relevant Topic: The study addresses an extremely pertinent issue in the Indian healthcare system—Out-of-Pocket Expenditure (OOPE). Given that a significant portion of the Indian population remains uninsured or underinsured, this issue directly impacts access to healthcare services. The study is timely, especially in light of the increasing adoption of schemes like AB-PMJAY, which aims to provide healthcare for the economically disadvantaged.\nFocus on Obstetrics and Gynecology: By focusing on Cesarean Section (C-Section) and other major gynecological surgeries, the study highlights in on a critical area of healthcare, as maternal and reproductive health is a major concern in India.\nMethodology - The methodology is described in sufficient detail to allow replication, including data collection and analysis methods. The use of the Shapiro-Wilk test for normality adds robustness, but supplementary explanations on why certain data distribution assumptions were made would enhance clarity. Analysis : The statistical analyses are generally appropriate, but the results could benefit from a deeper exploration of disparities among private health insurance providers. Data Source Source data is openly available, which supports transparency and reproducibility. The inclusion of anonymized data sets and validated proformas is commendable. The conclusions are well-supported by the presented data and effectively highlight the role of AB-PMJAY in reducing OOPE. However, further discussion of policy implications and potential strategies to enhance the effectiveness of private insurance would enrich the conclusion.\nRecommendations: This study offers significant contributions to understanding OOPE in obstetrics and gynaecology but could benefit from the following minor revisions:\n1. Sample size - The term \"905 maternal patients\" to be replaced by appropriate term. 2. Expand the discussion on the variation in OOPE among different private insurers. Include a justification for the selection of specific surgeries and their broader relevance to maternal healthcare. 3. The study is conducted in a single tertiary care hospital in Karnataka. While this provides in-depth insights into the OOPE experienced by patients in this specific setting, the results may not be generalizable to other parts of India. This should be added as limitation or generalization of the findings to be supported by the latest index.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] }, { "id": "351231", "date": "02 Jan 2025", "name": "Risky Kusuma Hartono", "expertise": [ "Reviewer Expertise Health Economic", "health insurance", "and disesase prevention" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntroduction:\nThere is insufficient emphasis on the importance of selecting specific types of operations to be analyzed or researched. The study does not address the local context in Karnataka, particularly the geographical or socio-economic differences that may influence OOPE (Out-of-Pocket Expenditure). Not yet linking the impact of OOPE with catastrophic conditions that can have an impact on poverty\n\nMethod:\nThere is no clear definition of OOPE in the method and other variables that significant influencing the OOPE incident Analysis using econometric and multivariate approaches will provide a more detailed description of the characteristics of patients who are more susceptible to OOPE.\n\nResults:\nThe graphs should have more in-depth interpretation. Too many graph, maybe some of them can be combined or adjusted There is insufficient emphasis on the social impact, particularly on uninsured patients.\n\nDiscussion:\nThe discussion is overly focused on the data presented without comparing it to previous studies. The discussion merely reiterates the results without analyzing the reasons behind differences in OOPE among groups. It does not address the impact of OOPE on patients. There is no detailed explanation of whether other factors, such as geographical location, educational level, or type of healthcare facility, influenced the results. There is no clear explanation of how these findings can influence policymakers, insurance providers, or hospitals.\n\nConclusion:\nThe study does not provide a conclusion summarizing the research findings. There are no specific recommendations for health insurance companies or hospitals to prevent OOPE in patients in the future.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? No", "responses": [ { "c_id": "13092", "date": "08 Jan 2025", "name": "rajesh kamath", "role": "Author Response", "response": "Introduction: 1. There is insufficient emphasis on the importance of selecting specific types of operations to be analyzed or researched: Response: The selection of surgeries—Cesarean Section (C-Section), Laparoscopic Hysterectomy, Laparoscopic Cystectomy, Laparoscopic Myomectomy, and Laparoscopic Assisted Vaginal Hysterectomy (LAVH)—was based on their high prevalence within the hospital’s obstetrics and gynecology department. These five surgeries were the top five most commonly performed surgeries during the study period. These surgeries were selected as they provide a comprehensive representation of the department’s surgical workload, allowing a focused analysis of OOPE trends among the most commonly encountered obstetrics and gynecology surgeries. And the same was mentioned in the last paragraph of the discussion part “C-Section, laparoscopic hysterectomy, laparoscopic cystectomy, laparoscopic myomectomy and LAVH were the top five most performed obstetrics and gynecology surgeries in the tertiary care teaching hospital between January 2023 and July 2023 and scrutinizing spending patterns associated with these five surgeries can provide precise insights for refining policies to enhance the accessibility of obstetrics and gynaecology patientsand to mitigate the financial burden.” 2. The study does not address the local context in Karnataka, particularly the geographical or socio-economic differences that may influence OOPE (Out-of-Pocket Expenditure). Response:The study primarily aimed to analyze OOPE patterns for five most common obstetrics and gynecology surgeries within the framework of a tertiary care teaching hospital in Karnataka. While the local context is implicitly addressed through the study setting, which serves as a referral center for a diverse population spanning rural and urban regions of Karnataka, the study did not specifically delve into variations based on socio-economic or geographical factors. By focusing on the hospital's patient population, the study aimed to offer insights that are actionable for policymakers, while laying the groundwork for future research to examine regional variations in OOPE more comprehensively. 3.Not yet linking the impact of OOPE with catastrophic conditions that can have an impact on poverty Response: We have made changes and addressed this in the second last paragraph of the introduction part. The revision explains how high OOPE can lead to catastrophic health expenditure, forcing households into poverty, and the role of government schemes like AB-PMJAY in alleviating this impact. Method: 1.There is no clear definition of OOPE in the method and other variables that significant influencing the OOPE incident Response: We have addressed the definition of Out-of-Pocket Expenditure (OOPE) in the Statistical Method section of the Method part of the study. 2.Econometric and multivariate analysis Response: The study was designed as a retrospective descriptive analysis using descriptive statistics such as means, medians, and the Shapiro-Wilk test for normality. While econometric and multivariate approaches could provide additional insights, they were beyond the scope of this study, given the available retrospective data and objectives. Nevertheless, the descriptive approach provided sufficient detail to highlight stark disparities in OOPE, such as the zero OOPE for AB-PMJAY beneficiaries compared to the median ₹33,257 ($406) incurred by uninsured patients for C-Sections. Results: 1. The graphs should have more in-depth interpretation. Response: Graphs were used to visually present data trends across surgeries and patient categories, providing readers with a clear understanding of OOPE variations. For example, Figure 18 demonstrates the median OOPE for uninsured patients across surgeries, which ranged from ₹33,257 ($406) for C-Sections to ₹57,053 ($696) for Laparoscopic Hysterectomies. The accompanying text explains these trends, highlighting the effectiveness of AB-PMJAY and the burden on uninsured patients. Expanding interpretations further could lead to redundancy, as the key observations are already summarized in the discussion section. 2.Too many graph, maybe some of them can be combined or adjusted Response: Each graph serves a distinct purpose by illustrating specific aspects of the results, such as OOPE variations by surgery type, patient category, and type of insurance. For example, Figures 3 to 6 detail the minimum, maximum, mean, and median OOPE for different surgeries, while Figure 17 compares the average OOPE across patient categories. Combining these graphs risks oversimplifying the findings, potentially obscuring important details. 3.There is insufficient emphasis on the social impact, particularly on uninsured patients. Response: The social implications of OOPE are indirectly addressed through the analysis of financial burdens across patient categories. For instance, uninsured patients faced significantly higher OOPE, with an average of ₹53,151 ($648.18) for LAVH, compared to ₹7,229 ($88.17) for private health insurance patients. This highlights the inequities in financial risk protection and the need for expanded insurance coverage. While the primary focus was on quantifying OOPE, the findings inherently underscore its social impact. Discussion: 1.The discussion is overly focused on the data presented without comparing it to previous studies. Response: As mentioned in the very first sentence of the discussion, \"There is little existing peer-reviewed literature on OOPE among obstetrics and gynaecology patients.\" This highlights the limited availability of prior research specifically focused on this subject area, making it challenging to provide a direct comparison. The study, therefore, serves as an important contribution to filling this knowledge gap by offering new insights into OOPE incurred by patients undergoing common obstetrics and gynaecology surgical procedures. Future research can build upon this study to facilitate more robust comparative analyses as additional data becomes available. 2.The discussion merely reiterates the results without analyzing the reasons behind differences in OOPE among groups. Response: We have addressed this in the third paragraph of the discussion. We have provided a detailed explanation for the variations in OOPE across the groups. 3.It does not address the impact of OOPE on patients. Response: The discussion does address the impact of OOPE on patients, particularly in terms of how high OOPE can create financial strain, limit access to timely healthcare, and affect health outcomes. For instance, the discussion highlights that uninsured patients faced substantial OOPE, ranging from Rs. 33,257 for a C-section to Rs. 57,053 for laparoscopic cystectomy, which could lead to financial hardship and adverse health outcomes. Additionally, it points out that OOPE remains a critical barrier to accessing quality obstetric and gynecological care, especially for disadvantaged socioeconomic groups, and that reducing OOPE through schemes like AB-PMJAY enhances financial protection, thus facilitating access to necessary surgeries and potentially mitigating maternal mortality. This analysis underscores the importance of reducing OOPE to improve access to healthcare and reduce health disparities among different patient groups. 4.There is no detailed explanation of whether other factors, such as geographical location, educational level, or type of healthcare facility, influenced the results. Response: The study does not delve into factors such as geographical location, educational level, or type of healthcare facility, as it was a retrospective study conducted within a single tertiary care teaching hospital in Karnataka. The study's focus was primarily on comparing OOPE across different insurance schemes (AB-PMJAY, private insurance, and uninsured patients), and the sample was limited to patients within this specific setting. However, acknowledging that these factors could potentially influence OOPE, future studies could explore their role across a more diverse range of healthcare settings and regions to provide a broader understanding of how these variables affect out-of-pocket expenses. 5.There is no clear explanation of how these findings can influence policymakers, insurance providers, or hospitals. Response: In the discussion, the study emphasizes the role of government-funded health insurance initiatives like AB-PMJAY in mitigating OOPE and promoting greater healthcare access, especially for vulnerable population. It also highlights the limitations of private insurance in fully covering the costs of surgeries for obstetrics and gynecology patients. These findings suggest that expanding government insurance schemes and refining private health insurance coverage could reduce OOPE and improve healthcare equity. Moreover, the study advocates for increasing participation in government health schemes to alleviate financial barriers, which can guide policymakers, insurance providers, and hospitals in improving healthcare accessibility and affordability. Conclusion: 1.The study does not provide a conclusion summarizing the research findings. Response: The discussion in the article provides a clear summary of the research findings, particularly in the comparison of OOPE across AB-PMJAY, private health insurance, and uninsured patients. It highlights how AB-PMJAY significantly reduced OOPE, while private health insurance did not fully alleviate the financial burden for patients. This summary of key findings can be considered a conclusion, reflecting the effectiveness of government health insurance and the need for further improvements in private insurance (as discussed in the sentences: \"The study demonstrates the effectiveness of AB-PMJAY in reducing OOPE...\"). 2.There are no specific recommendations for health insurance companies or hospitals to prevent OOPE in patients in the future. Response: While the study does not explicitly offer recommendations, it indirectly suggests areas for improvement in insurance coverage and healthcare policies. For instance, the discussion mentions that expanding government-funded insurance schemes like AB-PMJAY is crucial to mitigating financial barriers for patients, particularly for obstetrics and gynaecology services. Additionally, it points out that private insurance may not sufficiently cover surgical costs, which can serve as a recommendation for policy adjustments to better support patients (\"Expanding government-funded insurance initiatives like AB-PMJAY is critical to mitigating inequities...\")." } ] } ]	1	https://f1000research.com/articles/13-1511
https://f1000research.com/articles/13-1427/v1	26 Nov 24	{ "type": "Research Article", "title": "The Hidden Toll: Investigating the influence of Corruption on Persistent Suicide in the Americas", "authors": [ "Sherin Kularathne", "Ruwan Jayathilaka", "Sherin Kularathne" ], "abstract": "Background Corruption, a multifaceted governance issue, impacts public well-being globally. The recent trends reveal a rise in suicide rates across the Americas, while all other regions show declines over twenty years of time. This study investigates corruption’s effect on suicide in 26 American countries, considering moderating factors of unemployment, inflation, and economic growth.\n\nMethods This study analysed latest two decades of available data, using stepwise panel regression method to investigate the effects of corruption and economic variables on suicide across income levels. Data were sourced from Transparency International, World Bank and the World Health Organization. Initially, unit root tests and CUSUM plots were used to ensure the stability and stationarity of the dataset, and model specification were validated through F test, LM test and Hausman test to select the ideal econometric model - POLS, REM, or FEM for the study.\n\nResults A strong suicide rate persistence revealed, particularly in high-income countries, where the lagged suicide variable showed a coefficient of 0.8063 (p < 0.001). Corruption significantly impacted suicide rates in upper-middle-income countries (coefficient = -0.0268, p < 0.05), with higher corruption perceptions scores correlating with lower suicide rates. Additionally, unemployment acted as a significant moderator, intensifying the corruption’s adverse impact on suicide with a coefficient of 0.0022 (p < 0.001) in upper-middle income nations. Economic growth demonstrated a minor protective effect, particularly in high-income regions, with an interaction coefficient of -0.0005 (p < 0.1), suggesting slight suicide reduction linked to economic stability.\n\nConclusion This study found that corruption, unemployment, and economic growth significantly influence suicide rates across the Americas. Corruption exacerbates suicide risks in upper-middle-income countries, while unemployment amplifies this effect. Economic growth offers a slight protective effect, particularly in high-income regions, suggesting that economic stability may help mitigate suicide rates.", "keywords": [ "Corruption", "Suicide", "Inflation", "Unemployment", "Economic growth", "Americas", "Corruption", "Inflation", "Economic growth", "Latin America", "North America", "South America" ], "content": "Introduction\n\nCorruption is more than a mere failure of governance; it erodes the individual’s mental and emotional well-being, resulting in negative consequences, such as growing suicide rates. Previous research has shown that corruption and inadequate institutions such as weak legal systems, insufficient healthcare, and ineffective social services create despair severe enough to lead to suicide (Glaeser & Saks, 2006; Johnston, 1983; Stockman, 2013). Weak government, characterised by corruption and a lack of transparency, fosters a climate conducive to mental health crises, greatly influencing suicide rates (Desjarlais, 1995; Saad, 2022). These findings reveal a darker, often neglected element of corruption: it not only suppresses economic development but also compromises lives by creating a climate of despondency within the nation.\n\nAny government’s motive is to foster better living conditions and promote sustainable development, yet this ideal is often unmet (Yamamura et al., 2012). Suicide, a complicated worldwide public health issue, differs by gender, age, area, and geopolitical context, and is influenced by a variety of risk factors (Turecki & Brent, 2016). While some studies have revealed that corruption restricts economic growth (Mauro, 1995; Seligson, 2002), others have investigated its relationship with well-being and governance (Fischer & Andres, 2008; Helliwell & Huang, 2008; Ott, 2011). Furthermore, evidence also points to a high link between suicide and subjective well-being (Koivumaa-Honkanen et al., 2004). Similarly, studies conducted in the United States demonstrate common determinants of suicide rates and well-being (Daly & Wilson, 2009). However, despite efforts to improve well-being and governance, the persistent link between socio-political factors, economic inequality, and suicide highlights the need for more targeted and effective government interventions.\n\nWhile the negative impacts of corruption on mental health are obvious worldwide, regional trends in suicide rates suggest specific patterns that require further investigation, particularly in the Americas, where suicide mortality has increased between 2000 and 2019, despite global declines shown in other regions (M Ilic, 2022). The following Figure 1 depicts a visual representation of this finding.\n\nSource: Authors’ compilation based on World Health Organization data (2024).\n\nSuicide, a globally complex issue, is caused by the combination of several elements, including neurobiology, family history, societal settings, and economic pressures (Breault, 1986; Bunney et al., 2002; Quinlan-Davidson et al., 2014; Turecki & Brent, 2016).\n\nCurrent suicide preventative measures seem to be insufficient (especially in the Americas) because they frequently ignore deeper sociopolitical issues such as corruption and instability, which aggravate citizens’ despair. While worldwide efforts emphasise diagnosis and response, yet many related factors are there for investigation and governments, and policymakers must work persistently to improve suicide prevention (Yossi Levi-Belz et al., 2019). Thus, it is apparent that suicide prevention initiatives must go beyond immediate treatments to address the underlying socio-political and economic causes.\n\nThe primary goal of this study is to investigate how corruption, paired with economic factors such as unemployment, inflation, and economic growth, affects suicide rates across different income levels in the Americas. By evaluating these variables together, the study expects to uncover the complex, frequently overlooked relationships that influence mental health outcomes. This study contributes to a more holistic picture of how government failures and economic stressors interact to compound public health challenges, including suicide.\n\nThis study makes numerous essential contributions to the body of current literature and policy-making assistance. First, although earlier studies have investigated the relationship between mental health, macroeconomic variables, and corruption in local, national, global and sub-continent areas, there is a lack of investigation executed for the whole American region. The current study concentrates on the American region. In this critical geographic area, suicide rates have shown a unique upward trend over the past 20 years although worldwide decreases of other regions. There is a lack of recent research in the overall arena, which concentrates exclusively on the Americas. Therefore, this region is underexplored. This study seeks to fill the gap in the literature caused by the inadequate or outdated research that is currently available. Additionally, the study also utilises an income category-wise analysis, which provides a more detailed understanding of how these correlations fluctuate among countries among various economic circumstances.\n\nSecond, this study uses the most recent data from 2000 to 2019 that is available at present, making it one of the few that covers such a lengthy period with the most recent data, allowing for a more comprehensive and up-to-date understanding of long-term patterns and fluctuations explaining corruption’s impact on suicide. Hence, the study offers a new and contemporary viewpoint on the relationship between governance (corruption) and suicide rates in the American region. income category-wise analysis, with a particular focus on income category.\n\nThird, this study stands out in terms of its methodological approach. Few studies in current research, utilise Panel regression techniques that include interaction terms, particularly about moderating economic factors such as inflation, unemployment, and economic growth This study provides novel insights by taking a comprehensive approach to understand how corruption interacts with inflation, unemployment, and economic growth to affect suicide rates. The use of time-series visual analyses of factors incorporated in the study enriches the study by presenting trends and patterns in a clear and understandable manner, allowing for a more accurate data interpretation. These efforts in the s survey enhance the contextual understanding of the results, offering additional layers of insight.\n\nFurthermore, although previous studies have primarily evaluated these variables in isolation or within distinct contexts, this study bridges a gap by studying significant macroeconomic indicators and corruption together within the context of the Americas. The study’s findings have important significance for policymakers since they identify the primary causes contributing to growing suicide rates in the region, providing strategic insights for targeted responses. Understanding the macroeconomic and governance-related factors allows governments to develop more effective policies to combat corruption, while mitigating its devastating impact on suicide, which is a critical public health concern.\n\n\nLiterature review\n\nCorruption is widespread worldwide, and eliminating it is critical for equitable economic growth (Olken & Pande, 2012). Although its negative impact on nations is widely understood, the precise costs to individuals, notably mental health, are understudied. Suicide is a serious global public health hazard, accounting for about 700,000 deaths annually (2024). Addressing both corruption and suicide is crucial for society’s well-being, since they both risk individual mental health and long-term development.\n\nA victim of corruption can have several negative consequences for one’s mental health, including severe depression (Bai et al., 2019). Previous researchers have explained that in low-income nations, harassment bribes- defined as bribes frequently demanded by officials for services or rights to which people are already entitled, are a sort of regressive income tax that is typically a significant portion of one’s income, particularly for poorer households, and are unpredictable and frequent, causing chronic stress in low-income families (Adhvaryu et al., 2018). As a result, such corruption erodes trust in local governance, diminishes social capital, and damages mental health. A leading, study on OECD countries indicated lower suicide rates in nations with less corruption (Yamamura et al., 2012). On the other hand, another study revealed that poor governance causes more stress and despair among citizens, raising the likelihood of suicide (Sharma et al., 2021). This aligns with results that effective governments and strong social trust contribute to life satisfaction (Bjørnskov et al., 2010). Thus, corruption and poor governance not only weaken economic and social institutions but also have severe consequences for mental health, raising the risk of psychological distress and suicide across a wide range of socioeconomic circumstances.\n\nPast literature emphasises the undeniable link between corruption and worsening mental health, including higher suicide rates, particularly among poor communities. Corruption weakens economies, destroys institutional trust, and denies access to essential services, instilling hopelessness. Despite its clear public health implications, current research on corruption’s role in driving suicide, particularly in the Americas, is insufficient. The lack of contemporary, focused studies on this pressing issue reveals a critical gap in comprehending how deeply corruption impacts mental health, indicating an urgent need for further exploration.\n\nUnderstanding mental health and crime rates is made more difficult by macroeconomic issues such as inflation. Although there is conflicting evidence, some argue that decreasing inflation lowers crime, including suicides. For instance, growing food inflation in Turkey disproportionately increased male suicide rates, while rising inflation in the United States is associated with increasing criminality (Şentürk & Erbay, 2022). Though their success depends on political and financial support, welfare programs and minimum wage laws have been suggested as suicide prevention techniques (Stack, 2021; Tuttle, 2018). Increasing salaries has the potential to decrease suicide, but achieving this will be politically challenging (Kaufman et al., 2020).\n\nFurthermore, economic crises, such as the 2008 Great Recession, which experienced high inflation, intensify these psychological consequences, with repossessions and family breakdowns contributing to mental health toll (Agrrawal et al., 2017; Coope et al., 2014; Mucci et al., 2016). The broader socioeconomic implications, such as family breakdowns and lower academic accomplishment for children, compound the mental health concerns (National Council of La Raza, 2009). However, the linear assumption that financial crises cause an increase in suicide rates may oversimplify the issue. While financial stress is clearly a factor, it is essential to evaluate how other factors may influence these outcomes. Simply focussing on financial indicators without addressing underlying socioeconomic inequities risks providing an inadequate picture of the suicide-inflation nexus.\n\nThe literature also contains inconsistent knowledge, with some studies disputing the commonly held idea that inflation constantly raises suicide rates. For example, South African research discovered a negative association, with suicides increasing as inflation dropped, though this relationship became statistically insignificant when province adjustments were applied, particularly among women (Noh, 2009). Adding to the stated findings, similar studies reveal countercyclical suicide trends (Granados, 2008). This contradiction raises serious concerns regarding the universality of the inflation-suicide association. Such findings highlight the need to examine context-specific factors, such as cultural attitudes and thinking patterns of the public towards economic hardship and the availability of government safety nets, rather than assuming equal outcomes across countries.\n\nAlthough there is evidence associating inflation with suicide, this relationship is nuanced and complex to generalise. This demands a more concentrated approach that takes socioeconomic, gender, and regional variables into consideration. Understanding such a relationship and creating remedies that address the psychological as well as the economic aspects of inflation require thorough, context-sensitive studies. Without careful examination, policy recommendations have the potential of being detrimental or ineffectual, depending on the local or national contexts.\n\nUnemployment, especially during economic downturns, is a well-known cause of suicide (Jung et al., 2024; Schapiro & Ahlburg, 1982), And lower unemployment rates often improve mental health and lessen the risk of suicide. This fact underlines how important it is to conduct cross-national replication to assess the validity of the relationships between unemployment and societal outcomes, including suicides (Goulas & Zervoyianni, 2023; McKee-Ryan et al., 2005; Milner et al., 2012; Park et al., 2003; Paul & Moser, 2009; Yang & Lester, 1995). The Great Recession demonstrated this fact since growing unemployment was associated with greater suicide rates, especially in areas where supportive measures such as social programs were missing (Norström & Grönqvist, 2015; Shand et al., 2021). Also, a systematic review found that long-term unemployment increases the risk of suicide while the risk decreases over time, probably due to habituation (Milner et al., 2013).\n\nHowever, contradicting the majority of the past literature, some studies have revealed a negative association between unemployment and suicide in low-income countries (Barth et al., 2011). Unemployment in these regions may not carry the same social stigma or economic challenges, which could explain the lower suicide rates. In contrast, in high-income countries, unemployment tends to increase suicide rates due to increased psychological and societal pressures. This emphasises the significance of income levels in understanding the diverse effects of unemployment on suicide across different socioeconomic circumstances (Noh, 2009). This divergence in findings underscores the importance of considering regional economic structures and cultural contexts when studying the unemployment-suicide relationship.\n\nSuicide is a complicated issue driven by economic, social, and psychological factors, although the link between economic growth and suicide rates is still debated. Early studies revealed that economic downturns increase suicide risk by lowering prospects, whereas economic prosperity lowers these risks (Hamermesh & Soss, 1974). Also, it has found a negative association between GDP growth and suicide rates, supporting this viewpoint (Mattei & Pistoresi, 2019; Zhang et al., 2010). However, the drop in suicide was often only temporary during periods of economic prosperity, implying that economic growth alone may not be a long-term answer to lowering suicide rates. This emphasises the importance of rigorously examining the long-term psychological benefits of economic growth, which may be underestimated in standard economic theory.\n\nMore recent research indicated that GDP alone has poor predictive value for changes in suicide rates, calling into doubt the premise that economic prosperity inevitably improves mental health (Cao, 2024). In fact, it has also discovered a positive relationship between economic growth and suicide rates, particularly during periods of fast expansion, attributing these trends to increased workplace stress and cultural changes, notably among older populations (Fountoulakis et al., 2014; Rajagukguk et al., 2020). These conflicting findings imply that economic expansion might occasionally intensify rather than reduce pressures, challenging the myth that growth is always favourable to mental health.\n\nThe relationship between economic progress and suicide is more nuanced than previous research believed. While expansion may enhance material situations, it can also increase stress, which increases the possibility of suicide. The contradicting findings underscore the need for further research, emphasising the need to include social and mental health factors in economic policies. Focussing primarily on GDP growth risks ignoring significant public health implications, possibly increasing suicide rates. This demonstrates the crucial need for a more comprehensive approach to economic planning.\n\nAn extensive literature search was done in the Google Scholar database to acquire a basic understanding of the evolution and expansion of the related disciplines. Figure 2 illustrates the search results over decades.\n\nSource: Authors’ illustrations based on literature search.\n\nThis bar chart illustrates the distribution of key research publications over time, focussing on the studies included in this analysis. The figure reveals an interesting trend: while research on topics such as unemployment, economic growth, and inflation influencing suicide has risen over the years, studies on the link between corruption and suicide have only recently gained attention. Despite the growing global relevance of both corruption and suicide, these arenas remain unexplored in comparison to other common variables in this study. This study attempted to emphasise more recent key studies, which showed a rising but still limited focus on corruption as a suicide factor, highlighting the need for further research in the domain of corruption’s influence on suicide.\n\nFollowing Figure 3 illustrates the geographical distribution of major literature cited in the study, emphasising the global aspect of suicide risk factor research spanning on to various regions and countries.\n\nSource: Authors’ illustrations based on literature search.\n\nThis map depicts the geographic distribution of relevant literature included in the study, demonstrating that while regions such as Latin America, the Caribbean, and portions of Asia have gotten significant attention, there is a noticeable lack of focus on the broader American region, including North America. Especially, despite the crucial challenges of corruption, and suicide in the American region, research in these areas is still under-explored. The unlabelled icons in this map are country-wise studies. This literature map signals the need for more concentrated research in the American region, where socioeconomic issues and suicide rates are continuously growing. These studies highlight the key literature used in this study, emphasising geographical differences and the need to resolve these gaps in future research.\n\nThe conceptual base for the current study was built based on the literature study and existing knowledge. The independent variables mentioned have revealed a significant impact on suicide rates. Table 1 divides the supporting key literature into four independent variables relevant to the study of suicide: corruption, inflation, unemployment, and economic growth.\n\nWith this conceptual foundation, this study is executed to investigate the impact of corruption on suicide corruption, incorporating moderating macroeconomic indicators and their impact on suicide rates across the American region. This framework aims to provide a comprehensive understanding of how various economic and governance qualities influence the rising suicide rates in the Americas and to reveal the underlying dynamics that contribute to mental health crises in the region.\n\n\nMethods\n\nThe variables used in this study, the data sources used to collect data, and the statistical methods used to compute the results are illustrated in Figure 4. It begins with data collection and preparation, followed by stability/stationary testing and the execution of stepwise panel regression models to produce the final results.\n\nSource: Authors’ illustrations.\n\nThe study used secondary data sources that are presented in Table 2. The study used a panel dataset of 26 nations, focusing on the American region, across 20 years, starting from 2000. The latest reported data is the latest data available currently.\n\nThe study utilised stepwise panel regression models as analytical methodology. The analyses were executed for the whole Americas and for the three income level categories that can be primarily noticed within the region - high, upper-middle, and lower-middle income nations. First, the stationarity and the stability of the dataset were tested using the unit root tests: Levi-Lin-Chu (LLC) and Fisher Augmented Dicky Fuller (Fisher ADF), and the CUSUM tests. Ensuring stationarity is critical for maintaining stable relationships between variables throughout time (Kwiatkowski et al., 1992). The CUSUM plots are recommended for minimal projected movement to measure process stability (Saniga et al., 2006). Then, three specification tests were performed to determine the most suitable model: Pooled Ordinary Least Squares (POLS), Random Effect Model (REM), or Fixed Effect Model (FEM). The F test was used to assess the suitable model from POLS and FEM (Yang et al., 2007). The LM (Lagrange Multiplier) test assessed the best model from POLS and REM (Breusch & Pagan, 1980). Finally, the Hausman test was used to determine the applicability of the RE and FE models (Chmelarova, 2006). Furthermore, the analysis was performed with conventional robust error, which eliminated the issue of heteroscedasticity.\n\nNext, to analyse how CORR, with the influence of three selected moderating variables affects SUI with a focus on the American region, below Equation 1 was developed.\n\nThe SUIit is the suicide rate, with i as income category and t as time. SUI it-1 represents the lagged suicide rate. This variable was introduced to eliminate the stationary issue of the dataset.\n\nCORRit measures corruption levels, whereas (CORR × ΔINFL) it demonstrates the moderating effect of inflation (first-differenced). This ΔINFL was introduced to fix the stability issue of the INFL variable. The terms (CORR × UNEMP) it and (CORR × EG) it denote the moderating effects of unemployment and economic growth, respectively. The coefficients β0, β1, β2, β3, β4, and β5 represent the intercept and slopes of the regression line, which describe the impact of the independent variables on the dependent variable SUIit, and the error term is denoted by εit. Next, the initial stepwise panel regression models were developed to analyse the stepwise effects of SUI it-1, CORR, CORR × ΔINFL, CORR × UNEMP, and CORR × EG on SUI.\n\nUltimately, the final model was refined by stepwise panel regression, with variables added or eliminated based on statistical significance or discrepancies with previous studies. The model was rerun to obtain the final findings. Panel regression provides several advantages, including the capability to account for unobserved heterogeneity, improve statistical efficiency, model dynamic relationships, and accommodate both fixed and random variables, resulting in more robust and flexible findings (Hsiao, 2007). Furthermore, stepwise regression makes model selection easier by automatically finding relevant predictors, lowering the risk of overfitting, and enhancing model interpretability and generalisability, especially in large datasets. Thus, the technique is suitable for developing socioeconomic models.\n\nTo derive the results of the study, panel regressions and stationary tests were carried out using STATA whereas RStudio and DATAtab were utilised, to generate the CUSUM plots and violin plots respectively.\n\n\nResults\n\nThis study contains 520 observations, 160, 280, and 80 across 20 years, which are associated with high-income, upper-middle-income, and lower-middle-income countries in the American region, respectively.\n\nFigure 5 illustrates the descriptive statistics in violin plots for the ease of comparison between different income groups and the Americas, providing a clear visual representation of the distribution of critical variables among different income categories of the Americas. The 5(A) plots show that high-income countries have the greatest mean corruption levels, whereas lower- and middle-income countries have lower mean values with more variability. The SUI variable data distribution is depicted by the 5(B) plots, with high-income countries exhibiting both higher mean suicide rates and more considerable variability than other income categories. The 5(C) plots depict GDP growth, with lower-middle-income countries experiencing a greater variety of growth results. In contrast, upper-middle- and high-income countries demonstrate more consistent economic growth. The UNEMP factor is illustrated by the 5(D) plots, with middle-income countries seeing more significant variability than high-income countries, which maintain lower and more constant unemployment levels. Finally, the 5(E) violin plots depict INFL, the violin plots are shown in two value scales due to high performance in specific categories. The Americas and upper-middle income\" categories have extremely high maximum values due to special conditions faced by upper-middle- income countries (Especially, Venezuela’s hyperinflation). The upper lower-middle income countries have a larger range of inflation readings than the more stable high-income ones.\n\nSource: Authors’ illustrations based on the data from the World Bank (2024), Transparency International (2024), and the World Health Organization (2024).\n\nThese observations are supported by the detailed descriptive statistics which provide more information on the mean, standard deviation, and range for each variable (Available in repository - Appendix 1). Together, the visual and statistical summaries establish the path for a more in-depth examination of the linkages between economic conditions, corruption, and suicides in the subsequent sections of this study.\n\nThe observations of suicide rates across the American region from 20 years apart depicted in Figure 6, reveal considerable regional variations. Suicide rates in countries such as Guyana increased dramatically, from 31.35 in 2000 to 40.28 in 2019, while in Brazil, the rate nearly doubled, from 3.98 to 6.89. Conversely, specific countries, such as Argentina and Venezuela, saw their rates fall from 9.11 to 8.37 and 5.44 to 2.05, respectively. The United States had a significant increase, from 11.03 to 16.14. Overall, it shows a complex pattern of gains and falls, while overall, in many countries ‘suicides have risen (An illustration of suicide in the countries of the Americas during the same period (2000-2019) is available in repository - Appendix 2). Over two decades, Guyana had the highest suicide rates, showing significant growth. Canada, while the second highest, maintained consistent levels. Suriname and Uruguay had high rates with minor volatility. Canada, the U.S., and Argentina showed steady trends, while Venezuela, Jamaica, Honduras, and Panama consistently had low suicide rates.\n\nSource: Authors’ compilation based on the World Health Organization data (2024).\n\nThe analysis of corruption index values from 2000 to 2019 in Figure 7 depicts the Americas and reveals diverse trends across the American area. As key observations, Argentina improved from 35 to 45, indicating a decrease in corruption, whereas Brazil fell from 39 to 35. Canada and the United States both showed reductions, with Canada dropping from 92 to 77 and the United States from 78 to 69, indicating growing corruption. Guyana improved dramatically from 25 to 40, whereas Venezuela’s grade fell from 27 to 16, indicating worsening corruption. Overall, the region presents a mixed picture, with some governments making headway in tackling corruption and others falling back.\n\nSource: Authors’ compilation based on the Transparency International data (2024).\n\nFurthermore, Venezuela’s corruption score has dropped significantly, indicating that corruption is on the rise. In contrast, countries such as Canada, the United States, Guatemala, Nicaragua, and Barbados have all seen increased corruption in recent years. In contrast, Argentina, Guyana, Ecuador, Costa Rica, and Panama all improved, while Brazil and Barbados demonstrated more variable tendencies. Overall, the data show an increasing burden of corruption across the area, with notable differences between governments that manage corruption well and those that are losing control (An illustration of corruption in the countries of the Americas during the same period (2000-2019) is available inrepository - Appendix 3).\n\nThe following Figure 8 illustrates inflation rates in the Americas between 2000 and 2019. Venezuela encountered an exceptional increase in inflation, rising from 16.29% to 19,906.62%, indicating a period of hyperinflation Argentina similarly experienced a rise in inflation from -0.70% in 2000 to 53.80% in 2019. The fundamental cause of this crisis was the country’s reliance on oil exports, which made the economy sensitive to global oil price fluctuations, known as “Dutch disease.” Additional factors, such as Chavismo’s restrictive state-controlled policies, the growth of black markets, and the authoritarian government under Chávez and Maduro, intensified economic instability and hyperinflation (Wang, 2022). Other countries, including Mexico, Canada, and the United States, kept inflation rates relatively low and consistent during this time. However, the region’s inflationary tendencies are varied, with some nations stabilising and others, such as Argentina and Venezuela, experiencing intense inflationary pressures.\n\nSource: Authors’ compilation based on the World Bank data (2024).\n\nThe examination of unemployment rates from 2000 to 2019 yields varied results, as depicted in Figure 9. Argentina’s unemployment rate fell significantly from 15.00 to 9.84, whilst Brazil’s grew from 10.53 to 12.05. Colombia improved, going from 20.52 to 9.96, while Suriname decreased from 12.74 to 8.03. The United States saw a modest decline from 3.99 to 3.67. In comparison, Guyana’s rate increased marginally, from 11.89 to 13.52. Overall, while some nations made headway in lowering unemployment, others, such as Brazil and Guyana, saw rates rise, reflecting regional labour market patterns.\n\nSource: Authors’ compilation based on the World Bank data (2024).\n\nThe GDP growth comparison maps for the Americas from 2000 to 2019 are depicted in Figure 10, and they indicate unfavourable economic growth patterns in most Americas countries. Brazil’s growth rate dropped significantly, while Venezuela’s decreased dramatically from 3.69% to -27.67%. Argentina and Ecuador also saw near-zero or negative growth rates, indicating experiences of economically troublesome conditions. However, countries like the Dominican Republic, Bolivia, and Guyana performed well, maintaining or improving their growth rates. Overall, the region saw more economic setbacks than growth outcomes.\n\nSource: Authors’ compilation based on the World Bank data (2024).\n\nThese maps and line graphs provide insight into patterns of corruption, suicide rates, and economic indicators such as inflation, unemployment, and GDP growth throughout the Americas from 2000 to 2019. By analysing these trends at the country level, the report identifies significant socioeconomic concerns, setting the foundation for future research and policy interventions.\n\nThe primary analysis of this research is the stepwise panel regression. As the first step, the stationarity and stability of the datasets were tested. This step guarantees that the variables maintain stable associations across time. Table 3 below confirms that the datasets are stationarity, utilizing LLC and Fisher ADF tests.\n\nThe structural stability of the study’s datasets is confirmed through CUSUM plots, as depicted in Figure 11 wherein stability is measured under a 95% significance level.\n\nSource: Authors’ illustrations using RStudio.\n\nThe results of the stationarity and stability tests establish the dataset’s dependability for panel regression analysis, guaranteeing that the variables maintain stable associations across time and that the model is appropriate for the next stage of statistical research.\n\nNext, the selection of the best model fit for panel data analysis across all Americas is presented in Table 4, which includes separate income categories. The F-test shows that the POLS model is ineffective, whereas FEM is preferable. The LM test reveals no significant changes between income levels, indicating that the REM does not outperform POLS. The Hausman Test reveals that FEM is the best fit across all income levels (The stepwise results for each category is available in repository - Appendix 4).\n\nTable 5 shows the results of the final stepwise panel regression models for the Americas and three income categories: high, upper-middle, and lower-middle-income countries (The groundwork of the final stepwise panel regression is available in repository - Appendix 5). In the next step, the base for building the final regression models of the Americas and the different income groups was tested (The fixed and random effect estimates for the final stepwise model is available in repository - Appendix 6). When developing the Americas regression model, the CORR × ΔINFL variable is dropped due to changing coefficient signs across different stepwise models. All income level category regression models successfully included all the chosen variables since they aligned with the coefficient signs in previous literature and were consistent throughout stepwise models. These tests provided necessary information on the applicability and suitability of the various models, allowing to choose the most effective approach for the analysis.\n\nThe results of the final stepwise panel regression suggest that suicide rates persist over time, as evidenced by the lagged variable (SUIit-1), which is highly significant across all income levels, particularly in the whole Americas and the high-income countries. CORR has an insignificant direct influence, except in upper-middle-income nations, where it has a positive and significant coefficient. However, its interactions with economic moderators produce more substantial results. For example, the moderation between corruption and unemployment is positive and significant across all income levels. Yet, it shows the highest significance and impact in only upper-middle-income and lower-middle income nations, implying that corruption combined with increased unemployment rates increases suicide rates in middle-income countries. Economic growth has a minor negative impact across all categories. However, it is only significant in high-income and Americas models, implying that corruption moderated by economic growth may modestly reduce suicide risk.\n\nThe overall R2 levels across all income categories demonstrate a solid fit for the models. For the entire Americas, the overall R2 indicates the model explains that 98.93% of the variation in suicide rates. Similarly, in high-income countries, the R2 states 98.92% reflecting a very close level of explanatory power. Upper-middle-income countries’ overall R2 indicates 98.48% model success, while lower-middle-income countries show a slightly lower but still strong R2 explaining 94.53% of overall explanatory power. These high R2 values indicate that the models effectively capture the relationships between suicide rates and the included variables across all income categories.\n\nThe findings showed the persistent significance of the lagged suicide rate across all income levels, emphasising its importance as a predictor of future suicide rates. Although CORR has low direct importance, its interaction with other economic variables, particularly UNEMP, has significant moderating effects across income levels. The model accounts for over 94% of the difference in suicide rates across all income levels. These findings suggest that, while previous suicide rates remain a powerful predictor, the impact of corruption, particularly its relationship with unemployment, is an essential element to consider when studying suicide rates in the Americas.\n\n\nDiscussion\n\nThe complex interplay between corruption, economic variables, and mental health is visible in the Americas, where the socioeconomic landscape is marked by significant inequality, different levels of governance, and economic instability. The findings, based on a Panel data regression model, show that corruption, combined with financial stresses, have an influence on suicide rates across income categories of the American region.\n\nOne key finding is that suicide rates in the Americas have remained consistent throughout time across all income levels. The lagged suicide rate is a strong predictor, mainly in high-income countries. Once suicides rise, they tend to stay high, reflecting long-term social and economic challenges. In high-income countries, unmet expectations for personal and financial success can lead to ongoing mental health issues and rising suicide rates, even in stable economies (Helliwell & Huang, 2008; HeliKoivumaa-Honkanen et al., 2001). These findings emphasise the need to take proactive actions to address the underlying social and psychological elements that lead to persistent suicide rates.\n\nCorruption plays a crucial role in upper-middle-income countries, where it significantly increases suicide rates. Moreover, when corruption acts as a moderating factor, amplifying the effects of unemployment, inflation, and other economic stressors on mental health. Countries where corruption is widespread often see weakened public services, a lack of trust in institutions, and heightened social inequality, all of which contribute to a sense of hopelessness. As a result, the interaction between corruption and economic stressors intensifies the psychological burden on individuals, leading to higher suicide rates. Previous studies confirm that corruption erodes public trust and worsens economic disparities, disproportionately affecting vulnerable populations (Bjørnskov et al., 2010). This upper-middle income category’s findings stand with the empirical evidence suggesting that corruption worsens economic and social inequality, thereby contributing to emotions of despair and societal dissatisfaction and demonstrating that corruption undermines the effectiveness of public services and disproportionately affects the public (Gupta et al., 2001; Kaufmann et al., 2005). However, in the current study, the impact of corruption is less significant in high-income and lower-middle-income countries. In high-income countries, more robust governance and better social services may buffer the adverse effects of corruption. In contrast, in lower-middle-income countries, more immediate concerns like unemployment appear to take precedence over corruption in driving suicide rates.\n\nUnemployment has a significant role in explaining suicide rates at all economic levels, particularly in lower-middle-income countries. It functions as a moderating variable for corruption, exacerbating its harmful consequences. High unemployment and financial insecurity produce an environment of economic insecurity in low- and middle-income countries. Individuals who are unemployed for an extended period of time may lose hope in their ability to better their situation, which can lead to worsening psychological issues and, in some instances, suicide (Goulas & Zervoyianni, 2023; Skinner et al., 2023). This aligns with the research demonstrating that unemployment is strongly associated with declining mental health, particularly in countries with weak or non-existent social safety nets (Glaeser & Saks, 2006). Furthermore, the interplay between unemployment and corruption may worsen the psychological toll, as economic hardship and systemic governance failures compound one another, creating a vicious cycle of despair.\n\nDespite being statistically insignificant in all the final regression models, inflation is still confirmed to be a crucial variable as there is sufficient literature base to support the finding. Earlier research has shown that it might have a direct or indirect impact on mental health. While many of the studies argue that there is a positive association with inflation’s influence on suicide, the current study reflects more of the minority who suggested that inflation has a negative influence on suicide (Noh, 2009). The current finding suggests that unemployment in some countries may not carry the same social stigma or economic hardships; hence, in some countries and instances, inflation lowers suicide rates The absence of statistical significance in this study implies that inflation may not affect highly on suicide, specifically in the American region but rather a contributing factor when combined with other economic and governance failures.\n\nIn contrast, economic growth serves as a protective factor, lowering the suicide rate, especially in high-income nations. When economic growth is inclusive, it can raise living standards, lessen poverty, and eventually reduce the suicide rate (Sannapureddy et al., 2024). Even so, the moderating effect of economic growth is not simple to understand. Although economic growth lowers suicide rates in all the income categories, the impact seems to be extremely low.\n\nThis suggests that the benefits of economic growth do not necessarily reach the most vulnerable in lower- and upper-middle-income nations. If growth only benefits a small portion of the population, its protective effect is reduced and social inequality potentially worsened (Fischer & Andres, 2008). This highlights the need for inclusive economic policies.\n\nIn conclusion, the regression models show how historical trends, economic conditions, and corruption affect suicide rates in the Americas. Unemployment, inflation, and economic growth all serve as moderating or interacting variables that modify the impact of corruption and other pressures on mental health. While suicide rates continue to be a strong predictor, corruption is especially significant in upper-middle-income countries, increasing socioeconomic inequities and contributing to mental health crises. Unemployment is substantial at all income levels, especially in lower-middle-income countries, where it indicates that economic insecurity and poor governance cause significant psychological distress. While inflation has not been shown to have a substantial impact on suicide, it could play an indirect function in increasing financial instability.\n\nThis study’s findings reveal a complex nexus of corruption, economic issues, and rising suicide rates throughout the Americas. To address these linked concerns, focused policy actions are required, providing a way to minimise corruption and its destructive impact on mental health.\n\nCorruption has a significant impact on suicide rates, particularly in upper-middle-income countries, where the consequences are most severe. According to the current study, corruption damages public trust, reduces institutional performance, and promotes social inequalities, creating a climate of hopelessness and despair. In response, upper-middle-income countries in the American region can execute anti-corruption measures. The adverse effects of corruption on mental health can be minimised by strengthening governance, boosting transparency, and promoting public sector accountability.\n\nUnemployment is another factor that contributes to higher suicide rates across all income categories, particularly middle-income nations (upper and lower). Joblessness, economic insecurity, and insufficient social safety nets, add to increased emotional distress. To tackle this, unemployment support programs should be created. To lessen the psychological burden of unemployment, focused job development strategies, vocational training, and entrepreneurial support should be implemented. Furthermore, strengthening social safety nets, such as unemployment benefits and mental health services, is critical in providing economic and emotional stability to people who are unemployed.\n\nMental health initiatives must be prioritised in communities with high suicide rates, particularly those plagued by corruption and economic instability. It is critical to increase access to community-based mental health services and integrate mental health care into primary health care systems. These services should primarily target vulnerable groups, such as the unemployed and those living in highly corrupt local areas. Such interventions would lessen the psychological impact of economic stress while improving overall mental health outcomes, which can ultimately increase suicides.\n\nAccording to the current study, while economic progress gives some protection against suicide in high-income countries, its benefits do not necessarily extend to vulnerable populations in middle-income nations. Policies for inclusive growth are necessary to guarantee that more significant numbers of people benefit from economic benefits. While middle-income countries must concentrate on providing growth advantages to underprivileged domains, high-income countries should try to ensure that economic prosperity is distributed fairly. It is essential to carry out periodic assessments of the effects of economic expansion on mental health and inequality to prevent the increments of disparities or suicide rates.\n\nEven if there was only marginal and no statistically significant influence between inflation and suicide rates, controlling inflation is still essential to maintaining economic stability. As in the case of Venezuela, hyperinflation exacerbates economic instability and may have a secondary impact on mental health. Controlling the volatility of inflation should be a top priority for policymakers, especially in areas with high levels of inflation. Lowering the chances of suicide and the psychological effects of financial instability are two benefits of stabilising the overall economy.\n\nFinally, to address the interrelated problems of corruption, unstable economies, and mental health across the Americas, cross-national cooperation should be considered crucial. To exchange resources, best practices, and knowledge in economic policy, mental health interventions, and governance, countries should work together. Cooperation among nations can enhance anti-corruption initiatives, foster regional stability, and lead to better mental health outcomes. Cross-border collaborations, especially between neighbouring nations, will guarantee that these issues are addressed thoroughly and sustainably.\n\nMoreover, tackling the intricate associations among corruption, unemployment, economic growth, inflation, and mental health necessitates a multifaceted strategy. Vulnerable populations’ psychological burden can be lessened by implementing targeted anti-corruption measures, increasing unemployment support, encouraging inclusive growth, and improving mental health services. Cross-national collaboration is critical to sustaining these efforts and fostering long-term improvements in public health across the region to fight against the increasing trend of suicide in the American region.\n\n\nConclusion\n\nThis study investigates how corruption, combined with economic factors such as unemployment, inflation, and economic growth, affects suicide rates across different income levels in the Americas. Examining panel data from 26 nations over 20 years, yields the following significant findings.\n\nFirst, the persistence of suicide rates is a significant result at all socioeconomic levels. The lagged suicide variable repeatedly showed an overwhelmingly substantial positive association with current suicide rates, implying that once suicide rates rise in a country, they likely continue to be elevated over time. This emphasises the long-term psychological and social consequences of economic insecurity and societal negativity, mainly in high-income countries with severe societal pressure.\n\nSecond, corruption has been identified as a significant driver of suicide rates in upper-middle-income nations, exacerbating inequality and economic suffering. While corruption did not have a statistically significant impact at all income levels, there was a clear link between corruption and suicide in upper-middle-income countries, consistent with previous research linking poor governance and institutional corruption to adverse mental health outcomes.\n\nThird, unemployment was revealed as a significant moderator at all income levels, with a particularly substantial impact in lower-middle income nations. The combination of high unemployment and corruption produces an environment of economic uncertainty, which contributes to psychological stress and raises suicide rates. This implies that reducing unemployment is crucial in regions with substantial economic vulnerability.\n\nFourth, while inflation did not demonstrate consistent statistical significance in our study, its impact on worsening financial stress, particularly in hyperinflationary regions such as Venezuela, must be considered. Inflation indirectly contributes to economic uncertainty, which, combined with other variables such as corruption, may have a long-term impact on suicide rates.\n\nFinally, the study discovered that when economic development is evenly distributed, suicide rates tend to fall across all income categories. However, in areas with high corruption, the advantages of financial success are less likely to reach poor populations, limiting its protective impact on mental health.\n\nIn conclusion, this study emphasises the significance of a multifaceted approach to suicide prevention in the Americas, addressing not only corruption unemployment and inclusive economic growth Policy measures should prioritise strengthening governance, lowering economic inequities, and improving social safety, to reduce the psychological impact of corruption and financial instability. Future research should focus on these complicated relationships, particularly in low-income nations where the effects of economic factors may differ from those shown in this study. By tackling these crucial socioeconomic causes, authorities can more effectively counteract rising suicide rates and improve mental health outcomes throughout the American region.\n\nThis study, while providing valuable insights into the association between corruption and suicide rates in the Americas, has several limitations. First, the data included in the investigation spans a 20-year period, during which many social and political developments happened. These shifts may have altered the outcomes in ways the panel regression model does not entirely account for. Furthermore, the analysis is based on secondary data from trustworthy sources such as the World Bank and Transparency International, which may contain gaps or inconsistencies in reporting. Another limitation is that the current research only addresses governance and economic factors and, cultural and psychological characteristics, which are known to have a significant impact on suicide rates, outside the scope of this study.\n\n\nEthics and consent\n\nEthics and consent are not required for the performed study.", "appendix": "Data availability statement\n\nFigshare: (The Hidden Toll-Dataset), https://doi.org/10.6084/m9.figshare.27637182 (Kularathne & Jayathilaka, 2024).\n\nThis study contains the following extended data:\n\nFigshare: (Appendix 1), https://doi.org/10.6084/m9.figshare.27637434.v3 (Kularathne & Jayathilaka, 2024a)\n\nFigshare: (Appendix 2), https://doi.org/10.6084/m9.figshare.27637479.v1 (Kularathne & Jayathilaka, 2024b)\n\nFigshare: (Appendix 3), https://doi.org/10.6084/m9.figshare.27637557.v1 (Kularathne & Jayathilaka, 2024c)\n\nFigshare: (Appendix 4), https://doi.org/10.6084/m9.figshare.27637614.v1 (Kularathne & Jayathilaka, 2024d)\n\nFigshare: (Appendix 5), https://doi.org/10.6084/m9.figshare.27637647.v1 (Kularathne & Jayathilaka, 2024e)\n\nFigshare: (Appendix 6), https://doi.org/10.6084/m9.figshare.27637725.v1 (Kularathne & Jayathilaka, 2024f)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAdhvaryu A, Fenske J, Nyshadham A: Early Life Circumstance and Adult Mental Health. 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PubMed Abstract \| Publisher Full Text" }	[ { "id": "344324", "date": "11 Dec 2024", "name": "Eiji Yamamura", "expertise": [ "Reviewer Expertise Empirical economics." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReport on ‘The Hidden Toll: Investigating the influence of Corruption on Persistent Suicide in the Americas\nThe aim of the study is to examine correlation between government corruption and occurrence of suicide in countries in north, central and south America by considering economic condition. As widely known, hyper-inflation occurred in Venezuera. The outcome of inflation in countries in America is valuable to be addressed. However, readers would be confused due to puzzling definition of Corruption. Further, in some parts, interpretation of estimation results is not appropriate or not sufficiently provided. Further, estimation biases seem to occur. Authors should consider suggestions to improve the current version of manuscript.\n\nMajor issues: 1.\n\nCorruption index might lead readers to misunderstand estimation results because the definition is opposed to intuition. According to Table 2, \"Corruption Perception Index (0-100)\" was defined by Transparency International. Ordinary saying, larger the value, the more corrupted the government is. However, in the text, to take an example of interpretation for corruption index,\n\"As key observations, Argentina improved from 35 to 45, indicating a decrease in corruption,\"(p.11). This shows that smaller value of “corruption” is more corrupted. This is opposed to reader’s intuition. Probably, authors follow the definition of the data source. However, I strongly request to modify the definition to be suitable to reader’s intuition. Instead of it, in Table 2, authors explained that the definition is changed from that of “Transparency International” for convenience of reader’s interpretation.\n2.\n\nBy definition of variable, values of COR, SUI, and UNEMP must not be negative. I am not familiar with Violin plots in Figure 5. However, sharded area of these values covered negative area. What does it mean? Authors just mechanically illustrated the Figure 5, but was not informative unless authors carefully and appropriately explain importance of Violin plots. Figure 5 of current version is very curious and might lead readers to be confused. In my view, it is enough to just show mean value and 95% CI in Figure.\n\n3.\n\nIn results Fixed effects model in Table 5, estimation results of constant are shown. Basically, different from OLS, constant is not calculated in Fixed effects model because constant is completely captured by unobservable time invariant factors (Fixed effects). What does constant mean in Table 5?\n\n4.\n\nIn Table 5, Lagged dependent variable is included as independent variable. In this model, the dynamic panel model is preferred, where Arellano-bond is the basic model although various types of dynamic model have been developed. Especially, time points is relatively long (20 years) and so the dynamic model is appropriated. Most of independent variables seems to be endogenous, that should be mitigated. Fortunately, the Dynamic model mechanically enables authors to deal with the issue of endogenous bias.\n\n5.\n\nIn conclusion, influence of lagged suicide variables is shown as below, “The lagged suicide variable repeatedly showed an overwhelmingly substantial positive association with current suicide rates, implying that once suicide rates rise in a country, they likely continue to be elevated over time.” (p.20).\nTheir argument is too strong to be supported by the estimation results. In Fixed effects estimation results of Table 5, coefficient of lagged suicide variable is smaller than 1, despite being statistical significant positive sign. Suicide rate will converge among countries in the long run if the value is smaller than 1. That is, their argument is supported only if the value is statistically positive and larger than 1. Authors hardly interpret values of coefficients, which lead to misinterpretation.\n\n6.\n\nIn table 5, coefficient of CORR is not interpreted as effect of corruption because there are interaction terms between CORR and other variables. Authors should additionally report results including INFL, UNEMP, and EG, but excluding interaction term.\n7.\n\nAuthors only interpret statistical significance of independent variables in Table 5. Authors should more carefully value of coefficients to indicate degree of impact of variables (see also Comment 5).\n8.\n\nAuthor’s interpretation about results of Table 5 is ambiguous, and not so informative for readers. For instance, “corruption combined with increased unemployment rates increases suicide rates in middle-income countries.”\n\nThis is interpretation about “CORR×UNEMP” showing 0.0022 (coef) with 1 % level (*). Actually, authors interpretation above is meaningless. Indicate more clearly and meaningfully interpretation and implication of results. I request authors to show,\nIn the definition of CORR in the paper, large value of CORR show less corrupted government. Hence, in my interpretation, positive value of “CORR×UNEMP” means that less corrupted government reduces the negative effect of unemployment on citizen’s mental health, and so suicide rate. Is it true? To argue as above, negative sign of “UNEMP” should be shown However, actually, authors did not indicate results of “UNEMP” in this estimation. So, authors should indicate not only interaction terms but also independent “UNEMP”. Further, how do authors interpret 0.0022 by considering scale of CRR and Unemployment?\nApart from it, authors should interpret estimation results in more detail.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? No", "responses": [ { "c_id": "13140", "date": "28 Jan 2025", "name": "Ruwan Jayathilaka", "role": "Author Response", "response": "Authors Response to Reviewer 1 Dear Reviewer 1, We greatly appreciate the time invested in reading our manuscript and providing the necessary feedback to improve the overall quality of our work. All the mentioned comments have been considered and the revisions made accordingly. Thank you once again for your valuable feedback. Reviewer 1 comment 1: Corruption index might lead readers to misunderstand estimation results because the definition is opposed to intuition. According to Table 2, \"Corruption Perception Index (0-100)\" was defined by Transparency International. Ordinary saying, larger the value, the more corrupted the government is. However, in the text, to take an example of interpretation for corruption index, \"As key observations, Argentina improved from 35 to 45, indicating a decrease in corruption,\"(p.11). This shows that smaller value of “corruption” is more corrupted. This is opposed to reader’s intuition. Probably, authors follow the definition of the data source. However, I strongly request to modify the definition to be suitable to reader’s intuition. Instead of it, in Table 2, authors explained that the definition is changed from that of “Transparency International” for convenience of reader’s interpretation. Authors’ Response to Reviewer 1 comment 1: Thank you for highlighting this concern. As you fairly pointed out, we understand that the correct definition of the variable - “Corruption Score” (which represented the Corruption Perception Index), may battle with readers’ intuition, thinking the higher corruption score may indicate higher corruption. Therefore, we made changes in “Table 2” to clarify the measurement of Corruption Perception Index (0-100 scale, 100 is very clean and 0 is highly corrupt), and we changed the the variable name from Corruption score to corruption control score for readers clarity. This represents the definition and helps with readers' intuition on the variable’s behavior.) We also made some amendments to the manuscript body to ease readers’ understanding regarding this matter pointed out. Reviewer 1 comment 2: By definition of variable, values of COR, SUI, and UNEMP must not be negative. I am not familiar with Violin plots in Figure 5. However, sharded area of these values covered negative area. What does it mean? Authors just mechanically illustrated the Figure 5, but was not informative unless authors carefully and appropriately explain importance of Violin plots. Figure 5 of current version is very curious and might lead readers to be confused. In my view, it is enough to just show mean value and 95% CI in Figure. Authors’ Response to Reviewer 1 comment 2: As per the reviewer’s suggestion, we have replaced the violin plots figure with a new figure that illustrates mean value and 95% CI. A new detailed description was added to explain the figure (We have included this replaced Figure 5 in TIFF format in the Figures zip file attached herewith.). However, just to clarify the reviewer’s prior concern on Figure 5, the violin plots we illustrated extend into the negative values because they are based on a smoothed estimate of the data's distribution called kernel density estimation (KDE). This smoothing process doesn't strictly stop at the minimum or maximum values of the data - it spreads out to create a smooth curve. Even though there are no negative values in the dataset, the smoothing \"overflows\" slightly into the negative range because the KDE curve is designed to be continuous and smooth. However, the actual min and max values are in the upper and lower tails of the boxplot within the violin shape. But we understand the mean value and CI provides much more straightforward understanding for the study. Reviewer 1 comment 3: In results Fixed effects model in Table 5, estimation results of constant are shown. Basically, different from OLS, constant is not calculated in Fixed effects model because constant is completely captured by unobservable time invariant factors (Fixed effects). What does constant mean in Table 5? Authors’ Response to Reviewer 1 comment 3: Thank you for this valuable observation. We agree with you that in a Fixed Effects Model, the constant term is absorbed into the fixed effects and does not carry the same interpretative meaning as in an OLS model. In Table 5, the constant term represents the average fixed effects across all entities after accounting for deviations. However, its presence might be misleading in the context of FEM. To address this, we will revise Table 5 by adding a footnote clarifying that the constant is there for the completion of results, and reflects average fixed effects rather than a traditional intercept term. This ensures alignment with the theoretical framework of the FEM, and avoids potential misinterpretation. Reviewer 1 comment 4: In Table 5, Lagged dependent variable is included as independent variable. In this model, the dynamic panel model is preferred, where Arellano-bond is the basic model although various types of dynamic model have been developed. Especially, time points is relatively long (20 years) and so the dynamic model is appropriated. Most of independent variables seems to be endogenous, that should be mitigated. Fortunately, the Dynamic model mechanically enables authors to deal with the issue of endogenous bias. Authors’ Response to Reviewer 1 comment 4: Thank you for this thoughtful comment. We agree that addressing endogeneity is crucial, and we appreciate the suggestion to use a dynamic panel model like the Arellano-Bond estimator. However, we would like to clarify our rationale for using the Fixed Effects Model (FEM) with a lagged dependent variable: Purpose and Model Fit: The FEM was chosen to control for unobservable, time-invariant heterogeneity across countries in the Americas. This aligns with the study’s focus on examining variations in suicide rates influenced by country-specific characteristics. Lagged Dependent Variable and Time Period: While including a lagged dependent variable in FEM may introduce bias, this issue is significantly mitigated in panels with a relatively long time dimension. With 20 years of data, the Nickell bias is minimal, as supported by previous econometric literature (e.g., Judson & Owen, 1999). Endogeneity and Robustness: To address potential endogeneity, we employed robust standard errors and conducted specification tests. While dynamic models can mitigate endogeneity, their reliance on strong assumptions about instrument validity may introduce new challenges, especially with a small number of entities. Practical Considerations: The FEM results provide clear and interpretable insights for policymakers and stakeholders. Introducing a dynamic model could add complexity without significantly improving the robustness of our findings. Based on these considerations, we believe the Fixed Effects Model with a lagged dependent variable is an appropriate and reliable approach for our analysis. We are, however, open to further discussing the potential application of dynamic models in future iterations or complementary analyses. Reviewer 1 comment 5: In conclusion, influence of lagged suicide variables is shown as below, “The lagged suicide variable repeatedly showed an overwhelmingly substantial positive association with current suicide rates, implying that once suicide rates rise in a country, they likely continue to be elevated over time.” (p.20). Their argument is too strong to be supported by the estimation results. In Fixed effects estimation results of Table 5, coefficient of lagged suicide variable is smaller than 1, despite being statistical significant positive sign. Suicide rate will converge among countries in the long run if the value is smaller than 1. That is, their argument is supported only if the value is statistically positive and larger than 1. Authors hardly interpret values of coefficients, which lead to misinterpretation. Authors’ Response to Reviewer 1 comment 5: We appreciate the reviewer for pointing this out. As he advised, the argument is adjusted and explained. The coefficient values are explained descriptively. Reviewer 1 comment 6: In table 5, coefficient of CORR is not interpreted as effect of corruption because there are interaction terms between CORR and other variables. Authors should additionally report results including INFL, UNEMP, and EG, but excluding interaction term. Authors’ Response to Reviewer 1 comment 6: We express our gratitude for the thoughtful suggestion provided by the reviewer on including the direct effect of the chosen moderating factors. However, while this can be a valuable extension for our study, the current study’s scope limited to identifying the moderate effects. Therefore, we kindly suggest that measuring the individual effects of the moderating variables (INFL, UNEMP, and EG) may not be essential in this context. This study aims to explain how these moderating factors influence the strength and direction of corruption control’s impact on suicide rates. We made changes to the manuscript to explain this further. Reviewer 1 comment 7: Authors only interpret statistical significance of independent variables in Table 5. Authors should more carefully value of coefficients to indicate degree of impact of variables (see also Comment 5). Authors’ Response to Reviewer 1 comment 7: The manuscript is adjusted to explain the coefficient values more descriptively. Reviewer 1 comment 8: Author’s interpretation about results of Table 5 is ambiguous, and not so informative for readers. For instance, “corruption combined with increased unemployment rates increases suicide rates in middle-income countries.” This is interpretation about “CORR×UNEMP” showing 0.0022 (coef) with 1 % level (*). Actually, authors interpretation above is meaningless. Indicate more clearly and meaningfully interpretation and implication of results. I request authors to show, In the definition of CORR in the paper, large value of CORR show less corrupted government. Hence, in my interpretation, positive value of “CORR×UNEMP” means that less corrupted government reduces the negative effect of unemployment on citizen’s mental health, and so suicide rate. Is it true? To argue as above, negative sign of “UNEMP” should be shown However, actually, authors did not indicate results of “UNEMP” in this estimation. So, authors should indicate not only interaction terms but also independent “UNEMP”. Further, how do authors interpret 0.0022 by considering scale of CRR and Unemployment? Authors’ Response to Reviewer 1 comment 8: We sincerely appreciate the reviewer’s thoughtful request on clarifying his suggested interpretation - “A positive value of CORR × UNEMP means that less corruption reduces the negative effect of unemployment on citizens' mental health, thereby lowering the suicide rate.” However, we kindly note that this interpretation does not align with the focus our study. Our analysis suggests that unemployment moderates the impact of corruption control on suicide rates, rather than corruption control mitigating the negative effects of unemployment. As the study focuses on moderating factors, not mediating factors, we believe it is not necessary to measure the individual effects of the moderating variables (INFL, UNEMP, and EG). Instead, the study aims to explain how these moderating factors influence the strength and direction of corruption control’s impact on suicide rates. However, we have made amendments in the manuscript to highlight this to avoid any confusion to the readers." } ] }, { "id": "347489", "date": "08 Jan 2025", "name": "Febby Mutiara Nelson", "expertise": [ "Reviewer Expertise Criminal law", "Corruption Eradication", "Economic crimes." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReview\nStrenghts\n\nThe study addresses a critical and understudied intersection of corruption and suicide rates in the Americas. By filling a gap in literature that lacks comprehensive regional analyses, it offers significant value for public health and governance discourse. The research employs a robust framework to explore moderating variables like unemployment, inflation, and economic growth, effectively contributing to a nuanced understanding of the socio-economic determinants of suicide.\n\nAreas for Improvement:\nClarification of causal direction: The article implies a causal link between corruption and suicide but provides limited discussion of reverse causality or potential bidirectional influences. Policy Context: Although the article discusses policy implications, it could better integrate real-world examples or case studies where similar strategies have succeeded or failed.\nMethodological Review\nVariable Definitions and Justification: The rationale for using specific metrics like the Corruption Perceptions Index (CPI) needs more explicit justification regarding its relevance and limitations in capturing nuanced governance issues. Modeling of Interaction Terms: The interaction effects involving corruption, unemployment, and inflation need more theoretical grounding to explain why specific relationships are anticipated.\nTheoritical Review The literature review connects corruption to mental health through trust erosion and institutional failures, aligning well with existing governance theories\nAreas for Improvement:\nTheoretical Integration: The theoretical framework could be enriched by incorporating more psychological theories linking economic stressors directly to mental health outcomes. References to Durkheim’s theory of anomie or contemporary socio-political models would add depth. Conceptual Clarity: The term \"persistence\" of suicide rates is used frequently but could be defined more clearly, perhaps linking it to theories of path dependency in social outcomes.\nOverall Recommendations\nStrengthen the theoretical foundation by integrating more detailed explanations for the mechanisms connecting corruption, economic conditions, and mental health. Expand on policy recommendations by providing examples or scenarios demonstrating the impact of governance reforms on suicide rates. Consider alternative data sources or indices to triangulate findings on corruption and governance quality.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "13141", "date": "28 Jan 2025", "name": "Ruwan Jayathilaka", "role": "Author Response", "response": "Authors Response to Reviewer 2 Dear Reviewer 2, We greatly appreciate the time invested in reading our manuscript and providing the necessary feedback to improve the overall quality of our work. All the mentioned comments have been considered and the revisions made accordingly. Thank you once again for your valuable feedback. Reviewer 1 comment 1: Clarification of causal direction: The article implies a causal link between corruption and suicide but provides limited discussion of reverse causality or potential bidirectional influences. Authors’ Response to Reviewer 1 comment 1: We sincerely appreciate the reviewer’s insightful comment. However, we would like to kindly clarify that this study aimed to investigate the impact of corruption on suicide rates in the Americas, particularly how corruption interacts with economic moderators such as unemployment and economic growth. The study does not aim to analyze the potential bidirectional relationship between corruption and suicide rates, as this is beyond the scope of the current research. While the potential bidirectional relationship between corruption and suicide rates is indeed an important and interesting area of inquiry, it falls outside the scope of the current research. We hope this clarification aligns with the intended objectives of our study. Reviewer 1 comment 2: Policy Context: Although the article discusses policy implications, it could better integrate real-world examples or case studies where similar strategies have succeeded or failed. Authors’ Response to Reviewer 1 comment As per the reviewer’s valuable suggestion, we included real-world examples with proper references in the study. Reviewer 1 comment 3: Variable Definitions and Justification: The rationale for using specific metrics like the Corruption Perceptions Index (CPI) needs more explicit justification regarding its relevance and limitations in capturing nuanced governance issues. Authors’ Response to Reviewer 1 comment 3: We are grateful for this thoughtful feedback. In light of the reviewer’s suggestion, we have updated the data section to provide a clearer rationale for the use of the Corruption Perceptions Index (CPI). The limitations section also updated to acknowledge the nuances it may not fully capture. Reviewer 1 comment 4: Modeling of Interaction Terms: The interaction effects involving corruption, unemployment, and inflation need more theoretical grounding to explain why specific relationships are anticipated. Authors’ Response to Reviewer 1 comment 4: Thank you for the suggestion. Kindly note that in Table 1, conceptual linkages are shown, as grounding work to the current study. The moderate effects in the current study will be introduced as a novel approach, to this specific study. Reviewer 1 comment 5: Theoretical Integration: The theoretical framework could be enriched by incorporating more psychological theories linking economic stressors directly to mental health outcomes. References to Durkheim’s theory of anomie or contemporary socio-political models would add depth. Authors’ Response to Reviewer 1 comment 5: Thank you for this insightful suggestion. In response, we have enriched the theoretical framework by incorporating additional psychological theories, including references to Durkheim’s theory of anomie and contemporary socio-political models, to provide a more comprehensive foundation for the study. Reviewer 1 comment 6: Conceptual Clarity: The term \"persistence\" of suicide rates is used frequently but could be defined more clearly, perhaps linking it to theories of path dependency in social outcomes. Authors’ Response to Reviewer 1 comment 6: We appreciate for requesting more clarification on this to improve the clarity of the manuscript. In this study, “Persistence” means the continuing nature of suicides or the tendency of past suicide rates affecting future suicide. Evidence for this is mainly generated through results. As per the reviewer’s concern, theis is clearly mentioned in this revised version. Reviewer 1 comment 7: Consider alternative data sources or indices to triangulate findings on corruption and governance quality. Authors’ Response to Reviewer 1 comment 7: Thank you for this valuable suggestion. We appreciate the importance of triangulating findings to enhance the robustness of the study. For this research, we employed the Corruption Perceptions Index (CPI) from Transparency International due to its widespread acceptance, reliability, and comprehensive coverage across countries and time. The CPI is particularly well-suited for cross-country comparisons, which aligns with our study’s objective of analyzing corruption across the Americas. We acknowledge that exploring alternative data sources or indices, such as the Worldwide Governance Indicators (WGI) or Varieties of Democracy (V-Dem) dataset, could provide additional insights and strengthen our conclusions. While these datasets were considered during our initial planning, limitations such as shorter temporal coverage or lack of comparability for the specific variables of interest influenced our decision to focus on the CPI. To address your suggestion, we propose incorporating these alternative indices in future research to assess the robustness of our findings. This would enable a more nuanced understanding of how different measures of corruption and governance quality interact with suicide rates. We also included a discussion in the limitations section of the manuscript, acknowledging the potential benefits of triangulating data sources and suggesting this as an area for future exploration." } ] } ]	1	https://f1000research.com/articles/13-1427
https://f1000research.com/articles/13-1518/v1	13 Dec 24	{ "type": "Research Article", "title": "Implementation of mycotoxin binders to enhance immune response and large intestine histopathology against Newcastle disease in vaccinated broiler chickens fed naturally contaminated diet with mixed mycotoxins", "authors": [ "Erma Safitri", "Hery Purnobasuki", "Tita Damayanti Lestari", "Suzanita Utama", "Merisa Wahyu Erdhina", "Maulida Ilma Sadida", "Eka Pramyrtha Hestianah", "Mohammad Anam Al Arif", "Chairul Anwar Nidom", "Sri Mulyati", "Jola Rahmahani", "Martia Rani Tacharina", "Sri Hidanah", "Siti Darodjah Rasad", "Goo Jang", "Mitsuhiro Takagi", "Muhammad Thohawi Elziyad Purnama", "Hery Purnobasuki", "Tita Damayanti Lestari", "Suzanita Utama", "Merisa Wahyu Erdhina", "Maulida Ilma Sadida", "Eka Pramyrtha Hestianah", "Mohammad Anam Al Arif", "Chairul Anwar Nidom", "Sri Mulyati", "Jola Rahmahani", "Martia Rani Tacharina", "Sri Hidanah", "Siti Darodjah Rasad", "Goo Jang", "Mitsuhiro Takagi", "Muhammad Thohawi Elziyad Purnama" ], "abstract": "Background In broiler farming, vaccination against Newcastle disease (ND) is essential. Nonetheless, during the post-vaccination phase, production may be negatively impacted by mycotoxin contamination in feed. This study aimed to evaluate the effect of toxin binders on antibody titer and large intestine histopathology after ND vaccination in broiler with aflatoxin B1 (AFB1) and ochratoxin A (OTA) toxication.\n\nMethods A total of 20 broilers were randomly assigned into 4 groups with 5 replications i.e. (C-) broiler groups with basal feed, (C+) broiler groups with AFB1 and OTA feed contamination, (T1) and (T2) broiler groups with exposed AFB1, OTA, and toxin binders as feed additives with dose 1.1 g/kg and 1.6 g/kg feed, respectively. ND vaccination was carried out on day 7 and 21. Antibody titers were evaluated from serum samples of broiler on days 14, 28, and 35 for further hemagglutination inhibition (HI) test. Histopathology of the cecum and colon organs was evaluated using HE staining on day 36. HI test and histological scoring were analyzed using the One-Way ANOVA, followed by Duncan’s test with a p < 0.05 in SPSS v.26 software (IBM Corp., Armonk, NY).\n\nResults As a result, histopathological improvement of the cecum and colon was reported based on mucosal rupture, hemorrhage and necrosis on day 35. An increase in the mean antibody titer compared to days 14 and 28 was observed on day 35, with significant changes observed in serum samples based on the C+ group, which was significantly different from the C- and T2 groups (p < 0.05).\n\nConclusions This study revealed that toxin binder dose of 1.6 g/kg can increase antibody titer and histopathology of cecum and colon in broiler chickens after ND vaccination fed with mycotoxin-contaminated feed.", "keywords": [ "aflatoxin", "ochratoxin", "antibody titer", "broiler", "toxin binders", "food production" ], "content": "Introduction\n\nIndonesia is susceptible to mycotoxin exposure due to its tropical climate, including aflatoxins, ochratoxins, fumonisins, trichothecene, deoxynivalenol, and zearalenone.1 According to previously mentioned research, 72% of samples tested positive for at least one form of mycotoxin, and 38% were contaminated by a combination of multiple mycotoxins. This data pertains to mycotoxin exposure in feed raw materials and feed products globally. Aflatoxin B1 (AFB1) and ochratoxin A (OTA) in tandem are the mycotoxin combination that has been shown to have high toxicity.2 Extracellular signal-regulated kinase 1/2 (ERK1/2) signalling pathway-mediated oxidative stress responses and cell death, which impact T cell proliferation, can be linked to immunotoxic exposure to AFB1 and OTA.3 Immunosuppressive disorders result from T cell proliferation failure carried on by immunotoxic processes, which prevents the body from responding to the incoming vaccination. The goal of vaccination is to encourage the body to actively produce immunological components. This is an infection control procedure that is mostly used to treat viral infectious disorders, such as Newcastle disease (ND). Given the lack of success with ND treatment, vaccination against Newcastle Disease is crucial as a preventive measure. Upon reaching the protective antibody titers, the hemagglutination inhibition (HI) test result indicates the success of the immunisation. The HI test’s fundamental idea is the formation of a little red dot in the microplate wells, which is caused by hemagglutination inhibition brought on by the binding of antigens with certain antibodies. A protective antibody titer of ≥7 HI log 2 is observed against the ND vaccination.4\n\nThe presence of immunosuppressant substances, such as mycotoxins, which can decrease the body’s immune response to vaccination, may be the reason for antibody titer findings that indicate no protection against vaccination.3 In a similar vein, indicators for intestine and ovarian tissues are the expression of growth differentiation factor-9 (GDF-9) and other proteins including HSP70 and PGE2.5 In the short term, OTA and AFB1 interacting to contaminate chicken feed will provide a synergistic negative effect.6 The digestive system has the highest risk of exposure since animal feed is the first point in the food chain where mix mycotoxin can enter directly through plant goods like grains.7\n\nThe process of digesting and absorbing dietary fibre in chickens is significantly aided by the large intestine.8 This is corroborated by a statement that explains that since fowl lack the cellulase enzymes necessary to break down dietary fibre, digestion of the fibre takes place in the cecum with the assistance of bacteria.9 Ochratoxin A profoundly alters the microbiota’s composition and metabolism in the large intestine, which has an impact on the process of fermentative digestion that occurs there.10 Aflatoxin B1 plays a significant role in the production of reactive oxygen species (ROS), which damage DNA and cause lesions in the mitochondria.11,12 Damage to the membranes and nuclear structures of cells can result in necrosis or death of the cells.13 Mycotoxicosis is a poisoning that happens when a person eats feed that is too toxic for their body to tolerate. When mix mycotoxin is exposed to the large intestine, it first disrupts the synthesis and breakdown of proteins, which alters the integrity of the intestine and damages the intestinal mucosa. Mix mycotoxin exposure will eventually cause oxidative damage. Large volumes of reactive oxygen species (ROS) are released by activated phagocytes, injuring tissue and impeding tissue repair, ultimately leading to cell necrosis.14\n\nIn the gastrointestinal system, mycotoxin binders generally act as adsorbents. One form of adsorbent that has been extensively researched in vivo and in vitro that is effective at removing mycotoxins from the body is bentonite (dioctahedral montmorillonite). Because the fluid in the gastrointestinal system has a negative charge on its surface, bentonite will be distributed there and utilise cation exchange processes to absorb different biomolecules, including aflatoxin.15 Mycotoxin binder is a big molecular molecule that resembles a chemical sponge and is used to bind mixtures of mycotoxin in an animal’s digestive tract before it is expelled through its faeces. Mycotoxin binders have the ability to reduce the amount of mix mycotoxin in feed, which in turn lessens the amount of mix mycotoxin that penetrates the bloodstream and other bodily organs and causes mycotoxicosis.16 Mycotoxin modifiers, also known as transforming agents, function differently from mycotoxin binders in that they alter the chemical makeup of mycotoxins to produce non-toxic molecules. Trichosporon mycotoxinivorans is a yeast that is classified as a mycotoxin modifier. As a biotransforming agent, the aforementioned yeast can hydrolyse amide bonds in the chemical structure of OTA to break it down into new, non-toxic molecules.17 This study aimed to investigate the effect of toxin binders on antibody titer and histopathology of cecum and colon after ND vaccination in broilers exposed to a combination of AFB1 and OTA mycotoxins through feed.\n\n\nMethods\n\nThis study was approved by the Ethical Committee of Animal Care and Use, Faculty of Veterinary Medicine, Universitas Airlangga (No. 1.KEH.033.02.2023) on February 10, 2023. This study was also reported according to the Animal Research: Reporting of in vivo Experiments (ARRIVE) guidelines 2.0: author checklist.37 All efforts were made to ameliorate any suffering of animals.\n\nAll experiments in this study were conducted from February 27 to June 10, 2023 in an animal laboratory. Antibody titer evaluation was conducted in the microbiology laboratory, while histopathology evaluation was conducted in the pathology laboratory, Faculty of Veterinary Medicine, Universitas Airlangga.\n\nThe cage and all equipment were disinfected using disinfectant one week before the day-old chick (DOC) arrived. A total of 20 broiler chickens Cobb strain were reared for 35 days as final stock following broiler rearing standards. During rearing, the chickens were fed with a standard formulation for starter-stage broilers with the brand Hipprovite CP511 (Cat No. CP511-511, PT. Charoen Pokphand, Indonesia) and provided drinking water ad libitum. They were assigned into 4 treatment groups and 5 replications, i.e. (C-) was fed basal feed, (C+) was fed with AFB1 and OTA contamination, (T1) and (T2) were fed with AFB1 and OTA contamination and toxin binders (Mycofix®, Cat No. 20026289-FTS, PT. Biomin Indonesia) as feed additives with doses 1.1 g/kg and 1.6 g/kg feed, respectively.\n\nND vaccination was performed on seven-day-old broilers using La Sota inactivated ND vaccine (Medivac®, Cat No. 3526004001, PT. Medion Farma, Indonesia) via eye drops at a dose of 1 drop/head. Then 21-day-old broilers were booster vaccinated using the inactive ND Medivac® vaccine at a dose of 0.5 mL/head intramuscularly. The antibody titers were evaluated from serum samples on days 14, 28, and 35 for the hemagglutination inhibition (HI) test. The cecum and colon organs were collected on day 36 to evaluate histopathology using hematoxylin-eosin (HE) staining.\n\nErythrocytes suspension was collected from ND virus antibody-negative donor chickens. Blood was drawn from the brachial vein and collected in tubes containing EDTA solution (BD Vacutainer® EDTA Tubes, Cat No. 366643, USA). The blood was washed thrice using PBS by centrifuging at 1.500 rpm for 10 minutes. The buffy coat and plasma fluid were discarded at each washing. The erythrocyte residue was then diluted with PBS to a concentration of 0.5%.\n\nA total of 1 mL blood samples were collected through the brachial vein in broiler chickens aged 14, 28, and 35 days. Blood was then transferred into an Ependorf tube and allowed to cloth until serum was collected. The HA test was performed to determine the antigen titer that will be used for the HI test. This test begins with filling the microplate wells (A1–A12) with 25 μl of PBS. Furthermore, 25 μl of antigen was inserted into the A1 and A12 wells (antigen control). The antigen and PBS in the A1 well were then homogenized with the suction-blow technique using a 25 μl micropipette, then 25 μl of liquid was transferred from one well to the next well, and so on until it reached the A11 well. The remaining 25 μl in the micropipette was discarded. Furthermore, all A1–A12 wells were filled with 50 μl of 0.5% chicken erythrocyte suspension. The microplate was then shaken and incubated at room temperature for 30 minutes, and the titer was ready to evaluate.\n\nThe microplate was filled with 25 μl of PBS solution into number 1–5 wells in rows A and B (duplicate titration) using a micropipette. Then, the first well in rows A and B was filled with 25 μl of ND antigen. Antigen and PBS in 1 well were then homogenized by the suction-blowing technique using a 25 μl micropipette, then 25 μl of liquid was transferred from one well to the next well, and so on until reaching the 4 wells. Furthermore, all wells were filled with 50 μl of 0.5% chicken erythrocyte suspension. The microplate was then shaken and incubated at room temperature for 30 minutes, and the titer was ready to interpret.\n\nThe first until the twelfth microplate wells were filled with 25 μl of PBS using a micropipette. Then, the first and twelfth wells are filled with 25 μl of serum to be checked for titer. Serum and PBS were mixed in the first well by the suction-blowing technique using a micropipette, then 25 μl of liquid was transferred from the first well to the next well, and so on until the tenth well. Next, wells 1–10 were filled with 25 μl of ND four HAU antigen. The microplate was then shaken and incubated for 30 minutes at room temperature. Next, all wells were filled with 50 μl of 0.5% chicken erythrocyte suspension and incubated for 30 minutes for further evaluation.\n\nOn the 36th day, the cervical dislocation procedure was used to perform euthanasia. All efforts were made to ameliorate any suffering of animals. In the event that the study’s chickens displayed signs of illness prior to the termination time, they received vitamin supplements to enhance their health and were treated in accordance with the disease’s symptoms. Nevertheless, the deceased chicken was taken out and insinerated if it died before the termination time.\n\nThe procedure of manual cervical dislocation (CD) involves twisting and stretching the neck with the hands. After being picked up, the chickens were fed to help them relax. As we gradually repositioned our hold, we waited for the chickens to calm down. The non-dominant hand was used to grasp the chicken legs. We slowly turned the chicken so that its feet were pointing up at our chest. To keep them motionless, the chicken feet were securely held close to the base of their rear end. Grasping the upper part of the chicken’s neck, where the soft, spongy vertebrae meet the brain stem, fingers were wrapped around them. Gently, the thumb and index finger were encircling this section of the chicken’s neck. After that, the neck of the fowl was angled 90 degrees downward. The chicken’s body was gradually moved to position its head away from the dominant side. Their feet were securely grasped while the head and neck of the chicken were arranged in an L configuration, the beak pointing downward. The twisting motion dislocates the vertebral column from the skull and ruptures or stretches the blood vessels, while the stretching action tears the neck muscles, ligaments, connective tissues, and blood vessels. The cessation of the pupillary light reflex and nictitating membrane reflex were death indicators in broiler chickens.18,19\n\nSample collection was performed through abdominal dissection after euthanization. After the cecum and colon were collected, the organs were fixed in pot containers using a 10% formalin solution to preserve histopathological preparations using hematoxylin-eosin (HE) staining. The histopathological evaluation was performed using a microscope (Nikon Eclipse E200, Japan) in five fields of view to investigate rupture, hemorrhage, and necrosis. The scoring method used the following criteria, (0) no change, (1) <25% pathological findings, (2) 26–50% pathological findings, (3) 51–75% pathological findings, and (4) >76% pathological findings.20\n\nAll data were tabulated and then tested for normality using the Shapiro Wilk test. Normally distributed data were followed by One-Way analysis of variance (ANOVA) and Duncan’s multiple comparison post hoc test. Conversely, if not normally distributed, the Kruskal Wallis and Mann Whitney tests were used. All analyses were evaluated using SPSS v.26 for Windows (IBM Corp., Armonk, NY) with decision considerations using a 95% confidence level.\n\n\nResults\n\nAs a result, erythrocyte sediment at the bottom of the microplate without a hemagglutination process results in a positive HI test; conversely, hemagglutination in the form of a diffused erythrocyte layer at the bottom of the microplate without an erythrocyte sediment results in a negative outcome. Based on Figure 1, presents the HI test, (A) depicts the absence of hemagglutination, which is defined as erythrocyte sedimentation when the microplate is tilted, and (B) illustrates the occurrence of hemagglutination, which is defined as erythrocyte absence at the microplate well’s bottom. The maximum serum dilution that could prevent hemagglutination against four HAU antigens was also used to calculate the HI titer.\n\nThere were no discernible changes between groups C-, C+, T1, and T2 (p > 0.05) when the antibody titer of broiler chickens was examined at 14 days of age, or 7 days after the initial ND vaccination. Analysis by average revealed that all treatment groups’ antibody titers seemed to be moderate and did not yet exceed ND-protective titers (≥7 HI log 2).\n\nThe investigation of 35-day-old broiler chickens’ antibody titers revealed statistically different results, with a p-value of 0.010 (p < 0.05). The fact that the value of p < 0.05 suggests that the administration of a mycotoxin binders agent has an impact on the antibody titer after ND vaccination. According to the results of the Duncan test, there were no significant differences (p > 0.05) between the treatment groups C- with T1, C- with T2, C+ with T1, and T1 with T2, but the C+ with C- and C+ with T2 groups were significantly different (p < 0.05), as shown by different letter superscripts in the same column ( Table 1). On the other hand, compared to the average antibody titer of chickens at 14 and 28 days of age, the antibody titer of broilers at 35 days of age increased significantly. The immunological response to the vaccine has only recently started to emerge; the immune system is still in the stage of recognizing the first entered antigen, which accounts for the low mean of antibody titer in 14-day-old broilers (7 days after the initial ND vaccination). The main immune response is the body’s immunological reaction to antigens that initially enter the body.21\n\nThe findings of the scoring analysis of the broiler chickens’ mucosal rupture, necrosis, and hemorrhage in the cecum ( Table 2) and colon ( Table 3). The control group, treatment group C-, had the lowest mean rank. The C+ treatment group, which received a combination of mycotoxin at 0.1 mg/kg feed doses of ochratoxin A and aflatoxin B1, had the highest mean rank. The T1 treatment group received a combination of mycotoxin (0.1 mg/kg feed of aflatoxin B1 and ochratoxin A) and mycotoxin binder agent (1.1 g/kg feed) at each dose. Treatment group T2 received a combination of mycotoxin (0.1 mg/kg feed containing aflatoxin B1 and ochratoxin A) and mycotoxin binder agent (1.6 g/kg feed) as indicated in Table 2. Furthermore, the T2 group demonstrated a progressive improvement in the histological differences related to mucosal rupture, hemorrhage, and necrosis in the cecum organ ( Figures 2–4).\n\nThe control group, treatment group C-, had the lowest mean rank. Treatment group C+, which received a combination mycotoxin dose of 0.1 mg/kg feed containing both ochratoxin A and aflatoxin B1, had the highest mean rank. The T1 treatment group received a combination of mycotoxin (0.1 mg/kg feed) and mycotoxin binder agent (1.1 g/kg feed) at each dose of aflatoxin B1 and ochratoxin A. Table 3 shows that the T2 treatment group received a combination of mycotoxin (0.1 mg/kg feed containing each of the compounds aflatoxin B1 and ochratoxin A) and mycotoxin binder agent (1.6 g/kg feed). The T2 group demonstrated a progressive improvement in the histological differences of mucosal rupture, haemorrhage, and necrosis in the colon organ ( Figures 5–7).\n\n\nDiscussion\n\nInitiated by cell-mediated immunity (CMI), primary immune responses often follow a more gradual course than secondary immunological responses. T cells that serve the role of CMI will develop into effector T cells, or T helper (CD4+) and T cytotoxic (CD8+). Both CD8+ and CD4+ go through three phases in their response to antigens: the expansion phase, the death phase, and the memory phase.22 Seven days after the antigen enters the body, the organism enters the growth phase, which is followed by the death phase, in which homeostatic processes cause the death of over 90% of active T cells.23 Immunoglobulin or antibody levels tend to be low seven days after the first vaccination when the HI test is conducted because of this mechanism, which prevents IL-2 produced by CD4+ and CD8+ from signaling B cells to perform maximum cell differentiation. In order to remember and identify antigens to contribute to the secondary immune response during booster immunization, the remaining active T cells will go into the memory phase.24\n\nThe investigation of antibody titer evaluation performed seven days after booster vaccination in 28-day-old broilers following ND vaccination revealed no significant difference (p > 0.05) between the C-, C+, T1, and T2 groups. In contrast to the antibody titer at 14 days of age, the average antibody titer in the C-, C+, T1, and T2 groups increased. The development of a secondary immune response could be the cause of the increase in antibody titer at 28 days of age. Booster vaccinations containing the same antigen can accelerate the proliferation and differentiation of B cells by activating memory cells produced from the main immune response.25\n\nIn all treatment groups, the average antibody titer appears to have increased, but it is still below protective levels (≥ 7 HI log 2). Because the body’s production of antibodies against the inactive vaccine has not yet reached its maximal titer, this is conceivable. According to a prior study, because inactive vaccines contain an oil adjuvant, vaccination with them will result in the highest antibody titer occurring 14–21 days after the vaccination.22 In order to improve the immune response, adjuvants are substances that are added to vaccines. By slowing down the body’s process of destroying antigens, adjuvants prolong the time that the vaccination comes into touch with macrophages and lymphocytes, which delays the vaccine’s ability to induce the development of antibodies.26\n\nAt 35 days of age, the analysis of antibody titers revealed significant differences (p < 0.05) between the C+ group with C- and C+ with T2. In contrast, there was no significant difference (p > 0.05) between the C- and T1 groups, C- and T2 groups, C+ and T1 groups, and T1 and T2 groups. The broiler group with the lowest average antibody titer among the other treatment groups is C+, which was exposed to AFB1 and OTA without the use of any additional mycotoxin binder agents. According to a prior study, immunotoxic diseases might arise in the body as a result of mycotoxin exposure.27 The primary immune cell apoptotic pathways, autophagy, and oxidative stress will all play a role in the immunotoxic mechanism. These cells include B lymphocytes, dendritic cells, macrophages, neutrophils, and T cells. Moreover, the body experiences immunosuppression, autoimmunity, immunological dysfunction, and hypersensitivity reactions as a result of mycotoxin exposure.28\n\nThe impact of chronic mycotoxicosis conditions linked to weight loss, cancer, immunosuppression, and pathological conditions with other slow onset times is known as immunosuppression. In this study, the effect of immunosuppression resulting from mycotoxin exposure on post-vaccination antibody titers has not been observed significantly at 14 and 28 days of age examination. The type, duration, dose, age, and species of the mycotoxin all affect the intensity and symptoms of exposure. If mycotoxins are given to chickens for longer than three to four weeks, the result is chronic mycotoxicosis.29,30\n\nThe analysis of antibody titers at 35 days of age revealed significantly different findings in group C+ with T2 (p < 0.05) in addition to group C+ with C-. T2 is a group of broilers given commercial feed that has been exposed to AFB1 and OTA as well as a mycotoxin binder agent at a dose of 1.6 g/kg feed. In order to prevent the toxicity of mycotoxins from spreading throughout the body, mycotoxin binder agents as feed additives typically function by lowering the bioavailability of mycotoxins while they are still in the gastrointestinal tract. Mycotoxin binders, such as bentonite clay, and mycotoxin modifiers, such as Trichosporon mycotoxinivorans yeast, are two key components found in mycotoxin binder agent products. When it comes to removing mycotoxin exposure from the body, the two of them collaborate well.31\n\nAs an enterosorbent, bentonite can bind polar mycotoxins like AFB1 in a certain way. It disperses into the gastrointestinal tract’s fluid, becoming negatively charged. This negative charge can then absorb aflatoxins through cation exchange reactions or positive charges from AFB1 dicarbonyl bonds.32 The pH, binder content, mycotoxin kind and dosage, and incubation duration are just a few of the numerous variables that impact an adsorbent’s capacity to interact with mycotoxins.33 Unlike bentonite, the yeast Trichosporon mycotoxinivorans has the capacity to decrease the bioavailability of ochratoxin A (OTA) by the hydrolysis of the amide bond structure that links the hydro-isocoumarin ring and the phenylalanine group. Two less hazardous chemicals, L-β-phenylalanine and α-ochratoxin (OTα), will be produced if the amide link is effectively hydrolysed.34\n\nUsing mycotoxin binder chemicals as feed additives to bind mix mycotoxin can help prevent uncontrollably contaminated mycotoxin mixes. Using mycotoxin binders, the mix of mycotoxin is detoxified according to its specific features. In this work, the polar toxin known as aflatoxin B1 is detoxified using bentonite, an adsorbent that will boost enzyme activity and prevent exposure to the toxin in the digestive system. Mycotoxin binders function by biotransformation, which is the process of converting mixed mycotoxin into non-toxic metabolites, as opposed to ochratoxin A, which is non-polar.35\n\n\nConclusions\n\nThe study’s findings support the hypothesis that providing a mycotoxin binder agent to broilers exposed to AFB1 and OTA at a dose of 1.6 g/kg influences the development of antibody titers following ND vaccination and also guards against rupture, hemorrhage, and necrosis in cecum and colon.\n\n\nAuthor contributions\n\nErma Safitri, Siti Darodjah Rasad, Goo Jang, and Mitsuhiro Takagi: Supervision, Research Conceptualization, Methodology and Research Observation, Writing—Original Draft Preparation; Hery Purnobasuki, Tita Damayanti Lestari, Suzanita Utama, Eka Pramyrtha Hestianah, Mohammad Anam Al Arif, Chairul Anwar Nidom, Sri Mulyati, Sri Hidanah, and Jola Rahmahani: Curation for Data, Analysis and Formal Investigation, Resources of References, Visualization, Writing—Review and Editing; Merisa Wahyu Erdhina and Maulida Ilma Sadida: Curation for Data, Software and Validation; Martia Rani Tacharina and Muhammad Thohawi Elziyad Purnama: Curation for Data, Proof Read, Review and Editing.", "appendix": "Data availability\n\nFigshare: Database of hemagglutination inhibition test data, histopathology scoring of cecum and colon, and original histopathology figures. https://doi.org/10.6084/m9.figshare.27248592.v2.36\n\nThe extended data set contains the following data:\n\n• Antibody titer\n\n• Cecum histopathology scoring\n\n• Colon histopathology scoring\n\n• Histopathology figure of cecum\n\n• Histopathology figure of colon\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nFigshare: ARRIVE Guidelines 2.0 for Mycotoxin binders study. https://doi.org/10.6084/m9.figshare.27900534.v1.37\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgments\n\nThe authors express their profound gratitude to Dr. Gadis Meinar Sari, dr., M. Kes, Chairman of the Institute for Research and Community Service, Universitas Airlangga, and Prof. Dr. Mirni Lamid, drh., M.P., the Dean of the Faculty of Veterinary Medicine, Universitas Airlangga Surabaya for providing the research facilities.\n\n\nReferences\n\nSamik A, Safitri E: Mycotoxin binders potential on histological of ovary mice exposed by zearalenone. Vet. World. 2017; 10(3): 353–357. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nStreit E, Naehrer K, Rodrigues I, et al.: Mycotoxin occurrence in feed and feed raw materials worldwide: long-term analysis with special focus on Europe and Asia. J. Sci. Food Agric. 2013; 93(12): 2892–2899. PubMed Abstract \| Publisher Full Text\n\nHou L, Gan F, Zhou X, et al.: Immunotoxicity of ochratoxin A and aflatoxin B1 in combination is associated with the nuclear factor kappa B signaling pathway in 3D4/21 cells. Chemosphere. 2018; 199: 718–727. 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Publisher Full Text\n\nAnilkumar P, Sathyanarayana ML, Vijayasarathi SK, et al.: Evaluation of ameliorating effect of vitamin E and selenium in experimental aflatoxicosis and ochratoxicosis in broiler chicken. Indian J. Anim. Sci. 2009; 79(8).\n\nMartin JE, McKeegan DE, Sparrey J, et al.: Comparison of novel mechanical cervical dislocation and a modified captive bolt for on-farm killing of poultry on behavioural reflex responses and anatomical pathology. Anim. Welf. 2016; 25(2): 227–241. Publisher Full Text\n\nBandara RM, Torrey S, Turner PV, et al.: Efficacy of a novel mechanical cervical dislocation device in comparison to manual cervical dislocation in layer chickens. Animals. 2019; 9(7): 407. Publisher Full Text\n\nSong B, Li H, Wu Y, et al.: Effect of microencapsulated sodium butyrate dietary supplementation on growth performance and intestinal barrier function of broiler chickens infected with necrotic enteritis. Anim. Feed Sci. Technol. 2017; 232: 6–15. Publisher Full Text\n\nRozi F, Rahmahani J, Purnama MTE, et al.: Seroprevalensi Antibodi Newcastle Disease (ND) pada Itik di Desa Temuasri, Sempu, Banyuwangi. J. Med. Vet. 2020; 3(1): 108–113. Publisher Full Text\n\nLewis DA, Ly T: Cell cycle entry control in naïve and memory CD8+ T cells. Front. Cell Dev. Biol. 2021; 9: 727441. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nDerksen LY, Tesselaar K, Borghans JA: Memories that last: Dynamics of memory T cells throughout the body. Immunol. Rev. 2023; 316(1): 38–51. PubMed Abstract \| Publisher Full Text\n\nBugya Z, Prechl J, Szénási T, et al.: Multiple levels of immunological memory and their association with vaccination. Vaccines. 2021; 9(2): 174. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLuo W, Yin Q: B cell response to vaccination. Immunol. Investig. 2021; 50(7): 780–801. Publisher Full Text\n\nEl-Sayed A, Kamel M: Advances in nanomedical applications: diagnostic, therapeutic, immunization, and vaccine production. Environ. Sci. Pollut. Res. 2020; 27(16): 19200–19213. PubMed Abstract \| Publisher Full Text\n\nTesfamariam K, De Boevre M, Kolsteren P, et al.: Dietary mycotoxins exposure and child growth, immune system, morbidity, and mortality: A systematic literature review. Crit. Rev. Food Sci. Nutr. 2020; 60(19): 3321–3341. PubMed Abstract \| Publisher Full Text\n\nKraft S, Buchenauer L, Polte T: Mold, mycotoxins and a dysregulated immune system: a combination of concern? Int. J. Mol. Sci. 2021; 22(22): 12269. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWang A, Hogan NS: Performance effects of feed-borne Fusarium mycotoxins on broiler chickens: Influences of timing and duration of exposure. Anim. Nutr. 2019; 5(1): 32–40. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWeaver AC, King WD, Verax M, et al.: Impact of chronic levels of naturally multi-contaminated feed with Fusarium mycotoxins on broiler chickens and evaluation of the mitigation properties of different titers of yeast cell wall extract. Toxins. 2020; 12(10): 636. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBhatti SA, Khan MZ, Saleemi MK, et al.: Impact of dietary Trichosporon mycotoxinivorans on ochratoxin A induced immunotoxicity; in vivo study. Food Chem. Toxicol. 2019; 132: 110696. PubMed Abstract \| Publisher Full Text\n\nZhang N, Han X, Zhao Y, et al.: Removal of aflatoxin B1 and zearalenone by clay mineral materials: In the animal industry and environment. Appl. Clay Sci. 2022; 228: 106614. Publisher Full Text\n\nKihal A, Rodríguez-Prado M, Calsamiglia S: The efficacy of mycotoxin binders to control mycotoxins in feeds and the potential risk of interactions with nutrient: a review. J. Anim. Sci. 2022; 100(11): skac328. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSadamatsu H, Takahashi K, Tashiro H, et al.: A rare case of Trichosporon mycotoxinivorans and Cryptococcus neoformans co-infection in lung. J. Infect. Chemother. 2020; 26(8): 838–842. PubMed Abstract \| Publisher Full Text\n\nWang L, Hua X, Shi J, et al.: Ochratoxin A: Occurrence and recent advances in detoxification. Toxicon. 2022; 210: 11–18. PubMed Abstract \| Publisher Full Text\n\nPurnama MTE, Safitri E, Purnobasuki H, et al.: Database of hemagglutination inhibition test data, histopathology scoring of cecum and colon, and original histopathology figures. Dataset. figshare. 2024. Publisher Full Text\n\nSafitri E, Purnobasuki H, Lestari TD, et al.: ARRIVE Guidelines 2.0 for Mycotoxin binders study. Dataset. figshare. 2024. Publisher Full Text" }	[ { "id": "349350", "date": "26 Dec 2024", "name": "Essam S Soliman", "expertise": [ "Reviewer Expertise 1. Preventive medicine and prophylactics of animals (Large and small)", "poultry", "and fish. 2. Biosafety and biosecurity measures", "plans", "and strategies in animal and poultry farms. 3. Green environment and waste management and reuse. 4. Combating means of infectious and contagious diseases. 5. Air and water quality", "and environmental sanitation. 6. Epidemiology of infectious and contagious disease and measurement of disease occurrence." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nManuscript F1KR00CDE F1R-VER173650-R entitled “Implementation of mycotoxin binders to enhance immune response and large intestine histopathology against Newcastle disease in vaccinated broiler chickens fed naturally contaminated diet with mixed mycotoxins”. Please notice the following:\nGeneral view: The manuscript highlighted that a toxin binder dose of 1.6 g/kg can increase antibody titer and histopathology of cecum and colon in broiler chickens after ND vaccination fed with mycotoxin-contaminated feed. The manuscript was expressed using moderate English and grammar. A certain degree of copyediting & proofreading, proper display of the introduction, and declaring some explanations of the materials and methods have to be made to achieve better readability & understanding, and publication value. Title: Very long. Preferred to be modified for clarity and simplification into “Mycotoxin Immune and Intestinal Histopathology Ameliorations Against Newcastle Disease in Vaccinated Broilers”. Abstract: Please notice the following: 1. Clear to a great extent. 2. Some modifications must be made to enhance the readability and understanding of the text. Keywords: Re-arrange in alphabetical order as follows: “Aflatoxin, Antibody titer, Broilers, Food production, Ochratoxin, Toxin binders”. Introduction: Please notice the following:\nImproperly arranged into four paragraphs. The introduction has to be re-arranged into three paragraphs only i.e. 1. Introduction 2. Significance of the study, and 3. Aim of the study. Some modifications must be made to enhance the readability and understanding of the text.\nThe aim: Clear to a certain extent. Some modifications must be made to enhance the readability and understanding of the text. Materials and methods: Please notice the following: 1. MUST provide details on the microclimatic conditions used for rearing the experimental broilers such as ambient temperature, relative humidity, feeding system (manual/automated), watering system (mechanism and source & type of water), lighting program (Color, duration, and intensity), ventilation system, rodentproof, flyproof, cleaning procedures (Provide the active principle of the detergent used), disinfection protocol (Provide the active principle of the disinfectant used), and treatment applied if any. 2. Provide the total number of blood samples collected by the end of the study and specify their types (With or without anticoagulant). 3. Provide a reference for the Euthanasia technique used in broilers. 4. Explain how the carcasses were disposed of hygienically after sampling. 5. Specify the number of the histopathological samples collected. 6. Provide the statistical model exhausted in the statistical analysis. 7. Some modifications must be made to enhance the readability and understanding of the text. Results: Please notice the following: 1. MUST not list the P-value for the non-significant results. 2. Do not list the details of the treatment groups all over and use the symbols instead. 3. Reduce the illustration of numbers as much as possible as they are listed in tables and express them in your own words. 4. Some modifications must be made to enhance the readability and understanding of the text. Discussion: Please notice the following: 1. Clear to a certain extent. 2. A moderate degree of speculation and comparison was used. 3. Some modifications must be made to enhance the readability and understanding of the text. Conclusion: Clear and concise. Authors’ contributions: Clear. Acknowledgment: Clear. References: Sufficient as 62.1% (23 out of 37) were published in the last five years. Tables: Properly designed and well organized. Figures: Properly designed and well organized.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13126", "date": "27 Jan 2025", "name": "Muhammad Thohawi Elziyad Purnama", "role": "Author Response", "response": "Dear reviewers, We appreciate your advice on our manuscript. Your suggestions have been addressed and the manuscript has been updated. In our opinion, these changes result in a much better manuscript, and we hope that it is now suitable for publication. General view: The manuscript highlighted that a toxin binder dose of 1.6 g/kg can increase antibody titer and histopathology of cecum and colon in broiler chickens after ND vaccination fed with mycotoxin-contaminated feed. The manuscript was expressed using moderate English and grammar. A certain degree of copyediting & proofreading, proper display of the introduction, and declaring some explanations of the materials and methods have to be made to achieve better readability & understanding, and publication value. Title: Very long. Preferred to be modified for clarity and simplification into “Mycotoxin Immune and Intestinal Histopathology Ameliorations Against Newcastle Disease in Vaccinated Broilers”. Author Response: Yes, We agree to changed the title modification according to the reviewer's suggestion Abstract: Please notice the following: 1. Clear to a great extent. Author Response: Revision has been implemented. 2. Some modifications must be made to enhance the readability and understanding of the text. Author Response: We have revised in text Keywords: Re-arrange in alphabetical order as follows: “Aflatoxin, Antibody titer, Broilers, Food production, Ochratoxin, Toxin binders”. Author Response: Yes, We agree to re-arranged in alphabetical, according to the reviewer's suggestion Introduction: Please notice the following: Improperly arranged into four paragraphs. The introduction has to be re-arranged into three paragraphs only i.e. 1. Introduction 2. Significance of the study, and 3. Aim of the study. Some modifications must be made to enhance the readability and understanding of the text. The aim: Clear to a certain extent. Some modifications must be made to enhance the readability and understanding of the text. Author Response: We have revised in text Materials and methods: Please notice the following: 1. MUST provide details on the microclimatic conditions used for rearing the experimental broilers such as ambient temperature, relative humidity, feeding system (manual/automated), watering system (mechanism and source & type of water), lighting program (Color, duration, and intensity), ventilation system, rodentproof, flyproof, cleaning procedures (Provide the active principle of the detergent used), disinfection protocol (Provide the active principle of the disinfectant used), and treatment applied if any. Author Response: We have revised in text --> The five steps of preparation before acclimatization of day-old chicks (DOC) are as follows: 1. Clean and remove all physical materials from a chicken cage; 2. Wash and clean all equipment and the cage with soap and water, using scraping; 3. Spray liquid disinfectant on all equipment and the cage and close the cage for a week; 4. Spray solid disinfectant (lime) and mix it with water in the cage and close the cage for a week; 5. Fumigate with permanganate and formalin, close the cage, as this can irritate; and finally, wait a week before DOC arrives. --> A total of 20 DOC broiler chickens Cobb strain were reared for 35 days as final stock following broiler rearing standards. Rearing standards for broiler experiments include: basic ventilation system (open house), rodent and flyproof, cleaning and disinfection protocol (five steps before DOC arrived), ambient temperature (18 to 24°C), relative humidity (50 to 70%), manual feeding system, watering system (manual, ad libitum, and groundwater), lighting program (light color at 20 lux intensity for the first 7 days and 17-20 hours duration), and lighting program. 2. Provide the total number of blood samples collected by the end of the study and specify their types (With or without anticoagulant). Author Response: We have revised in text --> A total of 1 mL blood samples without anti-coagulant were collected through the brachial vein in 20 broiler chickens aged 14, 28, and 35 days. Blood was then allowed until collected serum and transferred into an Ependorf tube. 3. Provide a reference for the Euthanasia technique used in broilers. Author Response: Reference number 18 4. Explain how the carcasses were disposed of hygienically after sampling. Author Response: The process of incineration involves burning carcasses or residues at temperatures as high as 850 °C to create an inorganic ash. All infectious agents are anticipated to be destroyed by the treatment. Ash usually makes about 1–5% of the initial volume of the carcass, though this will vary depending on the type of incinerator, the method, the fuel, and the species of animal. 5. Specify the number of the histopathological samples collected. Author Response: After the cecum and colon from 20 broilers were collected 6. Provide the statistical model exhausted in the statistical analysis. Author Response: Revision has been implemented 7. Some modifications must be made to enhance the readability and understanding of the text. Author Response: We have revised in text Results: Please notice the following: 1. MUST not list the P-value for the non-significant results. Author Response: We have deleted in text 2. Do not list the details of the treatment groups all over and use the symbols instead. Author Response: We have revised 3. Reduce the illustration of numbers as much as possible as they are listed in tables and express them in your own words. Author Response: Revision has been implemented. 4. Some modifications must be made to enhance the readability and understanding of the text. Author Response: Revision has been implemented. Discussion: Please notice the following: 1. Clear to a certain extent. Author Response: Revision has been implemented. 2. A moderate degree of speculation and comparison was used. Author Response: Revision has been implemented. 3. Some modifications must be made to enhance the readability and understanding of the text. Author Response: Revision has been implemented. Conclusion: Clear and concise. Author Response: Thank you for your recommendation. Authors’ contributions: Clear. Author Response: Thank you for your recommendation. Acknowledgment: Clear. Author Response: Thank you for your recommendation. References: Sufficient as 62.1% (23 out of 37) were published in the last five years. Author Response: Now 65,7 % (25 out of 38) Tables: Properly designed and well organized. Author Response: Thank you for your recommendation. Figures: Properly designed and well organized. Author Response: Thank you for your recommendation." } ] }, { "id": "349347", "date": "06 Jan 2025", "name": "Agung Irawan", "expertise": [ "Reviewer Expertise Nutritional biochemistry of poultry and ruminants related to feed", "feed technology", "and feeding." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall Assessment: The authors evaluated the efficacy of mycotoxin binders on immunity and histopathology of broilers chickens. The topic of the manuscript is interesting and highly relevant to be disseminated. However, I found that in the current form, the manuscript requires substantial revision. Thorough the manuscript, it is poorly written, with significant issues in language, grammar, and coherence. Additionally, the scientific content is not presented in a manner consistent with standard academic practices, which undermines its clarity and impact.\nHere are some major issues for authors’ attention:\nThe introduction lacks a logical structure for hypothesis formulation. There is a lack of coherence between sentences. The narrative is disjointed, making it difficult to follow the authors' rationale. The results section contains many unnecessary descriptions that obscure the main findings. A more concise and focused presentation of the data is required. The discussion is poorly structured and hard to follow. The findings are not effectively described, and there is a lack of chronological organization. Critical interpretations are not adequately supported by references. The authors mention a \"hypothesis\" in the conclusion but fail to clearly state it in the introduction. The manuscript does not adequately discuss or revisit the hypothesis in the discussion section.\n\nFor more detailed review, please see below comments: #Introduction The introduction is not systematically written, there are too many issues with languages and grammar. Authors need to substantially revise the introduction both grammatically and scientific soundness. Between sentences’ connection is lacking in many parts of paragraphs, some unnecessary information is also found. Some information requires more clarity, such as:\n72% samples tested positive for…. -> please indicate what samples? It is not clear! Are the mycotoxin combination that has been shown to have high toxicity -> please be more specific on the toxicity effects and indicate whether the study was in humans or animals (specify the animal) There are some issues with the coherences of sentences in the first paragraph, making the reader a bit confused with the main idea of the paragraph. For instance, authors explain some molecular pathways associated with toxicity of AFB1 and OTA, and then jumped to failure of vaccination program etc. A large portion of the paragraph discuss ND vaccination issue while the importance of mycotoxin exposure issues is lost. Although they are relatable, but it is not written systematically. Please review and rewrite this part to be easier to understand. At the end of 2nd paragraph: plant goods -> what does that mean? I was unfortunately unable to understand. Can the authors please clarify? The statement of the first sentence of 3rd paragraph is not correct. Fiber digestion in poultry occurs primarily in the gizzard (mechanistic digestion) and only very little portion of the fiber is digested in the large intestine and this does not supply much energy for the bird. Please review this part and rewrite… The statement of mycotoxicosis in person is not relevant in this part. In the last paragraph, I do not see how the hypothesis was built, there is missing connection between the scientific background, gap of knowledge, and the objective being pursued in this study. Also, Trichosporon mycotoxinivorans is mentioned with no reason!\n\n#Materials and Methods\nRpm should be converted into g to be more standardized. In statistical analysis part, first sentence: followed -> analyzed. Authors mentioned Kruskal Wallis and Mann Whitney tests as well in this part, which one was actually used for the data analysis? Why Mann Whitney was used?\n\n#Results\nPlease rewrite the results to be more concise. At the present form, there are many unnecessary descriptions. It would be better to consult with other experts or to copyedit the manuscript. Some examples are given below: Please remove “as a result” in the first sentence of the section. “Based on Figure 1, presents the HI test” -> Figure 1 (A) depicts Paragraph 3: The investigation of 35-day-old broiler chickens’ antibody titers revealed statistically different results, with a p-value of 0.010 (p < 0.05). The fact that the value of p < 0.05 suggests that the administration of a mycotoxin binders agent has an impact on the antibody titer after ND vaccination -> Please change to “Antibody titers of broilers on day 35 differed (p = 0.010) between groups, suggesting an effect of mycotoxin binder on ND antibody titers establishment”.\n\n#Discussion The discussion is hard to follow. Some terms are not specified such as “organism enter the growth phase….” -> it is ambiguous what organism did the authors mean, whether bird or antigen? - This paper may be useful as a reference: Putra RP et al. (2024 [Ref-1]) https://link.springer.com/article/10.1007/s11259-023-10199-7\n\n#Conclusion: Authors mentioned the “hypothesis” but never stated their hypothesis in the introduction and never discussed it.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "13127", "date": "27 Jan 2025", "name": "Muhammad Thohawi Elziyad Purnama", "role": "Author Response", "response": "Dear reviewers, We appreciate your advice on our manuscript. Your suggestions have been addressed and the manuscript has been updated. In our opinion, these changes result in a much better manuscript, and we hope that it is now suitable for publication. Overall Assessment: The authors evaluated the efficacy of mycotoxin binders on immunity and histopathology of broilers chickens. The topic of the manuscript is interesting and highly relevant to be disseminated. However, I found that in the current form, the manuscript requires substantial revision. Thorough the manuscript, it is poorly written, with significant issues in language, grammar, and coherence. Additionally, the scientific content is not presented in a manner consistent with standard academic practices, which undermines its clarity and impact. Here are some major issues for authors’ attention: The introduction lacks a logical structure for hypothesis formulation Author Response: Revision has been implemented, We changed the hypothesis formulation with aims the research There is a lack of coherence between sentences Author Response: Revision has been implemented The narrative is disjointed, making it difficult to follow the authors' rationale. Author Response: Revision has been implemented The results section contains many unnecessary descriptions that obscure the main findings. Author Response: Revision has been implemented A more concise and focused presentation of the data is required. Author Response: Revision has been implemented The discussion is poorly structured and hard to follow. Author Response: Revision has been implemented The findings are not effectively described, and there is a lack of chronological organization. Author Response: Revision has been implemented Critical interpretations are not adequately supported by references. Author Response: Revision has been implemented The authors mention a \"hypothesis\" in the conclusion but fail to clearly state it in the introduction. Author Response: We have revised the word “hypothesis” in conclusion The manuscript does not adequately discuss or revisit the hypothesis in the discussion section. Author Response: Revision has been implemented For more detailed review, please see below comments: #Introduction The introduction is not systematically written, there are too many issues with languages and grammar. Authors need to substantially revise the introduction both grammatically and scientific soundness. Between sentences’ connection is lacking in many parts of paragraphs, some unnecessary information is also found Author Response: Revision has been implemented Some information requires more clarity, such as: 72% samples tested positive for…. -> please indicate what samples? It is not clear! Author Response: Revision has been implemented Are the mycotoxin combination that has been shown to have high toxicity -> please be more specific on the toxicity effects and indicate whether the study was in humans or animals (specify the animal) Author Response: We have rewrited There are some issues with the coherences of sentences in the first paragraph, making the reader a bit confused with the main idea of the paragraph. For instance, authors explain some molecular pathways associated with toxicity of AFB1 and OTA, and then jumped to failure of vaccination program etc. A large portion of the paragraph discuss ND vaccination issue while the importance of mycotoxin exposure issues is lost. Although they are relatable, but it is not written systematically. Please review and rewrite this part to be easier to understand. Author Response: We have revised in paragraph 1 & 2 introduction At the end of 2nd paragraph: plant goods -> what does that mean? I was unfortunately unable to understand. Can the authors please clarify? Author Response: We have changed the statement with this : The digestive system has the highest risk of exposure since animal feed is the first point in the food chain where mixed mycotoxins can enter directly through grains crop The statement of the first sentence of 3rd paragraph is not correct. Fiber digestion in poultry occurs primarily in the gizzard (mechanistic digestion) and only very little portion of the fiber is digested in the large intestine and this does not supply much energy for the bird. Please review this part and rewrite… Author Response: The process of digesting and absorbing dietary fibre in chickens is significantly aided by the gizzard (mechanistic digestion) and ends in the large intestine. (This sentence is at the end of the first paragraph) The statement of mycotoxicosis in person is not relevant in this part. Author Response: We have changed the statement with this : Mycotoxicosis is poisoning that occurs when animals eat feed containing mycotoxins, where the toxins from these mycotoxins cannot be tolerated by the body In the last paragraph, I do not see how the hypothesis was built, there is missing connection between the scientific background, gap of knowledge, and the objective being pursued in this study. Also, Trichosporon mycotoxinivorans is mentioned with no reason! Author Response: We have changed the hypothesis with aim statement. Also about Trichosporon mycotoxinivorans, we have rewrited #Materials and Methods Rpm should be converted into g to be more standardized. Author Response: Revision has been implemented In statistical analysis part, first sentence: followed -> analyzed. Authors mentioned Kruskal Wallis and Mann Whitney tests as well in this part, which one was actually used for the data analysis? Why Mann Whitney was used? Author Response: Revision has been implemented #Results Please rewrite the results to be more concise. At the present form, there are many unnecessary descriptions. It would be better to consult with other experts or to copyedit the manuscript. Some examples are given below: Please remove “as a result” in the first sentence of the section. Author Response: Revision has been implemented “Based on Figure 1, presents the HI test” -> Figure 1 (A) depicts Author Response: We have revised Paragraph 3: The investigation of 35-day-old broiler chickens’ antibody titers revealed statistically different results, with a p-value of 0.010 (p < 0.05). The fact that the value of p < 0.05 suggests that the administration of a mycotoxin binders agent has an impact on the antibody titer after ND vaccination -> Please change to “Antibody titers of broilers on day 35 differed (p = 0.010) between groups, suggesting an effect of mycotoxin binder on ND antibody titers establishment”. Author Response: I've changed it according to reviewer's suggestion #Discussion The discussion is hard to follow. Some terms are not specified such as “organism enter the growth phase….” -> it is ambiguous what organism did the authors mean, whether bird or antigen? Author Response: We have rewrited - This paper may be useful as a reference: Putra RP et al. (2024 [Ref-1]) https://link.springer.com/article/10.1007/s11259-023-10199-7 Putra RP, Astuti D, Respati AN, Ningsih N, et al.: Protective effects of feed additives on broiler chickens exposed to aflatoxins-contaminated feed: a systematic review and meta-analysis.Vet Res Commun. 2024; 48 (1): 225-244 Author Response: We have added in Reference number 35 #Conclusion: Authors mentioned the “hypothesis” but never stated their hypothesis in the introduction and never discussed it. Author Response: We have deleted the word “hypothesis” in conclusion" } ] } ]	1	https://f1000research.com/articles/13-1518
https://f1000research.com/articles/13-1010/v1	05 Sep 24	{ "type": "Research Article", "title": "Impact of distress and anxiety due to COVID-19 on digital addictions in university students in the third wave period ", "authors": [ "Walter Capa-Luque", "Luz Elizabeth Mayorga-Falcón", "Evelyn Barboza-Navarro", "Armando Martínez-Portillo", "Yovana Pardavé-Livia", "Edmundo Hervias-Guerra", "Aldo Bazán-Ramírez", "Catalina Bello-Vidal", "Walter Capa-Luque", "Luz Elizabeth Mayorga-Falcón", "Evelyn Barboza-Navarro", "Armando Martínez-Portillo", "Yovana Pardavé-Livia", "Edmundo Hervias-Guerra", "Catalina Bello-Vidal" ], "abstract": "Abstract*\n\nBackground Digital addictions are a major problem worldwide, which has increased considerably during the COVID-19 pandemic. In this scenario, two important impact factors to explain this problem are stress and anxiety because of COVID-19. The objective of this research was to determine the impact of distress and anxiety due to COVID-19 on digital addictions.\n\nMethods cross-sectional, explanatory study. A total of 802 students from public and private universities residing in the city of Lima and Callao (Peru), with a mean age of 21.68 (SD = 3.11), selected by convenience sampling, participated in the study. The MULTICAGE CAD-4 questionnaire, the distress scale, and the COVID-19 worry scale were applied.\n\nResults two models examined with structural equation modeling showed good fit indices (CFI and TLI > .95, RMSEA and SRMR < .06). The first model shows that the latent variables distress and anxiety due to COVID-19 have direct effects on digital addictions as a general construct (R2 = 22%). The second model shows that the exogenous latent variables (stress and anxiety) have direct effects of different magnitudes on each digital technology, so the variance explained on smartphone addiction was higher (R2 = 25%) with respect to internet (R2 = 19%) and video game addiction (R2 = 6%). It was also found that for every male, there are two females with high levels of distress and anxiety. Regarding the problematic use of smartphones and internet, there is a prevalence of 40% regardless of sex; but as for the problematic use of video games, there is a marked difference between males (18.8%) and females (2.7%).\n\nConclusion the distress and anxiety caused by COVID-19 have a direct impact in aggravating digital addictions.", "keywords": [ "Digital addictions", "addictive behaviors", "anxiety", "distress", "mental health", "smartphone", "internet", "video games" ], "content": "Introduction\n\nIn the present century, the COVID-19 pandemic is classified as the most serious because of its person-to-person transmission, with asymptomatic carriers and its high magnitude of contagion (Zhao et al., 2020). Globally, the COVID-19 pandemic has spread since December 2019 with consequences of risk of death due to viral infection and with many adverse psychological effects on the population (Bao et al., 2020). Because of the coronavirus, the general population has experienced psychological problems such as anxiety, depression and stress (Huarcaya-Victoria, 2020). According to the systematic review by Xiong et al. (2020), symptoms of depression, anxiety, psychological distress, stress, and post-traumatic stress disorder have increased markedly.\n\nThe university population is at risk for exposure to stress and anxiety (Deng et al., 2021; Saladino et al., 2020). Studies highlight that the university population has been affected by the pandemic. For example, 24.9% of Chinese university students presented with anxiety due to COVID-19 (Cao et al., 2020). University students in Bangladesh who were affected by the pandemic presented with anxiety between moderate (48.41%) and severe (44.59%) levels (Dhar et al., 2020). In Iran, the overall prevalence of anxiety was 33.2%, depression 26.1% and stress 5.8% (Parvar et al., 2022). In Jordan 70.6% of students reported mild to severe levels of anxiety. And those who were afraid of catching COVID-19 presented higher anxiety (Masha'al et al., 2022). Also, Savitsky et al. (2020) found in a sample of Israeli university students the presence of moderate (42.8%) and severe (13.1%) anxiety. For their part, Rudenstine et al. (2020) reported that 20.7% of New York college students had severe anxiety during the COVID-19 pandemic. Likewise, Biber et al. (2020) found in a sample of U.S. college students that 49% had moderate anxiety and 25% had severe anxiety. In Peru, Sandoval et al. (2023) found in medical students’ levels of depression (24.3%), anxiety (28.5%) and stress (13.0%) in the categories of moderate, severe, or extremely severe.\n\nIn addition, the COVID-19 pandemic not only brought with it a decrease in person-to-person social interactions, but also an increase in the excessive use of the internet, becoming another critical problem which has extended the time spent in front of screens and increased digital connection (Ferrara et al., 2021). This has modified leisure patterns and use of cell phones with an increase in online hobbies, such as games and video games (Lemenager et al., 2021). In the meta-analysis by Meng et al. (2022), the prevalence of addiction to cell phones is reported at 26.99%, to social networks at 17.42%, internet at 8.23% and to video games at 6.04%; they also observed a pattern of increase in these variables over the last decades, with a significantly higher rate during the COVID-19 pandemic. Sandoval et al. (2020) found that 31% of medical students at the Ricardo Palma University (Peru) were addicted to the internet, and those who failed more courses had more problems with the internet; they also found that males had more problems with video games. Similarly, another study with students at the University of Malaga revealed excessive and problematic use of video games, as well as the use of cell phones was placed in the categories of risk and abuse (Ruiz-Palmero et al., 2021).\n\nIn the academic environment, the mandatory implementation of virtual classes at the university generated changes in the lifestyle of students. The pandemic and the characteristics of virtual classes implied a considerable amount of academic work and online evaluations when they did not have the technological means or the skills to develop them effectively, pushing the students' adaptive capacity to the limit, causing a considerable number of students to present psychological problems such as stress, anxiety, intolerance to uncertainty, depression, as well as various physical health problems (Bazán-Ramírez et al., 2022; Capa-Luque et al., 2023).\n\nDistress. Der Feltz-Cornelis et al. (2020) indicate that distress is the negative stress that originates when the stressor stimulus and its exposure time increase and is characterized by anticipated negative thoughts about a particular event, anxiety, exhaustion, discomfort, restlessness, maladaptive states, emotional responses such as annoyance, sadness, phobias, depression, and psychoticism, among others.\n\nAnxiety due to COVID-19. Anxiety is an excessive emotional reaction to circumstances that are intuitively recognized as threatening, and this emotion may be accompanied by agitation, exhaustion, muscular rigidity, and attention deficit (Parvar et al., 2022).\n\nDigital addictions. The World Health Organization - WHO (2022) divides the phenomenon of addiction into those originated by the consumption of a substance and those that are due to behaviors in themselves. Addictive behaviors are considered problematic because of the lack of control by the individual, as well as the maintenance of this behavior despite having multiple negative repercussions in his or her life (Carbonell et al., 2021).\n\nInternet addiction is conceived as a particular type of digital addiction (Sarıalioğlu et al., 2021). It would be defined as lack of control over internet use (Lozano-Blasco et al., 2022), involving compulsive behavior in terms of use (Haberlin and Atkin, 2022), which can result in mood changes, tolerance, withdrawal, conflict, and relapse (Young et al., 2011). During the COVID-19 pandemic, the likelihood of internet addiction would have increased significantly due to increased time of use (Winther and Byrne, 2020).\n\nCell phone addiction is also recognized under other names such as problematic use, overuse, dependence, or smartphone addiction (Ran et al., 2022). It is defined as a behavioral addiction with negative effects on psychological, social, and physical functioning caused by excessive or abusive cell phone use (Peng et al., 2022; Ran et al., 2022), characterized by obsessive thoughts about the device, tolerance and elevated anxiety to cell phone withdrawal (Peng et al., 2022).\n\nGriffiths (1995) refers that video games are among the technological addictions and defines it as a behavioral addiction with compulsive involvement, lack of interest in other activities, and excessive human-machine interaction, which meets the criteria of prominence, mood change, tolerance, withdrawal symptoms, conflicts and relapses.\n\nGenerally, the studies that have been developed so far report the unfavorable psychological consequences of technological addictions and their impact on the performance and development of students; however, there is little research that explains the psychological causes that aggravate or favor students to develop technological addictions.\n\nAccording to the data found in publications from 2020 to 2022, a common pattern reported in international and national journal articles was the increase of addictive behaviors or problematic use of technological devices, as well as the increase of mental health problems in the university population (in particular the exacerbation of negative emotions). In this scenario, we did not properly find a psychological model that would enable an explanation of the increase in digital addictions.\n\nThe present study emerged as a project between January and February 2022, when the third wave of COVID-19 infection was beginning to grow rapidly in Peru. After the traumatic experience lived during the first and second waves, as well as the measures adopted by the government to counteract the contagion through social isolation, mandatory quarantine, virtual classes in universities, in addition to the accumulated research that showed the high prevalence or increase of negative emotions and the increase in the excessive or problematic use of various technologies, the following hypothesis emerged: distress and anxiety due to COVID-19 are factors with direct impact and aggravate the problematic use of digital and interactive devices with the consequent resultant propitiating pictures of digital addictions in Peruvian university students (see Figure 1).\n\nIf the proposed model is empirically validated, it would be very useful to propose new intervention modalities or strategies to counteract or reduce the problems associated with the excessive or addictive use of interactive technologies such as smartphones, internet and video games. As Zhang et al. (2020) argue, using a new explanatory model may allow the design or planning of effective interventions in the context of health problems such as the Covid-19 pandemic.\n\nIn the context of the analyzed, the main objective of the research was to determine the impact of distress and anxiety due to COVID-19 on digital addictions in Peruvian university students in the third wave period.\n\n\nMethods\n\nThe study corresponds to a non-experimental, cross-sectional, explanatory design (Ato et al., 2013). Due to the nature of the analysis of relationships configured by latent variables, according to Byrne (2010) it corresponds to structural equation modelling.\n\nThe population consisted of university students of different professional careers, residents of metropolitan Lima and Callao (Peru), enrolled during the first semester of 2022 in public and private universities, of both sexes, between 18 and 35 years of age. A total of 802 students participated in the study. Sampling was non-probabilistic by convenience. The sample was mostly female (64.1%), single (96%), students of health sciences (57.4%), from a national university (62%), about 50% were infected with COVID-19, with a family member infected in most households (69%), a third with a deceased family member in the household, and most had the third dose of vaccine against COVID-19 (84.4%).\n\nMULTICAGE CAD-4 Questionnaire. This questionnaire was designed by Pedrero-Pérez et al. (2007). From the version adapted by Rodríguez-Monje et al. (2019) that assesses behavioral addictions, three of the scales were taken for the present study: internet abuse (items 17 to 20), video games (items 5 to 8) and problematic cell phone use (items 13 to 16). Each scale comprises of four items with dichotomous response (yes = 1, no = 0). The terms CAGE and CAD are acronyms that accompany the term multiple which alludes to a multi-scale instrument. Each scale (CAGE) has four items because it evaluates self-perception of the problem, perception by cohabitants, associated feelings of guilt and signs of abstinence or inability to control the behavior. Satisfactory validity evidence is reported based on the internal structure of the construct (GFI = 0.99, AGFI = 0.98, RMR = 0.002) and Cronbach's alpha values greater than 0.85 for all self-report scales (Rodríguez-Monje et al., 2019).\n\nIn the present study for the three factors, very satisfactory fit indices were obtained that support the validity based on the internal structure of the construct (χ2 = 228.631, df = 50, p = 0.000; CFI = 0.97; TLI = 0.96; RMSEA = 0.06, SRMR = 0.08); the estimated internal consistency with McDonald omega was 0.77, 0.80 and 0.93 for smartphone, internet and video game use, respectively.\n\nDistress Scale (ED). A unidimensional self-report designed by Sandín et al. (2020) was used to assess distress based on items with indicators related to negative emotional experiences. It consists of 11 items with a 5-anchor Likert response format ranging from never (1) to always (5). The authors report high reliability estimated by internal consistency (α = 0.93, ɷ = 0.93). For use, validity (χ2 = 341.884, df = 35, p = 0.000; CFI = 0.98; TLI = 0.98; RMSEA = 0.05, SRMR = 0.04) and reliability (omega = 0.93). The scale scores were estimated very satisfactorily in this study.\n\nAnxiety Scale by COVID-19. To the scale designed by Matta et al. (2022) to assess COVID-19 anxiety, which consists of three items (I am worried about COVID-19, I am afraid of getting COVID-19 or becoming infected again, I am afraid of facing a situation related to COVID-19), an item “I am afraid of losing my life because of COVID-19” taken from the Coronavirus-19 fear scale by Ahorsu et al. (2020) was added. It presents response options ranging from strongly disagree (1) to strongly agree (7).\n\nFor its use in the present study, the psychometric properties of validity and reliability were examined. The AFC fit indices estimated with WLSMV (χ2 (2) = 42.885, p = 0.000; CFI = 0.998, TLI = 0.998, RMSEA = 0.038, SRMR = 0.017) confirm the validity based on the internal structure of the construct. The internal consistency estimated with ordinal alpha (0.94) and McDonald's omega (0.94) evidence high reliability for the instrument scores.\n\nThe instruments were administered through a format designed in Google Drive, for which the URL link was sent to the target population via email, WhatsApp, and Facebook. Only the students who offered consent were able to reply to the instruments anonymously.\n\nPrior to data transformation for analysis, data quality control was performed, eliminating cases with zero variance and cases with extreme data according to the multivariate centroid analysis with the Mahalanobis distance, and then data processing was performed according to the research objectives. The descriptive analysis of the variables was executed with frequency analysis; the latent structure regression models were examined with structural equation modeling. The statistical programs used according to the requirements were jamovi version 2.3.28 (The jamovi project, 2024), the free distribution package R version 4.3.1 (R Development Core Team, 2020) and RStudio version 2023.06.2 (RStudio Team, 2023).\n\n\nResults\n\nTable 1 shows two females for every male with a high level of distress. Likewise, a high level of anxiety due to COVID-19 is observed in approximately 3 out of 10 females and 2 out of 10 males.\n\nTable 2 shows that around 4 out of 10 have problems with smartphone use and one third have problems with internet use, regardless of gender. Likewise, for every woman there are 2.6 times more men with problems in the use of video games.\n\nThe proposed theoretical model is supported by the empirical evidence because the goodness-of-fit indices turn out to be very favorable: χ2 (132) = 525.061, p = 0.000; CFI = 0.979; TLI = 0.975; RMSEA = 0.061 [0.056, 0.066]; SRMR = 0.044; that is, the robust SEM model presents very good incremental fits (CFI and TLI) by being greater than 0.95 (Hu and Bentler, 1999), and the absolute fit index RMSEA that evaluates the closeness to a perfect model denotes adequate fit because it presents a value less than 0.08 and the SRMR index that evaluates the error in the model reproduction by presenting value less than 0.06 indicate a very good fit (Hu and Bentler, 1999).\n\nThe structural model (Figure 2) allows us to observe that the latent variables distress and anxiety due to COVID-19 have direct and positive effects on digital addictions, which as a latent construct is configured by addiction to smartphone, internet and video games. Path coefficients evidence that distress (β = 0.31, p < 0.001) is of higher incidence than anxiety due to COVID-19 (β = 0.28, p < 0.001). The joint impact of the two exogenous variables on digital addictions in college students is 22%. On the other hand, the exogenous variables present a positive covariance of low magnitude, denoting absence of collinearity or overlap.\n\nIn The specific proposed models evaluate the effects of distress and anxiety due to COVID-19 on each of the interactive technologies with addictive potential such as smartphones, internet and video games (Figure 3). The indices to assess the models turned out to be of very good fit: CFI and TLI > 0.95, RMSEA < 0.06, SRMR < 0.05.\n\nThe structural regression coefficients show that although the latent variables distress and anxiety by COVID-19 have direct and significant effects on each of the digital addictions, the impact on the criterion variables is varied. Distress impacts more strongly on internet addiction (β = 0.31, p < 0.001) while anxiety affects more strongly on smartphone addiction (β = 0.33, p < 0.001). The explained variances of the combined effects of the two exogenous latent variables are quite high on smartphone addiction (R2 = 25%) and internet (R2 = 19%) and to a lesser but equally significant extent on video games (R2 = 6%).\n\n\nDiscussion\n\nEven though technologies such as internet, smartphone and videogames can offer benefits for people's lives if their use is controlled (Capa-Luque et al., 2022; Ime et al., 2024), nevertheless, it should not be left aside the problems that could be generated in psychological and physical health when there is an problematic or addictive usage (Peng et al., 2022; Ran et al., 2022). In this regard, the findings of the present study show that the two latent and exogenous variables (stress and anxiety due to COVID-19) have direct effects on digital addictions, while the exogenous variables present a positive covariance as expected by theory and it is concordant with what has been found by Li et al. (2024).\n\nThe general model explains 22%, but in the specific models the explained variance of the exogenous variables on smartphone addiction (25%), internet (19%) and video game addiction (6%) were varied. The internal validity of all models was supported by goodness-of-fit indices that were found to be very satisfactory (CFI and TLI > 0.95, RMSEA and SRMR ≤ 0.06).\n\nThe data support the proposed hypothesis that some personal factors such as anxiety and distress can also promote or hinder positive adaptation of individuals (Hébert et al., 2022). In the pandemic context, students found an escape mechanism or refuge in the use of social networks through the Internet, smartphones and video games (Ime et al., 2024; Capa-Luque et al., 2023), with the risk that their uncontrolled use becomes problematic or addictive (Jalal et al., 2022; Sixto-Costoya et al., 2021). As this fact falls outside healthy parameters, it demands urgent attention to mitigate the negative impacts.\n\nAn alternative proposed by various researchers in the field of addictions to reduce the problematic use of interactive technologies would consist of strengthening awareness, self-control, skills and knowledge for a responsible use of digital resources (Chung et al., 2019; Greenfield, 2018). Another alternative approach would involve exposing students to promotional educational programs of skills and strategies for the management of negative emotions (distress and anxiety) to help the problematic or addicted user to better understand and manage their emotional functioning, based on the premise that resorting to the use of digital technologies is an inadequate coping mechanism to psychological and physical discomfort generated by distress and anxiety would consist, as proposed by Taquet et al. (2017).\n\nWith respect to the psychological distress experienced in the context of the COVID-19 pandemic, the results show that the great majority of students presented distress (around 80%) and anxiety (70%) between moderate and high levels; proportionally, for every male, two females were found with high levels of distress and anxiety.\n\nIn this sense, the findings of the present study definitively confirm what was pointed out by Deng et al. (2021) and Saladino et al. (2020), regarding the fact that the university population is considered a risk group for developing stress and anxiety. It is evident that, in the pandemic context, due to the implications of the state of emergency and virtual education, university students were more vulnerable in their physical and psychological health and quality of life (Parvar et al., 2022; Bazán-Ramírez et al., 2022).\n\nRegarding the use of digital technologies such as smartphones and internet, about 40% of students were found in the category of problematic or clinically significant use with risk of addiction, affecting males and females equally. This category of problematic use was established for a cut-off point of 95 to 99 percentile, and this would imply that students located in this category are not people who use these digital devices too much due to academic or work activities, but are very dependent users of these technologies. With respect to video games in the category of problematic use, the difference between males (18.8%) and females (2.7%) is quite marked. These results are consistent with several studies that report the increase in excessive use of digital connections; as referred by Meng et al. (2022), because they found a prevalence of 27% for addiction to cell phones, 8.23% to the internet and 6.04% to video games. Similarly, Sandoval et al. (2020) found the presence of internet addiction (31%) in university students who failed undergraduate courses and greater adherence to video games in men. Along the same lines, Ruiz-Palmero et al. (2021) found risk and abuse of video games and smartphones in university students.\n\nThe most important limitation of the study is its external validity due to the type of non-probabilistic sampling used, in this sense the possibility of generalization to other contexts should be carried out with caution; however, despite the limitation, the present study is considered important in view of the existing knowledge gap in relating the variables studied through explanatory models such as those addressed in the present study. That is, we consider that the findings obtained may be useful for mental health professionals to strengthen or expand knowledge, as well as to design programs aimed at facilitating effective management of negative emotions such as distress and anxiety, and to prevent or intervene early in behavioral problems related to digital addictions.\n\nOn the other hand, the model assumed in the study corresponds to structural regressions of latent variables of structural equation modeling (SEM), a strategy that allows the evaluation of weak causal relationships (Keith, 2019), because direct causality corresponds to experimental designs, in the SEM causal relationships are given by the fulfillment of three conditions (Byrne, 2010; Keith, 2019): 1. Existence of functional relationship between variables, 2. The cause precedes the effect in time (in a real or logical way) and the relationship must not be spurious. 3. The relationship must not be spurious. Therefore, despite the possible limitations of a cross-sectional study, the research satisfactorily fulfills the general objective of science of seeking models and theories to explain important facts of reality, which in the specific case of the present study consists of offering an explanation where the structural relationships between the constructs (latent variables) can imply causality (albeit weak, but causality) and covariances simultaneously.\n\nIt is also suggested to the agents of change and especially to the university authorities to promote the design and implementation of intervention programs aimed at reducing the problematic use of digital devices. It is urgent to raise awareness with timely information and expose to preventive programs for students to use interactive technologies such as smartphones, internet and video games to benefit from their responsible use and a means of social recreation and not a risk factor for the health of students.\n\n\nConclusions\n\nThe results of the proposed structural regression models allow us to argue that stress and anxiety due to COVID-19 favor the abuse of technological devices and the increase of digital addictions in university students, thus affecting not only their physical and psychological health but also their academic and professional training.\n\nThe problematic use or addiction to the smartphone and internet affects a significantly larger group of students (about 40%) compared to addiction to video games that affects men (20%) and women (3%) differentially.\n\nWith respect to stress, 8 out of 10 students present problems of consideration in the moderate and high categories. About 70% of the students present anxiety due to COVID-19 between moderate and severe levels. In addition, proportionally for every male there are two females with high levels of distress and anxiety.\n\nThe study was conducted in accordance with the Declaration of Helsinki and was approved by the Research Projects Office of the Central Institute of Research Management of the Vice Rectorate of Research, ratified the approval by the Faculty of Psychology of the Universidad Nacional Federico Villarreal by means of the Dean's Resolution N° 2076-2022-D-FAPS-UNFV dated March 30, 2022.\n\nAn informed consent form was designed and presented in the first section of the Google Form. Only students who read the consent form and agreed to participate in the research were invited to answer the instruments online. Participants were also informed that they were free to withdraw and stop filling out the instruments at any time by closing the virtual form without saving any information.\n\nDuring the year 2022 classes in Peruvian universities were still virtual due to the COVID-19 pandemic, which is why obtaining written informed consent was sent to students' emails or WhatsApp accounts. Along with the consent letter, the link to access the google form was sent. Consent that was also submitted within the google form. Both the informed consent and the google form are accessible at Data Availability statement (Capa, 2024).\n\nThis informed consent form was submitted as an annex together with the research project to the evaluating entity (Research Projects Office). The research project as well as its annexes (including the letter of consent used) complied with the approval report of the ethics committee of the Faculty of Psychology of the Federico Villarreal National University.", "appendix": "Data availability\n\nHarvard Dataverse: Impact of distress and anxiety due to COVID-19 on digital addictions in university students in the third wave period. https://doi.org/10.7910/DVN/UHDRCW (Capa, 2024)\n\nThis project contains the following underlying data:\n\n- Database research (Data_INV22_English.sav)\n\nData are available under the terms of the License/Data Use Agreement PUBLIC DOMAIN (CC0 1.0).\n\nHarvard Dataverse: Impact of distress and anxiety due to COVID-19 on digital addictions in university students in the third wave period. https://doi.org/10.7910/DVN/UHDRCW (Capa, 2024)\n\nThis project contains the following underlying data:\n\n- Psychometric properties of measuring instruments (Psychometric Properties.pdf )\n\n- Annexes – Instruments.docx\n\nData are available under the terms of the License/Data Use Agreement PUBLIC DOMAIN (CC0 1.0).\n\n\nAcknowledgements\n\nNone.\n\n\nReferences\n\nAhorsu DK, Lin CY, Imani V, et al.: The Fear of COVID-19 Scale: Development and Initial Validation. 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Publisher Full Text\n\nSaladino V, Algeri C, Auriemma V: The psychological and social impact of Covid-19: New perspectives of well-being. Front. Psychol. 2020; 11: Article 577684. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSandín B, Valiente R, García-Escalera J, et al.: Impacto psicológico de la pandemia de COVID-19: Efectos negativos y positivos en población española asociados al periodo de confinamiento nacional Bonifacio [Psychological impact of the COVID-19 pandemic: Negative and positive effects in Spanish people during the mandatory national quarantine]. Revista de Psicopatología y Psicología Clínica. 2020; 25: 1–22. Publisher Full Text\n\nSandoval CA, Ugarte GF, Zelada-Ríos M, et al.: Control of impulses and addictions in medical students of the Ricardo Palma University, Lima-Peru. Educación Médica. 2020; 22: 384–389. Publisher Full Text\n\nSandoval KD, Morote-Jayacc PV, Moreno-Molina M, et al.: Depression, Stress and Anxiety in Students of Human Medicine in Ayacucho (Peru) in the Context of the COVID-19 Pandemic. Rev. Colomb. Psiquiatr. 2023; 52: S77–S84. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSarıalioğlu A, Atay T, Arikan D: Determining the relationship between loneliness and internet addiction among adolescents during the covid-19 pandemic in Turkey. J. Pediatr. Nurs. 2021; 63: 117–124. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSavitsky B, Findling Y, Ereli A, et al.: Anxiety and coping strategies among nursing students during the covid-19 pandemic. Nurse Educ. Pract. 2020; 46: 102809. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSixto-Costoya A, Castelló-Cogollos L, Aleixandre-Benavent R, et al.: Global scientific production regarding behavioral addictions: An analysis of the literature from 1995 to 2019. Addict. Behav. 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PubMed Abstract \| Publisher Full Text \| Free Full Text" }	[ { "id": "322445", "date": "12 Sep 2024", "name": "Africa Borges", "expertise": [ "Reviewer Expertise Methodology of Behaioral Sciences" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article proposed for indexing has, in my view, sufficient value for this purpose. On the one hand, the subject is of great relevance, since the pandemic has been a turning point in life, both at the level of the various strata of society and from an international perspective. It has been a hard experience, but it is important to develop what we have been able to learn from it. In this sense, this study provides an important approach, relating additions that may have developed during the pandemic. The thoroughness of the analysis leaves no doubt as to its relevance.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13164", "date": "27 Jan 2025", "name": "ALDO BAZAN-RAMIREZ", "role": "Author Response", "response": "Dear Reviewer. Your comments have helped improve our manuscript. I appreciate the time and interest that you have focused on reviewing and giving feedback on our work One of our variables is distress and not stress, as can be seen in the title and throughout the paper. A correction has been made in the abstract, replacing a drafting error in the name of an instrument (COVID-19 worry scale) with the correct name (anxiety scale by COVID-19). The naming of the variables has been standardized throughout the article. Since we have used the structural equation modeling strategy, the relationship between the variables is expressed in terms of impact or direct effects of the exogenous variables on the endogenous or dependent variable. The variables distress and anxiety due to COVID-19 are unidimensional variables (no dimensions), and their description is shown in Table 1. The digital addictions variable is described by its dimensions (Smartphone, Internet and Video game) as shown in Table 2." } ] }, { "id": "334066", "date": "05 Dec 2024", "name": "Georgina Eugenia Bazán Riverón", "expertise": [], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article meets the requirements. I only suggest a few recommendations:\n- The title refers to stress and anxiety. In the summary and in the method section it names another variable (worry) and it does not speak of anxiety, but rather worry. They are not the same. It is suggested that variables are always named the same way. - It seems to me that the problem statement can be more specific, detailing the relationship between variables. - In the results, a detailed description of the dimensions of the instruments would help to a deeper understanding. - Review punctuation and spaces in the text\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13164", "date": "27 Jan 2025", "name": "ALDO BAZAN-RAMIREZ", "role": "Author Response", "response": "Dear Reviewer. Your comments have helped improve our manuscript. I appreciate the time and interest that you have focused on reviewing and giving feedback on our work One of our variables is distress and not stress, as can be seen in the title and throughout the paper. A correction has been made in the abstract, replacing a drafting error in the name of an instrument (COVID-19 worry scale) with the correct name (anxiety scale by COVID-19). The naming of the variables has been standardized throughout the article. Since we have used the structural equation modeling strategy, the relationship between the variables is expressed in terms of impact or direct effects of the exogenous variables on the endogenous or dependent variable. The variables distress and anxiety due to COVID-19 are unidimensional variables (no dimensions), and their description is shown in Table 1. The digital addictions variable is described by its dimensions (Smartphone, Internet and Video game) as shown in Table 2." } ] }, { "id": "334071", "date": "12 Dec 2024", "name": "Octaviano Garcia Robelo", "expertise": [ "Reviewer Expertise Education and psychology in higher education" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article can be approved: No minor changes are required. The article analyzes and statistically explains the effects of anxiety and stress factors on digital addictions in university students. Its theoretical framework helps to theoretically substantiate the existence of stress and anxiety in more than a quarter and about half young college students in various countries around the world, which are shown and substantiated in their research reports. Also, it presents and details the digital additions, mainly cell phone and video games, in young people, which increased as a result of the Pandemic COVID_19. The methodology for both the data collection and the use of structural equations, allows confirming and explaining with precision the statistically significant influence of the two models shown. This methodology can be replicated for other investigations. The results contribute to substantiate the consequences in mental health brought about by the COVID_19 pandemic in university students in Peru. This phenomenon, which undoubtedly occurred and occurs in other countries of the world, should be addressed and investigated for the prevention of major consequences, such as suicide, low performance and dropping out of their studies. The references are updated and totally related to her research topic.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13164", "date": "27 Jan 2025", "name": "ALDO BAZAN-RAMIREZ", "role": "Author Response", "response": "Dear Reviewer. Your comments have helped improve our manuscript. I appreciate the time and interest that you have focused on reviewing and giving feedback on our work One of our variables is distress and not stress, as can be seen in the title and throughout the paper. A correction has been made in the abstract, replacing a drafting error in the name of an instrument (COVID-19 worry scale) with the correct name (anxiety scale by COVID-19). The naming of the variables has been standardized throughout the article. Since we have used the structural equation modeling strategy, the relationship between the variables is expressed in terms of impact or direct effects of the exogenous variables on the endogenous or dependent variable. The variables distress and anxiety due to COVID-19 are unidimensional variables (no dimensions), and their description is shown in Table 1. The digital addictions variable is described by its dimensions (Smartphone, Internet and Video game) as shown in Table 2." } ] } ]	1	https://f1000research.com/articles/13-1010
https://f1000research.com/articles/13-1365/v1	14 Nov 24	{ "type": "Research Article", "title": "Evaluation of the fintech era on the performance of Moroccan banks: analysis through non-performing loans", "authors": [ "Hicham Sadok", "Mohamed El Hadi El Maknouzi", "Mohamed El Hadi El Maknouzi" ], "abstract": "Background This study aims to contribute to a better understanding of the impact of the financial technologies (fintech) era on the performance in the banking sector, measured through non-performing loans (NPL) and their coverage by provisions for NPL. It is a question of knowing whether banking investment in fintech makes it possible to better evaluate the granting of credits, and therefore makes it possible to reduce overdue credits.\n\nMethods To this end, the method used consists of using a regression analysis and a Pearson correlation applied to the financial data of Moroccan banks observed during two distinct periods, namely 2007-2014, considered pre-fintech, and the period 2015-2022, considered as the fintech period.\n\nResults With the emergence of the fintech era, the Moroccan banking situation improved slightly compared to the pre-fintech period: bad debts did not increase despite the significant increase in net banking income and the size of banking assets during the fintech era.\n\nConclusions The implementation of fintech has improved customer relationship management, credit risk analysis and loan monitoring services, which ultimately reduces non-performing loans and improves the coverage of non-performing loans by provisions. The main implication of the results allows us to deduce that the implementation of fintech makes it possible to have a positive impact on overdue credits, and they are also likely to serve as a lever for the inclusion of those excluded from banking services.", "keywords": [ "Fintech", "nonperforming loans", "banking performance", "loans provisions." ], "content": "1. Introduction\n\nThe evolution of technology is sometimes dizzying, innovative financial technologies, often called fintech, are making major inroads around the world (Mahboub et al., 2023). This advancement of the fintech revolution has changed the traditional role of banking by introducing new financial services such as digital lending, peer-to-peer lending, online payments, virtual currency, crowdfunding, etc. These new electronic financial services have increased the role of banking services as service providers, and have challenged the banking business (Sadok & El Maknouzi, 2021).\n\nHowever, historical hindsight shows that the arrival of fintech does not constitute the first technological “disruption” to occur in the banking markets. The development of ATMs and online banking also constituted profound changes brought about by new technologies, which have little changed the structure of banking markets (Mahboub and Sadok, 2022). The emergence of online banking has been a factor of radical change in the structure of banking markets, allowing the appearance of new players offering substitute banking services (Sakka et al., 2022). The effects of this emergence have not been a radical change in the banking landscape, but an evolution in consumer practices, with the implementation of digital banking services including in conventional banks. It is in this same state of mind that in 2021 only, 445 new fintech were created and 2.8 billion euros raised in 155 operations of which conventional banks were the first subscriber’s (Sadok, 2023a).\n\nSeveral researchers have described the fintech revolution for banks as a double-edged sword: on the one hand, it reduces banking costs by making it possible to better and quickly know customers, reduce the requirements of bank branches and therefore increase banking performance. On the other hand, fintech increases the operating costs necessary for setting up adequate infrastructure for the development of fintech technologies, particularly in emerging countries, and therefore deteriorates performance (Sadok & Assadi, 2023). Ozili (2018), Phan et al. (2020), Ozili (2021) and Gomber et al. (2018) explored the impact of the fintech era on banking performance through Non-Performing Loans (NPL). They concluded that the fintech era has a negative influence on banking sector NPLs. Zalan and Toufaily (2017) and Thakor (2019) also come to this conclusion. These authors also conclude that the fintech revolution negatively influences the performance of banks. It reduces market shares and revenues as well. Magee (2011) confirms this finding by stating that fintech loans are non-performing because the collateral requirements for loan recovery are low in fintech loans. However, Claessens et al. (2018) argued that the default risks in fintech loans are low because they have a short maturity, focused on consumer credit, compared to those of traditional banks, whose loans are also oriented towards real estate and the commercial sector. Other researchers such as Ozili (2018) and Wang et al. (2021) have highlighted other positive impacts of the fintech revolution in poverty reduction, contribution to sustainable development, reduction of costs generated by intermediaries and financial inclusion (Ozili, 2018; Wang et al., 2021).\n\nThese arguments reveal the non-existence of a consensus on the impact of the fintech revolution on banking performance. Once these elements of perspective have been established, and ignoring the effects of macroeconomics such as the unemployment rate, the real interest rate, the total external debt/GDP and the inflation rate on the performance of the banking sector, the objective of this article is to focus on the impact of the introduction of financial technologies in the operational processes of Moroccan conventional banks on their performance.\n\nTo our knowledge, there is no specific study that has examined the role of the fintech era on the performance of the banking sector in Morocco. This article attempts to contribute to filling this gap and add to the growing literature on the link between the fintech era and its impact on banking performance. Thus, to ensure whether fintech makes it possible to better evaluate the granting of bank credits, and therefore makes it possible to reduce overdue credits, measured by NPL, this work will be presented as follows: Section 2 reviews the available literature on the above issue; Section 3 presents the methodology and empirical framework; Section 4 covers the analysis and discussion of the results; the last section highlights the concluding remarks.\n\n\n2. The relationship between fintech and banking performance: literature review\n\nThe study of the effects of fintech on banking performance has been the subject of multiple studies in recent years. Several researchers have attempted, through different measures and approaches, to empirically examine the influence of fintech on financial services, and, consequently, its impact on the performance of the banking sector. By analyzing the opportunities and threats of fintech services on the traditional banking sector, Romānova and Kudinska (2016), concluded that the latter faces an existential risk in view of the fierce competition, and the adaptation challenges imposed on it by fintech. In the same vein, Wewege et al. (2020) confirm this finding and argue that innovation in financial services improves the banking sector. Financial innovation driven by fintechs contributes significantly to the improvement of services and products specifically tailored to each customer, as well as to the speed and profitability of financial operations (Sadok et al., 2022). Studies conducted by Haas et al. (2015), Setia et al. (2013), Mahboub and Sadok (2023a) corroborate these results and highlight the positive aspects of the fintech era on the performance of the banking sector.\n\nNavaretti et al. (2017) noticed that traditional banks, especially large commercial banks, are indifferent to fintech services. They argue that these major banks agree that the fintech era is not a temporary phenomenon and have therefore already started implementing digital financial services to ensure their long-term sustainability, and that the fintech revolution can only be beneficial (El Alami et al., 2015).\n\nIn this context, Tang (2019) explored whether fintech constitutes a substitute or complement to traditional banks. He wonders if they respond more to the needs of customers not covered by traditional banks, and in this case, it would be a complement, or rather to the new needs of customers of traditional banks, which means that fintech will be a substitute for banking conventional. He comes to a conclusion that fintech constitutes a substitute for traditional banks. This conclusion is therefore in line with a competitive impact of fintech on traditional banks, since the expansion of fintech is not achieved through complementarity of traditional banks on the credit market.\n\nThe main element through which fintech can affect banking performance lies in its lower operating costs than traditional banks (Sadok, 2023a). They are for several reasons:\n\nFirst, the use of information and communication technologies allows them to have granting techniques that are significantly less costly in terms of personnel, both quantitatively and qualitatively (Benkhayat et al., 2015). The project acceptance procedure can be fully automated without necessarily requiring human intervention: a person who wants a loan completes an online application. The request is accepted or rejected based on the elements provided, such as analysis of bank account record, or retrieved indirectly through other data sources. This process of evaluating loan requests, based on immediacy and big data, makes it possible to better select borrowers and reduce the volume of non-performing loans (NPL). Fintech can thus provide access to loans with reduced personnel costs, but also reduce physical capital costs due to the absence of a branch network. Fuster et al. (2019) carried out a study on real estate loans granted in the United States. Results showed that fintech process loan applications 20% faster than traditional banks. They also observed that this processing speed does not come at the expense of risk, since fintech do not suffer from a greater number of defects.\n\nSecondly, fintech, like all new entrants to a market, does not suffer, unlike long-established companies, from operating costs that are difficult to reduce such as employee acquired rights and significant structural costs (Sadok, 2023b). Fintech can thus afford to more easily adapt its cost structure to new services and have a cost advantage over traditional banks which allows them to fundamentally transform the structure of banking professions (Mahboub & Sadok, 2023b). Welltrado (2018) estimates that operating costs represent 2.7% of outstanding loans at Lending Club, compared to 7% at traditional banks. The very significant gap in operating costs can thus offer a major competitive advantage to fintech to conquer a significant market share in the credit markets. Hau et al. (2019) show that fintech credit providers in China enjoy a competitive advantage over traditional commercial banks. This therefore creates a negative influence on the credit market share held by conventional commercial banks.\n\nIn this same vein, Cortina and Schmukler (2018) estimate that the expansion of fintech services has little impact on banking services. They reported that as a result of this competitive pressure, just 1% of banking revenue losses were seen in North America. Philippon (2015) showed that the unit cost in financial intermediation has remained constant over the last 130 years. On this basis, Philippon (2017) concludes that there is plenty of room for improvement, which can be enabled by improvements in information technology through the arrival of Fintech. Pierri and Timmer (2020) investigated the role fintech on banking NPLs during the global financial recession. They concluded that banks that use more IT services in banking transactions have fewer NPLs. Ozili (2021), who explored the impact of the fintech on Non-Performing Loan (NPL) banking sectors in 35 countries, concluded that the fintech-led transition has a negative impact on banking NPLs. In the same line, Buchak et al. (2018) carried out a study on the United States where they concluded that fintech benefits from an advantage in terms of convenience for borrowers rather than lower service costs. They even note that the ease of online origination appears to allow fintech lenders to charge higher rates, particularly among less risky borrowers, presumably the least price and time sensitive. Maier (2016) reaches the same conclusion in an analysis of SMEs borrowing from a European fintech platform. The convenience and transparency of the process play much more role than economic criteria or aspects linked to customer relations. Thus, the flexibility offered by fintech would play a more decisive role than the cost of financing argument in attracting SME borrowers (El Maknouzi and Sadok, 2021).\n\nIn the same order of conclusion, Bröstrom et al. (2018) reveal that in the United States, the degree of distrust in banks favors the growth of fintech. The study by Fungacova et al. (2019) also shows that trust in banks is lowest in developed countries. Therefore, fintech expansion is expected to have a bright future in these countries, while in developing countries there is still much to reveal about the ins and outs of this relationship, more particularly in the role of fintechs in development. The experiences of implementing financial technology in certain southern countries such as Kenya and China, through pilot experiences such as that of Taoboa and M-Pesa, revealed that the success of fintech has made possible not only accessibility to banking services for the excluded, but more generally social inclusion and inclusive growth (Sadok, 2021).\n\nThe field of fintech, and their repercussions, in the Moroccan context is still not sufficiently studied. This analysis attempts to contribute through the treatment of a specific problem, namely whether the implementation of fintech in the Moroccan banking sector makes it possible to better evaluate the granting of credit.\n\n\n3. Methods\n\nTo analyze the existence of the relationship between the appearance of fintech in the operational and business processes of banks and the performance of the latter, we estimate a panel data model from a representative sample of data from Moroccan banks of 2007 to 2022. Thus, we divided the period of this study into 2 sub-periods: the first period where fintech was not sufficiently present in the business processes of Moroccan banks, namely the period 2007-2014. This period would serve as a reference to compare it to that of the second period studied, that of the fintech era, 2015-2022, to be able to determine whether the banks studied were more or less performant. The division of the period studied into 2 sub-periods, considering the fintech era as that beginning from 2015, is justified if we take into consideration the emergence of fintech and their generalization in the banking field from the second decade of this millennium in developing countries. We justify this temporal demarcation by referring to the work that raised the same theme in the literature review made above, and more particularly that of Ozili (2021).\n\nAt the end of 2022, the number of credit institutions and similar organizations approved in Morocco stands at 90 establishments, including: 19 banks, 5 participatory banks, 29 financing companies, 6 offshore banks, 11 micro-credit associations, 18 payment institutions, the Deposit and Management Fund and the Central Guarantee Fund. Our sample includes five Moroccan banks listed in the Table 1 in annexes, including the average size of their balance sheet, the average of their net banking income (NBI), as well as the average of their Return on Equity (ROE) during the 2 periods studied. The choice of these banks comes from the fact that the share of these first 5 banks in the total assets of the banking sector in Morocco stood at 76.4% in 2022, at 75.4% in 2014 against 78.1 % in 2007 (Mouline and Sadok, 2021a, 2021b). Therefore, the level of concentration of the banking activity of these 5 banks is high, and remains approximately the same throughout the period studied between 2007 and 2022.\n\n* In billions of dirhams (dhs).\n\nIn the present study aimed at investigating the influence of the fintech era on the performance of the banking sector, we have included the following proxies. We included the overall value of non-performing loans (NPLv) and the coverage rate of these loans (Cnpl) as indicators to measure the performance of the banking sector. In addition, the rate of variation of the interest margin (IMv), the variation of interest charges divided by net banking income(I/NBI), the variation margin on commissions (MCv), the operating coefficient (OC), the value of provisions for non-performing loans (Pnpl), are included as explanatory variables. These explanatory variables, synthesized here to analyze the problem studied, were chosen on the basis of the analysis of the literature (Phan et al., 2020; Ghosh, 2015; Dwumfour, 2017; Fernández et al., 2016).\n\nIn addition, to make the study more comprehensive, we have drawn up the figures (see Figures 1 and 2 in appendices): each figure corresponding to one of the 5 banks processed in this sample) summarizing the variables to be explained, namely the performance of banks, measured essentially by non-performing loans and the coverage rate of these loans, and explanatory variables namely, the rate of variation of the interest margin, the variation of interest charges divided by net banking income, the variation margin on commissions, the operating coefficient, the value of provisions for non-performing loans.\n\nIn the current analysis, we have included five explanatory variables, namely, the rate of variation of the interest margin (IMv), the variation of interest charges divided by net banking income (I/NBI), the variation margin on commissions (MCv), the operating ratio (OC) and the value of provisions for non-performing loans (Pnpl):\n\nThe rate of variation of the interest margin (IMv) is included because previous literature concludes that expansion in banking activities results in increasing banking profitability and capital buffer, which eventually decreases nonperforming loans (NPLv) and the amount allocated to cover these loans (Cnpl). Hence, we assume a negative relationship between the rate of variation of the interest margin and banking performance.\n\nThe variation of interest charges divided by net banking income (I/NBI) was chosen because countries facing higher interest charges have a higher chance of banking underperformance. Significant amounts of interest charges lead to defaults and poor bank performance.\n\nThe variation margin on commissions (MCv) also included as an explanatory variable because the increase in commissions promotes organizational efficiency and productivity, and therefore we can assume that the increase in this variable varies in the opposite direction as non-performing loans.\n\nThen, we also took the operating ratio (OC) as an independent variable because previous studies concluded that the increase in the operating ratio is the consequence of a reduction in non-performing loans. Therefore, we can assume a negative relationship between the OC and NPL. The value of provisions for non-performing loans (Pnpl) have been selected because previous literature exhibits that the value of provisions for doubtful debts is a determining criterion for the quality of outstanding debts: the higher this rate, the more the bank is convinced by the fact that these debts are irrecoverable even after recourse and trial. We assume a positive relationship between the value of provisions for non-performing loans and the variables to explain banking performance, namely, the nonperforming loans and the coverage rate of these loans.\n\nFinally, BIN variable is considered as a binary variable that takes the values 1 from 2015 to 2022 and 0 from 2007 to 2014. BIN is used to describe the influence of the fintech era on the performance of the banking sector. We assume here that BIN has a positive impact on the performance of the banking sector. Technological innovation and the growth of fintech products with adequate infrastructure can increase banking performance. The Table 2 in annexes shows the variable description and their expected relationship.\n\n\n4. Model framework and variables analysis\n\nThis section highlights the model framework used to analyze the determinants of the performance of the Moroccan banking sector in the fintech era. We used the financial data of the 5 banks in our sample from the fintech period compared to the pre-fintech period to seek the meaning, “intelligibility”, of the differences in bank performance during these two periods. The basic idea that linear structural equation modeling (LSEM) seeks to address below is to infer causal relationships from data of variables considered by the current state of knowledge to be explanatory. The objective here is to know whether the association observed between banking performance, measured by the good management of non-performing loans, is, or not, the result of a causal relationship induced by the arrival of fintech allowing better knowledge and a better evaluation of credit applicant files, and consequently an improvement in the explanatory variables of the model.\n\nEquations 1 and 2 above of the LSME model are a formalized representation of the relationships between the variables considered from existing knowledge. It is possible to draw valid causal inferences from observing covariations between these variables, except that we will extend the model to include analysis of interactions over time. Thus, the equation formulated after including the interaction variable of the fintech period (BIN = 2015-2022) is as follows:\n\nWhere NPLv represent nonperforming loans, Cnpl is used to measure coverage rate of these loans, IMv measure the rate of variation of the interest margin, I/NBI is used to describe the variation of interest charges divided by net banking income, MCv is represent the variation margin on commissions, OC denotes the operating coefficient, Pnpl measure the value of provisions for non-performing loans, BIN is used to describe the fintech era, t represents the time period, ε is used to show the error term, i denotes the country and c is the constant.\n\nTable 3 below presents the statistical description of these explanatory variables and to be explained during the first study period (2007-2014), and during the second study period (2015-2022), considered as the fintech era.\n\nThe descriptive statistic shows that during the fintech Eera (2015-2022), the mean value of nonperforming loans NPLv (9.48), coverage rate of these loans Cnpl (7.22), supposed to approximate banking performance remained the same compared to the pre-fintech period (2007-2014), if not even a deterioration in the capacity to cover non-performing loans.\n\nAll other explanatory variables in the model evolved in a favorable direction, and yet performance did not follow this momentum: banking indicators increased from one period to another, but non-performing loans remained almost stable with a reduction in the capacity to cover non-performing loans. This first observation leads us to a second stage of analysis at the following point to ensure, or not, that the arrival of technologies in the fintech era has stimulated banking activity, but has not enabled better knowledge of customer credit applications, and consequently a reduction in non-performing loans.\n\n\n5. Result and analysis\n\nAfter analyzing the descriptive statistics, we evaluated the correlation relationship between the variables. Table 4 in annexes presents the results of the correlation analysis. The Pearson correlation coefficient shows that the NPLv are weakly correlated with the variables supposed to reflect an impact on banking indicators induced by the wave of financial technologies. This implies that the NPLv remained constant as well as their provision value which decreased during the second period of the study which symbolizes the fintech revolution.\n\nFurthermore, the results show that the rate of variation of the interest margin (IMv), the variation of interest charges divided by the net banking product (I/NBI), and the variation margin on commissions (MCv), are negatively correlated with NPLv, even if this correlation is not statistically significant enough.\n\nConversely, the operating ratio (OC) and provisions for non-performing loans (Pnpl) are positively associated with NPLv. This shows that the levels of non-performing loans impact the operating result (OC) and reciprocally increase the amount allocated for the provision of NPLv (Pnpl).\n\nIn terms of the coverage rate of the non-performing loans (Cnpl), correlation results show that the latter is negatively correlated to the rate of variation of the interest margin (IMv), the variation of interest charges divided by the net banking product (I/NBI) and the variation margin on commissions (MCv): when the coverage of the bad debt provision increases, it has a negative impact on banking performance indicators. Likewise, the result also reveals the operating result (OC) and the amount allocated for the provision of NPLv (Pnpl) are positively associated with the coverage rate of the non-performing loans (Cnpl). These results generally mean that the fintech period was characterized by an improvement in operating income (OC) and in the level of the amount allocated to the provision of NPLv (Pnpl) thus improving banking performance measured by the value of non-performing loans (NPLv) and the coverage rate of these loans (Cnpl).\n\nThis considered fintec period was marked by an improvement in the interest margin (IMv), the variation in interest charges divided by net banking income (I/NBI) and the variation margin on commissions (MCv), however, these improvements in banking indicators have not had a positive impact on the performance of the Moroccan banking sector.\n\nAfter the correlation analysis done above, Table 5 in annexes below presents the results of the regression analysis. The results show that rate of variation of the interest margin (IMv) has a negative impact on value of non-performing loans NPLv (-0.618) and on the coverage rate of these loans (Cnpl) (-0.541). This implies that the value of non-performing loans decreases, as well as the coverage rate of these loans (Cnpl), with the increase in the level of the variation of the interest margin.\n\nBased on the coefficient value of explanatory variables, we can infer that:\n\n- Value of non-performing loans NPLv reduce with the increase in the variation of interest charges divided by net banking income (I/NBI), and increases with the rise of the coverage rate of these loans (Cnpl) (-0. 436, 0.098);\n\n- Value of non-performing loans NPLv reduce as does the value of the coverage rate of these loans (Cnpl) with the increase in the variation margin on commissions (MCv) (-0.169, -0.197);\n\n- The operating coefficient (OC) is negatively correlated with the Value of non-performing loans NPLv, and positively with the coverage rate of these loans (Cnpl) (-0.379, 0.116);\n\n- The value of provisions for non-performing loans (Pnpl) is positively correlated with, both, the Value of non-performing loans, and with the coverage rate of these loans (Cnpl) (0.159, 0.358).\n\nIn addition to the above analysis between the determinants of the value of non-performing loans (NPLv) and the coverage rate of these loans (Cnpl), we included the results of the interaction analysis. The latter describes how the determinants of NPLv and banking stability, measured by the coverage rate of these loans, react with the expansion of the wave of the fintech revolution (2015-2022) compared to the first period of the study (2007-2014).\n\nThe results indicate that the financial technology (fintech) wave did not contribute significantly to the decrease in the value of non-performing loans. These remain the same from one period to another. But if we take into consideration the financial variables of the banking sample before and during the fintech era, such as the value of assets, the net banking product (NBI), we can conclude that the arrival of fintech in this sector made it possible to contain non-performing loans in values similar to the previous period despite the increase in turnover of the five banks in our sample. In other words, the proportion of non-performing loans in relation to the sum of credits distributed has decreased between the 2 periods. This explains why the value of provisions for non-performing loans (Pnpl) has decreased when we compare the period 2007-2014 with the fintech period (2015-2022).\n\nThe values of the BIN coefficient are negative for NPLv and positive for the coverage rate of these loans (Cnpl) because the expansion of fintech services has led to an increase in the number of fintech lenders, without leading to an increase in bad borrowers generating an increase in non - performing loans (NPLv). It appears that the increase in fintech services has improved customer management, file assessment and loan monitoring services, which ultimately reduced non-performing loans and improved the coverage rate of non-performing loans (Cnpl).\n\nFurthermore, the above interaction results also conclude that the fintech era has had the effect of reducing the rate of variation of the interest margin (IMv), improving the variation of interest charges divided by the net banking product (I/PNB), and promote the rate of variation of the interest margin (IMv) and the variation margin on commissions (MCv), which cumulatively contributed to stabilizing the NPLv and reducing the value provisions for non-performing loans (Pnpl).\n\nThe result shows that the coefficient value of the explanatory variable (BIN* IMv, BIN* I/NBI, BIN* MCv, BIN* OC, BIN* Pnpl) is negative in the case of NPLv and positive for the Cnpl. Hence, we can conclude that during the fintech era, the Morrocan banking condition has improved slightly: the non-performing loans did not increase despite the significant increase in net banking income and the size of bank assets during the fintech era compared to the first period. This increase in business volume did not produce an increase in provisions for non-performing loans. The results of this study are consistent with the results conducted by Ozili (2021) and those of Pierri and Timmer (2020).\n\n\n6. Conclusion, recommendations and limitations\n\nThis study explores the influence of the fintech era on Moroccan banking performance addressed through non-performing loans and their provisions. The question is whether the implementation of fintechs in the Moroccan bank’s credit evaluation process makes it possible to reduce overdue credits. Experiences carried out in certain countries of the South have revealed that these technological innovations in the banking sector have made it possible not only to reduce risk, but also to facilitate the inclusion of those excluded from banking services (Sadok & El Maknouzi, 2023).\n\nTo measure the impact of the fintech era, we separated the data between two periods. The first covers the period 2007-2014 and the second covers the period 2015-2022, considered the period of the fintech revolution (Arner et al., 2016). The results of our study show that the arrival of fintech in this sector made it possible to contain non-performing loans in values similar to the previous period despite the increase in turnover of the five banks in our sample. In other words, the proportion of non-performing loans in relation to the sum of loans granted decreased between the two periods studied. This explains why the value of provisions for non-performing loans (Pnpl) decreased when comparing the period 2007-2014 with the fintech period (2015-2022). This result corroborates those obtained by Buchak et al. (2018), Phan et al. (2020) and Ozili (2021).\n\nThe findings from the interaction analysis conclude that the second era of the fintech revolution had an effect in reducing the rate of variation of the interest margin (IMv), improving the variation of interest charges divided by the net banking product (I/PNB), and promote the rate of variation of the interest margin (IMv) and the variation margin on commissions (MCv), which cumulatively contributed to stabilizing the non-performing loans (NPLv) and reducing the value provisions for non-performing loans (Pnpl).\n\nHowever, the findings of the present study suggest the following policy recommendations. First, the expansion of financial technologies is a progressive measure for developing countries that contributes to improving banking stability and a smooth social revolution for greater transparency and of inclusion (Sadok, 2023b). Then the use of fintech makes it possible to improve credit assessment services to control and monitor non-performing loans, and therefore better gauge the solvency of borrowers.\n\nIf the originality of this work consists in the analysis of the interactions between the era of financial technologies and the determinants of the performance of the Moroccan banking sector through non-performing loans, this study suffers, however, from some limitations: the first limit is the size of the data and the sample, and the second limit relates to the choice of variables to characterize banking performance. These limits will serve in the future as new potential directions for future research to better explore the problem studied.\n\n\nEthics and consent\n\nEthical approval and consent were not required.", "appendix": "Data availability statement\n\nOSF: Evaluation of the fintech era on the performance of Moroccan banks: analysis through non-performing loans. https://doi.org/10.17605/OSF.IO/7MXAZ (Sadok, 2024).\n\nThe project contains the following underlying data:\n\n• Data file 1. Updated Rating Database.xlsx\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nOSF: Evaluation of the fintech era on the performance of Moroccan banks: analysis through non-performing loans. https://doi.org/10.17605/OSF.IO/7MXAZ (Sadok, 2024).\n\nThis project contains the following extended data:\n\n• Data file 2. Figures (1).JPG\n\n• Data file 3. Figures (2).JPG\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nOSF: STROBE checklist for ‘Evaluation of the fintech era on the performance of Moroccan banks: analysis through non-performing loans’. https://doi.org/10.17605/OSF.IO/7MXAZ\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nArner DW, Barberis J, Buckey RP: FinTech, RegTech, and the reconceptualization of financial regulation. Northwestern Journal of International Law and Business. 2016; 37: 371.\n\nBenkhayat A, Manouar A, Sadok H: Firm business strategy and IT strategy alignment: A proposal of a new model. Xth International Scientific and Technical Conference “Computer Sciences and Information Technologies” (CSIT). Lviv, Ukraine; 2015; 2015: pp. 172–178. 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Publisher Full Text\n\nSadok H, El Maknouzi ME: Prospective View on Central Bank Digital Currency Issuance Conditions: Implementation and Financial Implications. [S.l.]: SSRN.2023. Publisher Full Text Reference Source\n\nSadok H, El Maknouzi MEH: The regulation of virtual currencies in comparative perspective: new private money or niche technological innovation? Journal of Money Laundering Control. 2021; 24(4): 712–724. Publisher Full Text\n\nSadok H, Sakka F, El Maknouzi ME : Artificial intelligence and bank credit analysis: A review. Cogent Economics & Finance. 2022; 10: 1. Publisher Full Text\n\nSakka F, Maknouzi MEH El, Sadok H: Human resource management in the era of artificial intelligence: future HR work practices, anticipated skill set, financial and legal implications.Academy of Strategic Management Journal.2022.\n\nSetia P, Venkatesh V, Joglekar S: Leveraging digital technologies: How information quality leads to localized capabilities and customer service performance. MIS Q. 2013; 37: 565–590. Publisher Full Text\n\nTang H: Peer-to-Peer Lenders versus Banks: Substitutes or Complements? The Review of Financial Studies. 2019; 32(5): 1900–1938. Publisher Full Text\n\nThakor AV: Fintech and banking: What do we know? Journal of Financial Intermediation. 2019; 41: 1–13.\n\nWang R, Liu J, Luo H: Fintech development and bank risk taking in China. The European Journal of Finance. 2021; 27(4-5): 397–418. Publisher Full Text\n\nWelltrado: Global Blockchain-Backed Loans Marketplace ICO. White Paper, mars; 2018.\n\nWewege L, Lee J, Thomsett MC: Disruptions and Digital Banking Trends. Journal of Applied Finance and Banking. 2020; 10(6): 15–56.\n\nZalan T, Toufaily E: The promise of fintech in emerging markets: Not as disruptive. Contemporary Economics. 2017; 11(4): 415–431." }	[ { "id": "341384", "date": "04 Dec 2024", "name": "Ooi Kok Loang", "expertise": [ "Reviewer Expertise Finance", "Capital Market" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for submitting the paper. Kindly refer to my comments below: 1.\n\nThe introduction should include the reasons for conducting this study. Why do we need this study? Is it important, and what are the novelty contributions? 2.\n\nThere are some grammatical, formatting and structure errors. Please do proper proofreading before the next submission (if available). 3.\n\nThe literature review and underlying theories are missing. A letter should critically examine what previous studies have done and the gaps found that lead to the necessity of the study. 4.\n\nThe source of the data and sampling should be explained. Why select the 2015-2022, and why focus on Moroccan banks? All these have to be explained clearly. 5.\n\nA robustness test should be added in order to increase the credibility of the study. 6.\n\nThe study has involved 11 variables in a regression, which is quite a high number. Have the author(s) examined the potential correlation between variables? Granger causality? 7.\n\nComparison analysis with previous studies is not available. 8.\n\nTheoretical, managerial and policy implications are missing. Similarly, limitations and recommendations for future studies are not presented.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "12921", "date": "10 Dec 2024", "name": "Hicham Sadok", "role": "Author Response", "response": "Dear Ooi Kok Loang We greatly appreciate the time and effort you have devoted to our work, and we are deeply grateful for your insightful comments that will surely help improve the quality of our work. We look forward to receiving further comments and suggestions from other reviewers, and once received, we will consider your eight comments in the revised version of this article. Sincerely," }, { "c_id": "13041", "date": "27 Jan 2025", "name": "Hicham Sadok", "role": "Author Response", "response": "Response letter for reviewers Dear Editor, Thank you for allowing us to submit a revised version of our manuscript entitled “Evaluation of the fintech era on the performance of Moroccan banks: analysis through non-performing loans” We greatly appreciate the time and efforts invested, and are deeply grateful to the reviewers for their insightful comments regarding our paper, which contributed significantly to improve its overall quality. We have been able to incorporate the changes and suggestions provided by reviewers, and have highlighted the changes within the manuscript in red color. Please find below a point-by-point response to the reviewers' comments and concerns. Comments of Pr Ooi Kok Loang: Comment 1: The introduction should include the reasons for conducting this study. Why do we need this study? Is it important, and what are the novelty contributions? Answer of authors: Thank you for this valuable comment. We have introduced the reasons for this study in the revised version of this article. Indeed, digitalization is supposed to offer banks substantial gains in terms of operational efficiency, significantly reduce delays and errors, and consequently a better assessment of the solvency of credit applicants, thus optimizing decision-making and risk management. This efficiency is often not verified in the literature, and even less in the Moroccan context. This is why we have outlined this study to try to better shed light on this topic. Comment 2: There are some grammatical, formatting and structure errors. Please do proper proofreading before the next submission. Answer of authors: Thank you for this comment and suggestion. Indeed, we have proofread and corrected the grammar, formatting and structure errors in this revised version. Comment 3: The literature review and underlying theories are missing. A letter should critically examine what previous studies have done and the gaps found that lead to the necessity of the study. Answer of authors: Thank you for this relevant remark. In the revised version, we have restructured the literature review to better highlight the results of the main studies on this topic. This analysis made it possible to frame our problem, to outline the approach to follow, the variables to study with its contextualization for the case of Moroccan banks. This contextualization allows for more in-depth reflection, in subsequent work, around this topic in order to ensure whether banking investment in digital is a rational decision or an injunction of the situation? Comment 4: The source of the data and sampling should be explained. Why select the 2015-2022, and why focus on Moroccan banks? All these have to be explained clearly. Answer of authors: Thank you for this valuable comment. We have taken your suggestion into consideration in the revised version of the paper and have integrated the data relating to our sample into the text. As for the choice of the segmented periods (2007-2014) and (2015-2022), we referred to the literature review, and more particularly to that of Ozili (2021) and Arner et al (2016)., who generally considers that conventional banks in developing countries are beginning to show a growing interest in online banking and the digitalization of their processes from the beginning of the second decade of this millennium. And to have a more precise anchor point for this growing interest in the digitalization of Moroccan banks, we examined the management reports of these five banks from 2010, and this interest proved to be more concrete in terms of investment, and especially the deployment of digital processes and applications from 2015. Comment 5: A robustness test should be added in order to increase the credibility of the study. The study has involved 11 variables in a regression, which is quite a high number. Have the author(s) examined the potential correlation between variables? Granger causality? Answer of authors: Thank you for your valuable comments and feedback. When analyzing the variables, we used a correlation analysis (Pearson test) between the 7 variables that did not present any significant threshold. Therefore, the use of multicollinearity between these independent variables of our regression model is no longer recommended when the variables are not correlated. We have better structured the sections related to this part of the study, since the data and tests were previously put in the appendix, as recommended by the editor, while in the new version we put them in the text so that the empirical treatment can gain clarity. Comment 6: “Comparison analysis with previous studies is not available”. “ Theoretical, managerial and policy implications are missing. Similarly, limitations and recommendations for future studies are not presented”. Answer of authors: We thank you for your insightful comments. In the conclusion, recommendations and limitations section, we discussed the results obtained with the studies mentioned in the literature review. We also highlighted some managerial and policy implications such as the implications of fintech in monetary stability and financial incursion. Regarding the limitations, we highlighted the problem of data and sample size, as well as the choice of variables to characterize the notion of banking performance." } ] }, { "id": "344296", "date": "23 Dec 2024", "name": "Anas Ahmad Bani Atta", "expertise": [ "Reviewer Expertise Fintech", "Digital transformation", "Bank performance", "mutual funds" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nGeneral Suggestions\n1. Language and Proofreading: The manuscript has several grammatical and formatting issues that should be corrected. 2. Novelty and Contribution: The study needs to make a stronger case for its novelty and contribution to the literature. This could be by add more recent studies (i.e. 2024 studies). 3. Statistical Rigor: If can add robustness tests and address potential methodological issues like multicollinearity and endogeneity.\nTitle and Abstract\n1. Title: The title is clear and indicates the research focus. 2. Abstract: The abstract summarizes the study well but lacks specificity regarding the novelty of the findings. Including a clearer statement of the research gap and main contribution would strengthen it.\nIntroduction\n1. The introduction does not clearly articulate the research gap or the novelty of the study. Why is it important to study Moroccan banks during the fintech era? This should be emphasized more explicitly. 2. While the background is informative, it lacks critical engagement with recent prior literature.\nLiterature Review\n1. The literature review provides a broad overview of fintech and banking performance. 2. Key gaps in existing research and how this study addresses those gaps are not explicitly outlined. Additionally, theoretical frameworks supporting the relationship between fintech and banking performance could be better developed. 3. update the references look at the references below\n\nMethodology\n1. The justification for dividing the study period into pre- and post-fintech eras needs more clarity, especially why 2015 is chosen as the start of the fintech era in Morocco. 2. While the selection of variables is explained, the rationale for their inclusion could be stronger, with references to relevant studies. 3. No mention of robustness checks or tests for multicollinearity, which are critical given the number of variables used in the regression analysis.\nResults and Analysis\n1. The results are well-structured, but there is a lack of critical discussion comparing these findings with prior studies especially the recent studies. 2. Some correlations are reported as significant without discussing their practical implications.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13017", "date": "27 Dec 2024", "name": "Hicham Sadok", "role": "Author Response", "response": "Dear Pr Anas Ahmad Bani Atta, Thank you for the time and effort you have devoted to this article and we are deeply grateful for your comments and suggestions to improve the quality of our work. We will revise the article in the next few days and then publish a new version on the platform. Best regards Hicham Sadok" }, { "c_id": "13042", "date": "27 Jan 2025", "name": "Hicham Sadok", "role": "Author Response", "response": "Response letter for reviewers Dear Editor, Thank you for allowing us to submit a revised version of our manuscript entitled “Evaluation of the fintech era on the performance of Moroccan banks: analysis through non-performing loans” We greatly appreciate the time and efforts invested, and are deeply grateful to the reviewers for their insightful comments regarding our paper, which contributed significantly to improve its overall quality. We have been able to incorporate the changes and suggestions provided by reviewers, and have highlighted the changes within the manuscript in red color. Please find below a point-by-point response to the reviewers' comments and concerns. Comments of Pr Anas Ahmad Bani Atta: General Suggestions Comment 1: Language and Proofreading: The manuscript has several grammatical and formatting issues that should be corrected. Answer of authors: Thank you for this comment and suggestion. Indeed, we have proofread and corrected the grammar, formatting and structure errors in this revised version. Comment 2: Novelty and Contribution: The study needs to make a stronger case for its novelty and contribution to the literature. This could be by add more recent studies (i.e. 2024 studies). Answer of authors: We have taken your remark into account in this revised version, by providing more recent studies, including, among others, those suggested. Comment 3: Statistical Rigor: If can add robustness tests and address potential methodological issues like multicollinearity and endogeneity. Answer of authors: Thank for your valuable comments and suggestion. When analyzing the variables, we used a correlation analysis (Pearson test) between the 7 variables that did not present any significant threshold. Therefore, the use of multicollinearity between these independent variables of our regression model is no longer recommended when the variables are not correlated. We have than better structured the sections related to this part of the study, since the data and tests were previously put in the appendix, as recommended by the editor, while in the new version we put them in the text so that the empirical treatment of this paper can gain clarity. Introduction Comment 4: The introduction does not clearly articulate the research gap or the novelty of the study. Why is it important to study Moroccan banks during the fintech era? This should be emphasized more explicitly. Answer of authors: Thank you for this valuable comment. We have taken your suggestion into consideration in the revised version of this article. Indeed, digitalization is supposed to offer banks substantial gains in terms of operational efficiency, significantly reduce delays and errors, and consequently a better assessment of the solvency of credit applicants, thus optimizing decision-making and risk management. This efficiency is often not verified in the literature, and even less in the Moroccan context. This is why we have outlined this study to try to better shed light on this topic. Comment 5: While the background is informative, it lacks critical engagement with recent prior literature. Answer of authors: Thank you for this remark. Our approach in this article was not that of a literature review or a theoretical article to be able to afford a critical analysis of the literature and questioning, but rather that of deduction to understand the approaches of previous works and the results obtained in order to implement ours in a context where, to our knowledge, this study has not yet been conducted. A certain critical engagement of the literature and our results will however be the subject of a discussion before the conclusion of this article. Literature Review Comment 6: 1. The literature review provides a broad overview of fintech and banking performance. 2. Key gaps in existing research and how this study addresses those gaps are not explicitly outlined. Additionally, theoretical frameworks supporting the relationship between fintech and banking performance could be better developed. 3. Update the references look at the references below Answer of authors: Thank you for your valuable remarks and comments. We have taken it into account in this revised version by providing a nuance on the results of the existing literature on this topic. We have also introduced other recent references such as those suggested. The literature review carried out did not aim to engage in a critical analysis, but rather to frame the problem in order to outline the approach to follow, the variables to study with the aim of its contextualization on Moroccan banks. Methodology Comment 7: 1. The justification for dividing the study period into pre- and post-fintech eras needs more clarity, especially why 2015 is chosen as the start of the fintech era in Morocco. Answer of authors: We thank you for this important methodological remark. Indeed, the segmentation of the period studied into 2 sub-periods (2007-2014) and (2015-2022), finds a justification in the literature, and more particularly in that of Ozili (2021) and Arner et al, (2016)., who generally considers that conventional banks in developing countries are beginning to show a growing interest in online banking and the digitalization of their processes from the beginning of the second decade of this millennium. And to have a more precise anchor point for this interest, allowing us to subsequently analyze whether or not this interest impacted the performance of Moroccan banks, we examined the management reports of these five banks from 2010, and this interest proved to be more concrete in terms of investment, and especially the deployment of digital processes and applications from 2015. This is why we carried out a comparative study between the two periods to see whether or not there was an effect on performance, measured here by NPLs. Comment 8: While the selection of variables is explained, the rationale for their inclusion could be stronger, with references to relevant studies. Answer of authors: In the revised version of the document, we have provided more details on the variables. This time, we have included the explanatory table of the variables in the text, whereas it was in the appendix, as well as the references of previous studies that have opted for the same proxies to address the variables studied. Comment 9: No mention of robustness checks or tests for multicollinearity, which are critical given the number of variables used in the regression analysis. Answer of authors: Thank you for your valuable comments and feedback. When analyzing the variables, we used a correlation analysis between the variables that did not present any significant threshold. Therefore, the use of multicollinearity between these independent variables of our regression model is no longer recommended when the variables are not correlated. We have better structured the sections related to this part of the study, since the data and tests were previously put in the appendix, as recommended by the editor, while in the new version we put them in the text so that the empirical treatment can gain clarity. Results and Analysis Comment 10: The results are well-structured, but there is a lack of critical discussion comparing these findings with prior studies especially the recent studies. Some correlations are reported as significant without discussing their practical implications. Answer of authors: We thank you for your insightful comments. In the conclusion, recommendations and limitations section, we discussed the results obtained by highlighting the studies mentioned in the literature review and having obtained the same results or findings. We also highlighted some managerial and political implications such as the impacts of fintech in monetary stability and financial incursion." } ] } ]	1	https://f1000research.com/articles/13-1365
https://f1000research.com/articles/14-134/v1	27 Jan 25	{ "type": "Review", "title": "Heavy Metal Contamination: Sources, Health Impacts, and Sustainable Mitigation Strategies with Insights from Nigerian Case Studies", "authors": [ "Babafemi Laoye", "Peter Olagbemide", "Tolulope Ogunnusi", "Oghenerobor Akpor", "Peter Olagbemide", "Tolulope Ogunnusi", "Oghenerobor Akpor" ], "abstract": "Heavy metal contamination has gradually become a very much important significant global issue due to its continual existence in the environment and bioaccumulation in the ecosystems, posing deleterious risks to human health. This review aims to investigate the sources, pathways, and toxicological impacts of heavy metals such as cadmium, lead, mercury, and arsenic, elucidating their health consequences and plausible mitigation strategies. Furthermore, the review explores the dual origins of heavy metal contamination; natural geological processes and anthropogenic activities such as industrial emissions, mining, and agricultural practices. These heavy metals sip into soil, water, and food chains, leading to bioaccumulation, bio-magnification and causing significant health risks, including cardiovascular diseases, neurological disorders, and reproductive toxicity. Additionally, the addition of indigenous case studies from Nigeria, such as lead poisoning in Zamfara State and contamination in the Great Kwa River of Cross Rivers State underscores the disproportionate impact of heavy metal pollution in developing nations. These case studies reveal the socio-economic and environmental dimensions of the issue, providing a contextual understanding of region-specific vulnerabilities and health outcomes. To address these problems, the review evaluates already existing mitigation strategies, including chelation therapy and phytoremediation, while proposing sustainable, cost-effective solutions for reducing exposure and mitigating impacts. It emphasizes the importance of integrative approaches involving policy, community engagement, and technological innovations to fight heavy metal contamination effectively. In conclusion, this seminar contributes to the understanding of heavy metal toxicity, giving and showcasing very much important insights into the sources and health implications of contamination. By integrating theoretical perspectives with practical solutions, this review provides a robust framework for informing policy makers and advancing sustainable environmental management practices.", "keywords": [ "Heavy metal", "Phytoremediation", "DNA", "Cadmium", "Lead", "Arsenic", "Mecury Anthropogenic", "Bioaccumulation", "Bio-magnification." ], "content": "1. Introduction\n\nHeavy metals are naturally occurring elements with a relatively high density present in the ecosystem (De Carvalho Machado and Dinis-Oliveira, 2023; Ali and Khan, 2018). They are popularly known as metals of environmental concern (Kothapalli, 2021; Rahman and Singh, 2020). Heavy metal pollution or contamination in water is one of the most consequential environmental issues (Mishra et al., 2019). This is due to the sturdiness of heavy metals, which cannot be consumed by the body, and the danger they pose to the health of humans contaminated water with heavy metals is used for irrigating crops, and during the rainy season, the water fills groundwater sources, contaminating the drinking water. Thus, heavy metals present in the crops, groundwater, and drinking water lead to several health risks (Vielee and Wise Jr, 2023; Vetrimurugan et al., 2017). Heavy metals are stable and do not break down into less toxic products. Heavy metals bio accumulate in the food chain and can therefore have debilitating impacts on the health of humans (Acharya, 2024). The complex metabolic machinery in our body is affected by heavy metal pollution or toxicity, leading to negative health manifestations such as hemolytic anemia (Teschke, 2024), nerve damage (Aljelehawy, 2022), nausea (Engwa et al., 2019) diarrhea (Su et al., 2023) and feto-maternal bleeding (Tabassum et al., 2023). Lead is toxic to the kidney (Khalaf et al., 2024), liver (Chen et al., 2023) reproductive and nervous systems of people of all ages. Mainly, lead poisoning in children can cause behavioral and cognitive problems (Gudadhe et al., 2024). Inorganic arsenic (iAs) is the most prevalent toxic form of arsenic in drinking water, which increases the rate of skin diseases in humans (Abtahi et al., 2023). Cadmium has been implicated to cause hypercalciuria in humans (Obaid et al., 2023). A recent review revealed that of this exposure to cadmium in human leads to a 31% increase in risk of lung cancer (Farahmandian et al., 2024). Moreso, mercury have been implicated to cause kidney diseases in humans as a result of bioaccumulation (Kumar et al., 2023). Also, occupational exposure to chronic viral infections can lead to skin and nasal ulcers, as well as lung cancer (Yasmeen and Hafeez, 2023) Heavy metals have also been implicated to cause skin pigmentation (de Carvalho, 2023) skin tumors (Fu and Xi, 2020) and dermatitis (Alam et al., 2019).\n\nMoreso, it is imperative to be abreast of the rationale and significance of this review shedding light on the impacts of “Heavy Metal Contamination on Human Health”. Water is very much the most vigorous arsenal for life, however when water is polluted or contaminated with heavy metals like Mercury (Hg), Chromium (Cr), Cadmium (Cd), Pb (lead), As (Arsenic), and Nickel (Ni) it leads to vulnerable diseases such as neural disorders (Singh and Sharma, 2024), psychosomatic (Teschke, 2024; Hosen, 2021) mental retardation in neonates (Dórea, 2019) tumorigenesis and even death (Kothapalli, 2021). Heavy metal contamination cannot be overemphasized heavy contamination in the food chain, e.g. in fish, milk, drinking water, and also crops irrigated with polluted water that accumulate heavy metals (Ugoeze et al., 2021). Research have shown that the irrigation water had not only been responsible for the contamination of the crops but also the water sources in the surroundings of the dumping site areas (Nyiramigisha, 2021). For example, the potential health hazard due to the consumption of contaminated vegetables may arise when the heavy metals are ingested by the consumer (Rai et al., 2019), or the soils are contaminated to such an extent that they enter into the food chain, and dietary intake as well as drinking water become further contaminated (Nkwunonwo et al., 2020).\n\nHeavy metals have received considerable attention as a result of too much utilization in different industries, as well as their debilitating injurious impact on human health and the environment (Vielee and Wise Jr, 2023; Kaur and Sharma, 2021). Heavy metal contamination in the ecosystem as an effect human health via different routes, including soil, water, and industrial emissions (Briffa et al., 2020). There is a great need to pin point risk populations, and identify plausible avenues and methodology to ameliorate the debilitating effects of heavy metals in our environment.\n\n\n2. Sources of heavy metal contamination\n\nIn the natural ecosystem, heavy metals are introduced to the environment perpetually from bed rocks and volcanic substances as a result of disintegration of rocks (weathering) (Deng et al., 2022). Contamination of heavy metals in the environment is largely due to human interferences (anthropogenic activities) (Christophoridis et al., 2019). Anthropogenic heavy metals are derived from (a) industrial activities, including the mining, smelting and refining of ores, steel production, and other metallurgical operations; electrical products manufacturing; product finishing and surface coating such as painting and electroplating; the application of heavy metal-based pesticides; preservation of woods and leather (Marriage and Gjerde, 2024; Obasi et al., 2022), (b) uncontrolled disposal of effluents and smudges from heavy industries (Elbasiouny et al., 2021); household disposal of domestic hazardous wastes (Elbeshbishy and Okoye, 2019) and (c) other sources such as the disposal of domestic sewage sludge on agricultural land (Latosińska et al., 2021) sewer drop manholes (Wicke et al., 2021) and gully traps made of cast iron (Rana et al., 2024) welding operations (Abdullahi and Sani, 2020), motor vehicles, source of emissions (Kryshtopa et al., 2019) and second-hand tobacco smoke (Karatela et al., 2019).\n\nFurthermore, besides point sources (mainly from industrial processes), whereas they can also get into the environment from nonpoint sources (from the atmosphere and from the water, land and biomass already contaminated by a previous heavy metals pollution (Wang et al., 2022a). When introduced into the environment, heavy metals are exposed to a plethora of environmental processes and are distributed into the atmosphere, water and soil. Once in the environment, heavy metals are either degraded or stored (Dongre, 2021). The net effect, whether the heavy metals are degraded or accumulated, depends on the duration and the quantity of the release and the difficulty in degrading the compound (Rahman and Singh, 2020).\n\nAs a result of numerous geochemical, mineral residues and deposits, it is very much difficult to categorize heavy metals. Classifying the source of contamination of heavy metals is very difficult because of the various linkage and interconnectivity of a plethora of courses or regions associated with the same origin and nature. Moreso, research has shown different sources following sources based on mechanism of release (Obasi and Akudinobi, 2020). It is imperative to understand that heavy metals are present in the earth’s crust and are part of the exponential scale of the naturally occurring elements (Ali and Khan, 2018). The primary source of heavy metals in the environment is the geologic origin of the major and accessory minerals contained in the soil and rocks (Subasinghe et al., 2022; Hultman and Pollard, 2022).\n\nHeavy metals are naturally occurring elements and are released in diverse ways from rocks and soils (Bharti and Sharma, 2022). Weathering, tectonic activity, and pan-genetic processes represent a trio of principal mechanisms of heavy metal geological introduction from primary or secondary minerals (Wu et al., 2021).\n\nHuman activities in terms heavy metal release is categorized into two; Essential and non-essential (Campbell and Gailer, 2016). Essential heavy metals such as copper, zinc, iron, and others are known for their vital role in human health, while non-essential heavy metals such as arsenic, lead, mercury, cadmium, and antimony have been reported to cause a high level of biological toxicity (Mitra et al., 2022). Human activities (anthropogenic), mainly industrial processes, have been reported to lead to an increase in the release of non-essential heavy metals into the environment at a dazzling rate, leading to an ecosystem crisis (Mansor et al., 2024). Heavy metal poisoning can lead to a variety of illnesses in humans, some potentially lethal, including blood (Zahra et al., 2017) and neuromuscular problems (Toledano, 2020) and many forms of cancer (Khanniri et al., 2023). Moreso, as human population increases year in year out, heavy metal pollution never decreases instead it increases significantly, leading to potential health hazards as a result of changes in environmental conditions and demographic trends (Crocetto et al., 2023).\n\nHuman beings and the environment is exposed to heavy metals via various sources. Human activities are responsible (anthropogenic activities) for approximately 60% of metal pollution in various terrestrial and aquatic ecosystems throughout the world (Mitra et al., 2022; Mondal, 2023). The joint precipitation of heavy metals from innate and anthropogenic activities in various environmental spaces has been revealed and reported in various research (Chen et al., 2021; Verma et al., 2021; Akoto and Anning, 2021; Li et al., 2020). Human activities are the major source of heavy metal pollution globally (Adnan et al., 2022; Rai et al., 2019). The two most important anthropogenic sources of heavy metals are as follows: (1) Industrial sources: These sources are responsible for the deterioration of air quality within urban and industrial areas (Roy et al., 2024) (2) Non-point sources: Non-point sources are responsible for the overall deposition of heavy metals within the environment (Hussain et al., 2023).\n\nOver the years, research have shown of that several heavy metals are ubiquitously prevalent in the ecosystem, which are of global concern as a result of to their deleterious effects on human health (Briffa et al., 2020). Although, many heavy metals, such as copper (Cu), manganese (Mn), iron (Fe), and zinc (Zn), are essential for normal cellular performance, these metals, however, can also be toxic to the human body when present in excess of the normal concentration (Jomova et al., 2022) Literature has revealed a few popular heavy metals which have shown to cause vicious health effects. Moreso, distinguishing and varying attributes have also been described a plethora of literature (Meharg and Meharg, 2021; Mishra et al., 2019: Charkiewicz et al., 2023; Baig et al., 2024a; Baig et al., 2024b).\n\nLead is eccentrically the oldest popularly known and the most surplus heavy metal pollutant/contaminant (Sable et al., 2024) and it is unsusceptible to corrosion under brassy environmental conditions while being easily transformed into various forms at room temperature (Rihan et al., 2020). Over the years, lead has been widely used in gasoline (Collin et al., 2022), paint (Charkiewicz and Backstrand, 2020), water pipelines (Levin et al., 2021), and batteries (Kumar et al., 2022), in the production of cooking utensils (Kuhangana et al., 2024) construction materials (Dong et al., 2023) and the toy industry (Yazdanfar et al., 2022). As a result of this, the primary sources of lead exposure have been from the atmosphere (Wu et al., 2022), water (Charkiewicz and Backstrand, 2020), food and drinking water (Gump et al., 2020), contaminated soil and dust (Stanek et al., 2020) or lead-containing consumer products, especially vintage items (Guney et al., 2020) and flaking peeling paints (Afolayan et al., 2021). Also, mercury has been reported in research as a key component of dental amalgam, and arsenic-containing compounds have also been reported being used for chemotherapeutic and insecticidal purposes (Khatun et al., 2022; Genchi et al., 2020b). Also, mecury and arsenic take part in microbial methylation mechanisms in their inorganic forms which involves the addition of a methyl group to the toxic moiety to form a less toxic, but mainly water-soluble and easily absorbed, methylated compound (Byeon et al., 2021). Precisely, chronic release of inorganic mercury or other organic moieties in the air to disrupt motor and sensory functions leads to the emergence of Minamata disease (Niede and Benbi, 2022). In the same vein, subtly, arsenic-laden underground water bombards cereals and tubers to develop a mild form of neurotoxicity in contaminated areas due to long-term arsenic exposure (Sevak and Pushkar, 2024), Methylmercury (Me-Hg) in seafood, particularly in pregnant mothers’ diet, has been implicated to sparks off neurobehavioral symptoms during early development (Wu et al., 2024), and fish and seafood likely account for 90% of Hg exposure in people residing near rivers and lakes (Vergara et al., 2024). Furthermore, Cadmium is a highly toxic non-essential element used in electroplating, the television industry, battery production, and coating agents of iron and steel products (Sable et al., 2024). The major route of human exposure of cadmium is via the ingestion of polluted food, such as rice, shellfish and vegetables (Zhao et al., 2023) or through inhalation of tobacco smoke (Genchi et al., 2020b). Alarminly, a huge proportion of cigarettes are haphazardly intermittently irrigated with cadmium fertilizers, which may subsequently release the heavy metal (cadmium) from tobacco during smoking\n\nIn recent years, widespread human exposure to heavy metals has fascinated increasing public awareness to the probable threat to public health (Qureshi, 2021). Lead (Pb) has much long been reported by researchers and medical experts to have baleful effects on human health (Wang et al., 2022b). The major sources of lead exposure are environmental lead pollution (Raj and Das, 2023). Particularly, there is no safe portal for lead exposure, and the toxicological profile of lead is influenced by the age at exposure, sex (Gade et al., 2021) and genetic polymorphism (Sekovanić et al., 2020). Furthermore, lead pollution is an environment-related global health concern, recognized as a public health issue by several global organizations (WHO, 2023; Muzamil et al., 2024; Słota et al., 2022; Obeng-Gyasi, 2019).\n\nMetallic lead is relatively unreactive under many conditions (Liu et al., 2021). When heated or subjected to moist air, it can be oxidized and form a variety of inorganic and organic lead compounds, which can further decompose into other lead materials, such as organo-lead and alkyllead (Nielsen, 2020). Inorganic and organic lead are the two main species linked with detrimental human health effects (Borah et al., 2020). Due to the long-term presence of lead, in the atmosphere, soil, and water, the exposure of the global population to lead inevitably results in pollution of resources and impacts on the biota (Mousavi, et al., 2022). Occupational exposures have long been closely associated with painters who use paints containing lead pigments and workers exposed to smoke from burning fuels containing added organic halogenated lead (Wei et al., 2022; Thangavel et al., 2022). In addition to providing extensive exposure to lead, anthropogenic activities have been reported to trigger environmental spills, such as zinc-lead and copper-silver deposits in the Mississippi valley (Rosa et al., 2023). The introduction of Tetraethyl lead (TEL) into gasoline supplies also contributed to significant environmental pollution, with large-scale human exposure (Sarkar, 2020). Lead has also been reported to be released from smelters, recycling centers in municipal areas (Du et al., 2020) and young ones have been lead-exposed by previously used sources of drinking water (Olufemi et al., 2022). However, lifestyle choices such as smoking and the use of lead-containing diet fillings have been reported as other means of human exposure to lead. Also research has shown that use of beauty products such as cosmetic products facial creams (Rico et al., 2023) and surfactants containing lead-based chemicals can result in direct lead toxicity without consuming them (Abed et al., 2023).\n\nFurthermore, in developing countries, increasing occurrences of lead poisoning have been reported and linked to informal or unregulated electronic waste (e-waste) management practices resulting in severe environmental contamination (Gollakota et al., 2020) Through various exposure routes (ingestion, inhalation and dermal exposure), lead pollutants threaten human health (Natasha et al., 2020). Particularly In humans, lead can trigger impacts widely, and these harmful effects are persistent (Briffa et al., 2020), hence, long-term lead accumulated in the body can increase the gravity of the toxic effects with advancing age. Research have shown that lead exposure to humans can affect the following systems negatively; pulmonary (Wei et al., 2020), bone (Boskabady et al., 2022), hepatic and renal systems (Satarug et al., 2020) neurologic (Eiró et al., 2021) cognitive and behaviour system (Shvachiy et al., 2020). Over the years, lead exposure have been reported in a plethora of articles to cause anemia in many individuals (Wang et al., 2021; Mukisa et al., 2020; Kaneko et al., 2020 ) particularly children being susceptible to the neurotoxic effects (Brittenham et al., 2023) Some of the weighty consequences of chronic exposure are arthritis (Fang et al., 2023) and chronic kidney disease that may lead to renal dysfunction (Balali-Mood et al., 2021). Considering its plausible worrisome effects on the wellbeing of humans and the ecosystem lead exposure is very much a major public health concern globally (WHO, 2023).\n\nMercury contamination is amongst the most significant and universal pollution problems in the aquatic environment (Gupta and Yadav, 2024) It primarily occurs in the aquatic environment (Luo et al., 2020). In industries, huge amounts of effluents containing mercury are discharged as a result of poor industrial operations (pharmaceutical, paint, paper, and other industries), fertilizer industry, landfill leaching, and carbon combustion. Dead zones, otherwise termed as zones of oxygen-depleted water, have been reported to be the repository of huge deposits of inorganic mercury (AlgarnI et al., 2023; Jonidi Jafari et al., 2020).\n\nThe mercury in the environment rapidly makes its entry into aquatic biota. The mercury is consecutively transported to the aquatic food chain via bioaccumulation (Saidon et al., 2024). Aquatic diet have been reported to contain a huge amount of mercury (Barone et al., 2021) which puts the concept of food from the aquatic environment in doubt. The widespread presence of mercury contaminated fish in all types of water bodies has grave effects on the global aquatic environment, economy, and public health (Abhishek et al., 2022). Therefore, it imperative to fathom the coaction between mercury content in fish and the source of water, fish size, and type of species, well-known poisoning effects, extreme intolerance effects, and treatments. Hence, this review will provide an unbiased interpretation of the effects of heavy metal mercury on global health and the aquatic environment.\n\nCadmium (Cd) is toxic, nonessential, and carcinogenic for humans and animals (Genchi et al., 2020b). Cadmium exposure to the environment is primarily due to anthropogenic activities (Zhao et al., 2023; Knoell and Wyatt, 2021; Adil et al., 2020), just like every other heavy metals and not much of natural sources exist. Cadmium have been reported to be present in tobacco products , particularly cigarettes (Dinh et al., 2021). Also, cadmium is also present in foods, such as shellfish, rice, mushrooms, drinking water, spinach, and other green leafy vegetables (Genchi et al., 2020b), with rice being one of the major routes of exposure via food. Major sources of cadmium pollution are nonferrous smelters (Wei et al., 2022), industrial production involving cadmium ( Suhani et al., 2021), incineration of municipal waste and sewage sludges Król et al., 2022). Research have shown that bio- transfer is the common way for the entry of cadmium into the food web (Peana et al., 2022; Sun et al., 2020) Cadmium is taken up by the plants and also accumulates in the soil (Sterckeman and Thomine, 2020), it is also easily ignored in the environment for a longer time due to its chemical nature and releases gradually unlike other metals. Also, cadmium takes a longer time to degrade in the environment due to its long biological half-life (Genchi et al., 2020a).\n\nHuman exposure to high-level of cadmium have been reported in a plethora of research to leading to severe damage to the liver, kidneys, and lungs (Satarug, 2012; Branca et al., 2020; Knoell and Wyatt, 2021; Chandravanshi, et al., 2021; Owonikoko et al., 2023; Farh et al., 2024). Also, lots of animal studies have shown neurotoxic effects as a result of cadmium exposure (Branca et al., 2020; Zhou et al., 2020; Gade et al., 2021; Ruczaj and Brzóska, 2023; Patel et al., 2021) Clinical symptoms such as headaches (Söderholm et al., 2020), osteoarthritis (Frangos and Maret, 2020; Xia et al., 2022) dizziness (Dumpala et al., 2024), cough (Li et al., 2020 ), bronchitis (Ibrahimou et al., 2021), and fever has been reported via research to be associated with cadmium exposure (Elmas, 2023) Furthermore, plausible bone damages have been reported to be caused by cadmium exposure (Ma et al., 2022). Also, research as also emphasized in recent years that low-level chronic cadmium may also lead to kidney damage (Tsai et al., 2021), which primarily focuses on the degree of damage observed in the process of β2-microglobulin excretion and α-glutathione-S-transferase in the urine of human (Polaka et al., 2023). A recent study has revealed that cadmium-induced renal tubulointerstitial injury might ultimately lead to decreased functionality (Xu et al., 2021) Also a plethora of research have revealed that environmental that environmental exposure to cadmium also causes endocrine and hormone-disrupting effects (Rai et al., 2019; Li and Li, 2020; Di Ciaula and Nazarian et al., 2024; Yang et al., 2024). A recent study have also revealed that cadmium exposure in humans through inhalation may induce lung cancer (Lee and Lee, 2024) and cadmium ingestion through tobacco has been reported to cause oral cancer (Satir, 2022). In addition, environmental cadmium may be associated with primary liver cancer (Cirovic and Satarug, 2024) Research has also revealed that children exposed to cadmium via dietary intake exhibit lower intelligence than those not exposed (Kampouri et al., 2024).\n\nArsenic is a metalloid which is naturally present lithosphere (Meharg and Meharg, 2021). It enters the environment either due to anthropogenic usage or through removal from iron, manganese, and aluminum oxides (Raju, 2022). Several anthropogenic sources, such as mining activities, smelting, and burning of fossil fuels, release arsenic into the environment (Kar, 2022). Chronic or acute exposure to arsenic have been reported to cause debilitating health effects (Thankachan et al., 2023 Muzaffar et al., 2023; Rehman et al., 2020). Organo-arsenic compounds dominate arsenic exposure, but these compounds have been reported to transform into inorganic forms and hence more toxic forms in the body (Valskys et al., 2022). Groundwater is the primary source of arsenic exposure (Monteiro De Oliveira et al., 2021), about 21 countries have been found to contain arsenic-ridden drinking water (WHO, 2022).\n\nChronic exposure to arsenic-rich drinking water may lead to the development of skin lesions (Rajiv et al., 2023; WHO, 2022), internal cancers of the blood vessels (Rahaman et al., 2021) or urinary bladders among others (Jaafarzadeh et al., 2023). This phenomenon have been reflected in a plethora of studies (Mayer and Goldman, 2016; Kumar and Ghosh, 2019; Rahaman et al., 2021; Kumar et al., 2022; Rehman et al., 2020; Chikkanna et al., 2019). Cadmium has been implicated in several biological pathways to cause carcinogenesis (Peana et al., 2022; Zhu and Costa, 2020; Cui et al., 2021; Luparello, 2021) including oxidative stress (Branca et al., 2020). mitochondrial DNA damage and apoptosis (Mohamed, 2022) impairment of DNA methylation (Genchi et al., 2020b), and changes in methyltransferases (Sun et al., 2021). Moreso, It is acute arsenic exposure can lead to systemic poisoning and ultimately death (Ganie et al., 2024). A single lethal dose of arsenic compounds ranges between 100 to 200 mg (Chen et al., 2021). Symptoms of acute poisoning include diarrhea, poor appetite, extreme tiredness, sores on the skin, numbness, muscle cramps and hair loss (Rehberg and Rehberg, 2024) However, acute poisonings from waterborne arsenic exposure are uncommon (Roy and Edwards, 2022). Long-term skin exposure may cause skin changes, such as darkening of the skin (Passeron et al., 2020) and the appearance of small “corns” or “warts” on the palms soles, and body (Hamza et al., 2022). Also, research studies have revealed plausible effects of arsenic exposure on reproductive health and impaired fetal brain development (Dutta et al., 2022).\n\n\n4. Routes of human exposure and mechanisms of heavy metal toxicity\n\nThe avenues through which humans come into contact with heavy metals vary greatly between different contaminants and among different populations. Ingestion represents the main route of exposure for most human population groups (Kabir et al., 2022). Affected individuals generally include those living close to contaminated areas , those accidentally exposed to pollutants and occupationally-exposed individuals . Inhalation (Briffa et al., 2020) and, to a lesser extent, dermal contact may also represent more relevant exposure routes for special populations, such as workers engaged in mining smelting (Xu et al., 2021; Li et al., 2020) or in the production and application of herbicides, pesticides, and fertilizers . Human exposure to heavy metals includes, at least, ten different interconnected exposure pathways. These pathways include affected food and drinking water resources and lead to the wide distribution of hazardous heavy metals in the tissues, organs, and fluids of the human body (Zhao et al., 2022). Taken together, human intake of heavy metals is driven by lifestyle local environment (Mitra et al., 2022) occupation (Baig et al., 2024b), nutrition and the occurrence and concentration of heavy metals in affected air, water, and soil resources (Fu and Xi, 2020).\n\nIngestion represents the major pathway of human exposure to heavy metals . A number of food sources contain considerable levels of heavy metals, such as crops grown in heavy metals-contaminated soils (Bwatanglang et al., 2022) fish from mercury-contaminated waters and beverages containing lead carried by deteriorated distribution systems. Human dietary intake typically ranges from approximately 0.1 to 1.0 g/day, with higher intake levels observed in diets rich in seafood and other wild foods. Overall, high daily intakes and the evidence from research suggest that moderate to high levels of heavy metal residues in food and water can trigger significant toxicological effects in humans (Ahmad et al., 2021).\n\na. Ingestion\n\nThe major medium for human exposure to toxic metals is ingestion (Dippong et al., 2024). This is facilitated by the consumption of micro- or macro-nutrients and subsequent accumulation of metals in human food, water, air, or soil (Kara et al., 2024). An acute part usually comes from water used for gardening or agriculture (Munir et al., 2021). Stationary plants take up toxic metals from the soil and enrich the water table, this water is used for cultivating terrestrial and aqueous food as well (Zheng et al., 2023; Chaturvedi et al., 2021; Wicke et al., 2021). Research have shown that children are particularly susceptible to soil contamination due to hand-to-mouth activities and due to their low body mass (Karatela et al., 2020) and potential for higher ingestion of air, water, and food in comparison to adults on a body weight basis (Frings et al., 2024; Ahmad et al., 2021). During pregnancy, the narrow teenaged pelvis tends to concentrate nutrients and lead into mothers’ bone thickness (Haeusler et al., 2021) calcium is rapidly pulled out during menopause. The lead stored in the bones may cause fetal wastage, fertility decrements, and low birth weight (Collin et al., 2022). Exposure via this route may result in poor breathing and hence directly absorbed through cell membranes of the lung (Khoshakhlagh et al., 2024). Water can also be very high in toxic metals and hence be detrimental to the consumer (Briffa et al., 2020). Food grown near or processed with such commodities from contaminated water will also result in toxic ingestion (Yüksel et al., 2023 ). The taste of water is important to determine when water becomes unfit for human consumption; therefore, heavy metals in solution or in a state of suspension can be ingested through water as drinking water or through food and is vital to prevent water and food pollution (Mazinder Baruah and Singh, 2022; Sonone et al., 2020). Fish rearing in polluted soil, nitrogenized ponds take up metals via food and gill; hence fish as a food can affect the public and should not be cooked and fed to children (Porretti et al., 2022). Fish is a good indicator for bioaccumulation of metals (Sheikhzadeh and Hamidian, 2021; Pironti et al., 2021).\n\nb. Inhalation\n\nHumans are predominantly exposed to toxic heavy metals from a plethora of industries in the surroundings (Singh et al., 2023). Inhalation happens as a result of direct exposure; as a result, it is one of the most hazardous routes (Yasmeen and Hafeez, 2023; Sonwani et al., 2022; Kurt and Basaran, 2020). The heavy metals are present both in particles and in fumes (Hedberg et al., 2021; Sonwani et al., 2021). Inhalation of particles is more common, although heavy metals are excreted from the system as they are insoluble in water. Heavy metal inhalation have been reported to cause a plethora of disorders that exert their effects on numerous body systems (Fulke et al., 2024). Even if the systemic manifestations are not noticeable at the outset, the disease will ultimately harm other systems, (Abd Elnabi et al., 2023) particularly the central nervous system . Approximately 95% of inhaled lead particles are 1-2 μm in diameter and therefore do not eliminate easily and persist in the body for a long time. Respiratory disturbances can be induced by long-term or higher-lead exposure (Dumková et al., 2020). Airborne free cadmium have shown to produce hazardous effects by the respiratory system (Bhattacharyya et al., 2023); conversely, its oxide and chloride have been reported to have no effect (Genchi et al., 2020a). Moreso, exposure to a higher level of cadmium have been reported via literature to cause inflammation and emphysema (Wang et al., 2024). Also, there is strong evidence from literature that heavy metal have impacted workers; revealing nickel refinery workers have been reported to have more nasal and nasal-chronic disorders than non-impacted workers (Kurt and Basaran, 2020; Syurin and Vinnikov, 2022). Cadmium sulfate and smoker’s cadmium have been revealed to be deleterious to the upper respiratory pathways (Genchi et al., 2020b).\n\nc. Dermal contact\n\nHeavy metals are a growing threat to general public health and exhibit known toxic impacts on humans and the environment (Mitra et al., 2022) Nowadays, heavy metals are scattered in every nook and cranny of the environment (Adeola, 2020; Kumar et al., 2023). The circulation of heavy metals occurs through the air, water, and food cycle, with plants representing the primary source (Sonone et al., 2020). Nonetheless exposure to heavy metals can also be via the skin. The dermal surface area in adults varies from 1.5 to 2 m2, whereas in children, the ratio of skin surface area to body weight is higher (Zhao et al., 2023). Hence, children are at a higher risk of exposure to heavy metals in the environment compared to adults (Zheng et al., 2023). Even dust on the floor of houses and soil can cause health problems when inhaled or ingested with food (Roy et al., 2024). The uptake of heavy metals, either through respiration or via the skin, now creates debilitating health hazards (Edo et al., 2024; Passeron et al., 2020). To determine the significance of dermal contact as a route of human exposure to toxic metals, it is imperative to fathom that wherever required, metal ions must be mobilized from the surface of a contaminant particle that contacts human skin. However, toxic metals are normally present in an oxidized or insoluble state in natural environmental particles (Saravanan et al., 2022).\n\nHeavy metals exert their toxic effects in a highly complex process with thorough mechanisms which are yet to be understood (Mitra et al., 2022; Engwa et al., 2019). However, several direct mechanisms have been proven to be involved in exerting the deleterious effects of heavy metals including oxidative stress DNA damage (Fu and XI, 2020), membrane damage quenching of in vivo antioxidants (Pisoschi et al., 2021), protein dysfunction and enzyme inactivation (Balali-Mood et al., 2021),\n\nIn an effort to elucidate the mechanisms of metal toxicity, Shi et al. (2004) reported that via oxidative stress, heavy metals were able to form complexes with biological molecules such as lipids, proteins, and DNA, which lead to cell injury by generating or regulating the content of reactive oxygen species (ROS) effects (Acharya, 2024; Fasae and Abolaji, 2022). Reduced antioxidant status effects and dysregulation of antioxidant enzymes have been reported to decrease antioxidant status effects and allow formation of free radicals, thus cumulative body injury (García-Sánchez et al., 2020). Metallic oxides are able to reduce cytochromes and to generate active oxygen species this can further result in cellular levels of adsorption and the resultant genomic deoxyribonucleic acid (DNA) methylation (Mitra et al., 2022). All of the aforementioned mechanisms may gradually results into carcinogenesis. A review by Adil et al. (2020) heavy metals in various cells were able to induce changes in signal transduction pathways, thus alterations in gene expression, DNA repair organelles, cause inflammation, and genotoxic stress. All these changes ultimately lead to carcinogenesis. One highly prominent DNA modifying mechanism that is thought to occur is the generation of ROS. In addition to ROS generation, metals have also been found to have a direct effect on DNA via the formation of metal-DNA adducts where a single base pair is displaced and metal ions then sit in the space created (Marchi, 2023).\n\na. Oxidative stress\n\nThe human body has a conglomerate of elements such as heavy metals that perform numerous functions in the body (Mitra et al., 2022: Some metals are essential for the homeostasis of the organisms (REF). while some are toxic when they overly interact and get supplemented in the cells (REF). A plethora of heavy metals such as lead, mercury, arsenic, and cadmium have no specified physiological function (Balali-Mood et al., 2021). Above that, they disrupt numerous enzymatic processes happening inside the body (Muzaffar et al., 2023). The generation of reactive oxygen species (ROS) is noticeable by metals, concerning oxidative stress that ultimately leads to imbalances between the body’s antioxidant defense mechanisms and prooxidants (Afzal et al., 2023). In recent years, extensive heavy metal poisoning cases have been reported in a plethora of research (Guo et al., 2020; Hu et al., 2020; Obasi and Akudinobi, 2020). Hence, it has become an imperative area of research to investigate the source and remediation of heavy metals. Oxidative stress is an unpleasant condition created by the buildup of free radicals or any mismatch between the production of free radicals and application of antioxidants (Marchi 2023; Martemucci et al., 2022). Many pathological and psychological disorders have been reported to have been caused by oxidative stress in the human body (Kowalczyk et al., 2021). It can further spur up numerous acute or chronic diseases (Wood et al., 2021). If the balance between the formation of free radicals and the ability of cells to survive against a redox any of an abnormality in the production of antioxidants surpasses the free radicals, oxidative stress will occur (Chaudhary et al., 2023). In the cells of humans oxidative stress gives rise to the formation of free radical products that are life-threatening to the physiology of the cell (Zahra et al., 2017). Heavy metal toxicity can directly be linked with oxidative stress, either by redox-cycling or by deactivation of antioxidant systems (Nowicka, 2022). Antioxidants act as a natural defense system and neutralize excessive production of oxidants in the body due to any plausible agents (Pisoschi et al., 2021).\n\nb. DNA damage\n\nOver the years, several studies, including in vitro and in vivo studies, have shown the direct and indirect genotoxic and cytogenetic effects of several metals (Sánchez-Alarcón et al., 2021). Damage of DNA can be caused by metals such as Ni, NiO, and NiSO4 (Genchi et al., 2020a). DNA damage have been investigated in irradiated and non-irradiated cells/nickel-containing solution, revealing he results of this study showed that DNA strand breaks, induced by nickel-titanium (NiTi) and pure nickel under the presence of ultraviolet light caused the result of the synergy between the UV light and the nickel (Umaña et al., 2024). The mechanism(s) leading to nicking of DNA by nickel is not yet fully understood in the scientific world understood, but studies have shown that nickel binding to chromatin can affect the structure of the DNA and greatly increase susceptibility to strand scission by stripping the histone proteins from the chromatin (Kasprzak, 2023; Sekovanić et al., 2020).\n\nHeavy metal-induced DNA damage is a serious risk factor for many human health issues, including cancer (Paithankar et al., 2021), aging (Vielee and Wise JP Jr ., 2023), and neurodegenerative diseases (Stoccoro and Coppedè, 2024). The damaging effect of exposure to metal ions and other nonessential metals on DNA has been investigated in many in vitro and in vivo studies (Ren et al., 2024; Kasprzak, 2023; Fasae and Abolaji, 2022; Slobodian et al., 2021; Peana et al., 2021). The negative effects of heavy metals on genetic material occur mainly at four major levels: cytotoxic, genotoxic, mutagenic, and carcinogenic, depending on the exposure dose, duration, and concentration (Dutta and Ruden, 2024; Stoccoro and Coppedè, 2024; Mitra et al., 2022).\n\nc. Protein dysfunction\n\nChanges in protein expression and phosphorylation have been reported in several tissues after exposure to heavy metals (Mondal, 2023; Mansoor et al., 2023; Renu et al., 2021; Fu and Xi et al., 2020). The human body has several classes of proteins, including enzymes with well-conserved active sites, transmembrane proteins, signal transduction proteins, or transporters that heavy metals may bind to, disrupting their function (Riziotis and Thornton, 2022). Consequently, heavy metal-binding proteins may not be released from the transporter or receptor, forming a new entity that may continuously send signal transduction, resulting in persistent acute or chronic contamination, e.g. lead intoxication , Furthermore, some proteins have been reported to be sensitive to heavy metals (Pillai et al., 2020). Although, the effect that heavy metals have on proteins is not always very much clear but there may be a catalytic role for the heavy metals, for example Cd have been reported to collapse the structure of the hemoglobin tetramer, leading to the release of free alpha plus Cd and beta chains (Pillai et al., 2020).\n\nFurthermore, cadmium have been implicated to affect the enzymatic function of several proteins, including kinases, transcription factors, and metalloprotease (Mondal, 2023). Chronic exposure of patients (humans) to cadmium (i.e., Cd-induced itai-itai disease) has been reported by medical experts (Dutta et al., 2022; Sakurai et al., 2023) and sporadically accelerating breakdown of postmenopausal women bone by inhibiting the function of matrix metalloproteases, which stimulates bone formation and thus exacerbates the hypercalciuretic effect on the body (Ciosek et al., 2023 Rastgar et al., 2022). Also, lead exposure have shown to cause causes amino acid substitution and increased expression of heavy metal-responsive proteins, accompanied by the induction of heme oxygenase-1 (Kapoor et al., 2021; Haeusler et al. 2021).\n\n\n5. Health effects of heavy metal exposure and case studies\n\nThroughout the regions of the world, humans are habitually exposed to various toxic metals via water, food, and air (Parui et al., 2024). In the Homo sapiens species these metals are known to bioaccumulate and biomagnify thereby leading to injury in a plethora of body systems (Parida and Patel 2023; Shah and Kumar, 2022; Semwal et al., 2022). High level of heavy metal in the blood may result into a negative cardiovascular effects with individuals showing signs like increase in heart rate (Mitra et al., 2022) and arterial stiffness (Wan et al., 2023). Some heavy metals that can cross the blood-brain barrier induce neurotoxic effects such as neuropathy and cognitive dysfunction or encephalopathy (Singh and Sharma, 2021; Baig et al., 2024a). Other non-neurotoxic symptoms, such as gastric erosion and vomiting, increase the mortality risk for poisonings and septicemia when exposed to high levels (Parida and Patel 2023; Benhalima et al., 2023).\n\nLong-term exposure to lead and cadmium is the most common causes of chronic kidney disease and is significantly associated with decreased estimated glomerular filtration rate, consistent with the underlying pathology of chronic kidney disease (Satarug et al., 2020). In pregnant mothers, babies, research has shown that at a level of mercury in the form of methylmercury of 1 ppm can result into numerous inappropriate effects on brain development (Fujimura and Usuki, 2022). Also, research has shown via animal experimental studies that low accumulation of heavy metals in tissues can cause adverse effects on the reproductive system such as sperm quality (Heidari et al., 2021) hormone levels, mutations, sperm necrosis, fertilization capacity and pregnancy . However, some cases of human death have been reported via due to oral exposure to heavy metals (Street et al., 2024; Fu and Xi, 2020; Satarug et al., 2020 M Balali-Mood et al., 2021). Besides all of these aforementioned effects, heavy metals have also been reported to propagate tumorigenesis, thereby leading to cancer (Briffa et al., 2020). A detailed understanding of the mechanisms of improvement and toxicity of heavy metals will help to provide an improved specialized approach.\n\nTaken together, a plethora of studies have described and shown the toxic effects on the nervous, cardiovascular and reproductive systems after exposure to heavy metals, and also suggest that the administration of heavy metals in medical applications should be viewed by the accumulating body of evidence as a potentially hazardous route ( Mitra et al., 2022; Taslima et al., 2022). In addition, these heavy metal-induced diseases have deleterious impact on the quality of life of individuals (Briffa et al., 2020).\n\nThe deleterious effects observed by the effects of heavy metals may be in the form of neurodevelopmental disorders like autism (Błażewicz and Grabrucker, 2022) and attention deficit/hyperactivity disorders (Gu et al., 2024). Medical experts have reported cognitive impairments in patients and seizures as a result of heavy metal contamination (Singh and Sharma). Along with these, changes in the level of some neurotransmitters like acetylcholine, noradrenaline, and dopamine in humans as a result of heavy metal accumulation (Pyatha et al., 2023). Hence, suggesting that neurotoxicity has a huge health effect which should be considered at heavy metal-contaminated sites (Baig et al., 2024b). Also, Heavy metals are known to act as neurotoxicants to all age groups of humans (Gade et al., 2021). Exposure to heavy metals during pregnancy have been reported to result into various neurodevelopmental disorders in children (Ijomone et al., 2020; Heng et al., 2022; Ding et al., 2023; Farmani et al., 2024; Nehzomi and Shirani, 2024). The cognitive functions of exposed children have been reported to be pathetic (Ding et al., 2023). Lead has been implicated to cause as a result of exposure in children (Parithathvi et al., 2024). About 1 in 100 children has autism of people have been diagnosed with autism (Nehzomi and Shirani, 2024; WHO, 2023). A study shows that children with autism spectrum disorder have lifted harbors of various heavy metals-small molecular weight proteins such as zinc and copper (Błażewicz and Grabrucker, 2022). In recent literature, mercury, lead, arsenic and cadmium have emerged as the two most common heavy metals linked to attention deficit hyper activity disorder (ADHD) in recent literature (Dutta et al., 2022). The deficiency in zinc in the body of the individual is responsible. Noradrenergic and dopaminergic dysfunction have also been reported in heavy metal neurotoxicity (Medda et al., 2020). Other forms of toxicity reported via literature in terms of prolonged exposure, is a decrease in the level of acetylcholine, which leads to cognitive and behavioral alterations (Althobaiti, 2024). Apart from all of these, effects like Parkinsonism, depression and anxiety have also been reported in recent studies (Mitra et al., 2022; Vellingiri et al., 2022; Baig et al., 2024a; Tizabi et al., 2024). The presence of genotoxicity on neurological systems of patients on exposure to heavy metals has also been reported via literature (Stoccoro and Coppedè, 2024). Taken together, neurotoxicity is basically one of the important endpoints for site assessment and clean-up goals, and immediate action should be taken to prevent heavy metal exposure.\n\nAnimal studies of heavy metals have revealed cardiovascular effects (Sonone et al., 2020; Mitra et al., 2022). This strongly indicates an association between heavy metals and the development of hypertension or hypertension-induced end-organ damage. Cadmium is the most widely studied heavy metal with respect to cardiovascular toxicity (Garai et al., 2021). Experimental studies suggest that Cd in a general population is associated with atherosclerosis or peripheral arterial disease (Barregard et al., 2021). Also, lead has been implicated in numerous processes associated with cellular stimulation leading to atherosclerotic plaque formation (Libby, 2021), as well as affecting the integrity of blood vessel walls through neurotoxic and cardiotoxic effects (Rajpoot et al., 2024). The mechanism that shows the effects of another heavy metal, arsenic, on cardiovascular health is yet to be understood. In a study that included some Bangladesh’s rural community members as well as individuals from a more general (urban as well as rural) health center, the authors reported an exposure-response relation between arthritis and heavy metal exposure, particularly for inorganic arsenic (Choi et al., 2011). Taken together, evidence suggests that agricultural tasks can inadvertently lead to the uptake of high levels of heavy metals and that these heavy metals may act in a discriminatory nature, targeting the meninges and/or dopaminergic system, culminating in Parkinson’s disease.\n\nReproductive structures are very much imperative not only for existence of an individual but also for growth, enlargement and multiplication (Massányi et al., 2020). The response of reproductive organs to toxic substances differs from that of other target organs, and they may serve as an ideal measurement for the deleterious effects of environmental contamination on animal and human health (Massányi et al., 2020). Heavy metal exposure can cause a plethora of deleterious effects on the reproductive region of human health (Fulke et al., 2024). Heavy metals can cause sperm DNA damage and lower sperm quality, thus affecting male fertility (López-Botella et al., 2021) Heavy metals can also disturb sex steroid hormone levels and types of semen, resulting in subfertility (Bhardwaj et al., 2021). On the other hand, lead, cadmium, and mercury can damage the ovaries of females who are then further at the risk of giving birth to anatomically or neurologically malformed offspring because of heavy metal-induced prenatal effects (Yan et al., 2023). During the entire process of maturation of sperm, the cells are exposed to generated reactive oxygen species. This excessive exposure can lead to oxidative stress resulting in sperm DNA damage (Gautam et al., 2024), which can be one of the reasons for making sperm immobile. Lead has been reported in literature to disrupt sex steroid homeostasis in human circulation (Kasten-Jolly and Lawrence, 2017). Lower levels of luteinizing hormone, progesterone, and 17OH-progesterone have been linked with an increase in cadmium accumulation in testes and seminal plasma of infertile and asthenospermic men (Obasi et al., 2022). Also, research as shown that once copper gets absorbed into the systemic circulation, it temporarily disrupts spermatozoa production, maturation, and hormonal homeostasis (Bhardwaj et al., 2021). Meta-analysis evidence has revealed that the epididymis is very much sensitive to heavy metal contamination (Machado-Neves, 2022). Furthermore, lead and cadmium are endocrine disruptors that harm the male and female reproductive system, thereby disturbing the fertility of humans. Cadmium for example was reported by Machado-Neves (2022) to be deleterious to the epididymis, leading reduction in the weight of the epidermis and reducing the number of sperms. Moreso, aluminum has also been implicated cause reduction in blood level of FSH and LH (Ojoghoro et al., 2021), therefore affecting male fertility (Ali et al., 2024; Di Ciaula and Portincasa, 2021). Similarly in females, heavy metals can cause negative effects in the female reproductive tracts, a recent study by Tian et al. (2024) revealed that lead is highly linked to diminished ovarian reserve at during the reproductive age of females. A plethora of research over the years have implicated cadmium in the reduction of ovaries in females (Nna et al., 2017; Nasiadek et al., 2019; Massányi et al., 2020; Ruslee et al., 2020). Exposure to lead and transfer of lead across the placenta may cause miscarriage in females and subfertility (Dutta et al., 2022). An increased spontaneous abortion rate as a result of lead poisoning has also been reported in animals (Mosaad et al., 2024). Therefore, essential to assess the reproductive health of females areas in the environment likely to be contaminated with heavy metals.\n\nItai-itai disease is the most popular case of cadmium (Cd) pollution reported in Japan (Sasaki et al., 2024). The term \"itai-itai\" is from a Japanese word which means “it hurts, it hurts” in English vocabulary (Kaji, 2015). Around 1500 people had severe symptoms such as liver damage, osteomalacia, and bone deformities during the initial phase of the outbreak . Mostly women were the victims, and the male to female ratio of the patients was 1:2 or 1:3 (Kasuya, 2000) Furthermore, The damage it caused in the Jinzu River basin (Japan) and surrounding areas in Toyama Prefecture was recorded by Kozukue as early as 1981. It was reported that the cause of the itai-itai disease was huge ingestion of rice. Much higher cadmium levels were found in the rice which was consumed by patients than by people living in the non-polluted areas (Kasuya, 2000).\n\nThe main clinical symptoms were osteomalacia, renal dysfunctions, and pathological fractures. It was also reported that there were single cases of lung and prostatic cancers among the patients (Zhang et al., 2023). The cases of chemical-induced itai-itai patients, especially, showed severe osteomalacia manifested in similar deformities of the elbow, femoral neck, and knee.\n\n\n6. Case studies of heavy metal pollution in Nigeria\n\nIn a recent study by Orimisan et al. (2024) investigation of precisely five heavy metals (copper, lead, and nickel iron, cadmium,) were scrutinized in two vegetables (Talinum triangulare and Chromolaena odorata) at two dumpsites in Ondo town, Nigeria. A dumpsite located between Ondo Town and Okeigbo was represented as site A and another dumpsite located at Okelaje-Ondo road was represented as Site B. Surprisingly the heavy metal levels identified in and vegetables were below WHO threshold limit with the exception of Cadmium in the control site except for cadmium in site A which was slightly higher. The heavy metals concentration examined in this investigation followed the sequence Fe > Cu > Cd > Ni > Pb for soil from locations A, and Fe > Pb > Cu > Ni > Cd for soil from sites B The dumpsites and the tested two vegetables revealed elevated levels of the heavy metals in comparison to the control area, suggesting a gradual accumulation of these metals in these vegetables. Although the concentration of heavy metals detected in the vegetables in these areas in Ondo town had minimal levels of the selected heavy metals tested, but the fact that they were present in the vegetables is a huge problem, hence may bio accumulate gradually, integrate into the food chain causing chronic debilitating health hazards.\n\nA study by Suleiman et al. (2021) revealed heavy metal contamination in drinking water at six wards in Bade local government area, Yobe, Nigeria, which was as a turnout of pollution in the environment, ultimately affecting the drinking water in Gahua town Gombe negatively. The level of concentration of the following heavy metals; Iron, Manganese, Cadmium, Cobalt, Copper, Mercury and Nickel in boreholes across six wards the Gashua metropolis were assayed. The wards are as follows; Lawan Musa, Sabon Gari, Sarkin Hausawa Katuzu, Lawan Fannami, and Zango Wards. Water samples collected from eighteen sampling point across six urban wards showed no significant difference in terms of heavy metal contamination. Albeit, Suleiman et al. (2021) suggested that water from some ward were not suitable for drinking because of the huge build up some of the heavy metals that may cause kidney stones or renal failure.\n\nThe mean concentration from the study by Suleiman et al. (2021) for Cadmium showed higher levels in Lawan Fannami, Zango and Lawan Musa wards. Sabon Gari and Lawan Musa revealed higher values of Copper (Cu). Katuzu and Lawan Fannami have higher value of iron concentration that is higher than the acceptable standard, suggesting if precautionary measures are not taken it may lead to hideous diseases which can lead death. Alarmingly, all the six wards from this study have higher value of Lead (Pb) that is higher than the accepted standard using USEPA standard of 0.015 mg/kg. The continuous accumulation of this element may lead to serious health problem such as renal failure and kidney stones. Katuzu ward revealed higher concentration of Manganese (Mn) of 0.27, which is higher than the accepted standard. Zango, Sarkin Hausawa. The mean concentration for Mercury (Hg) shows that they are within acceptable value with no trace in Sabon Gari ward while a higher value in Lawan Fannami ward.\n\nTaken together, this case study suggests a heavy metal contamination is of great concern in Nigeria owing to the fact that there is the presence of very much common heavy metals that may be injurious to the health and can cause serious havoc to the body of human and may even results into death.\n\nA recent study by Nneoyi-Egbe (2024) on heavy metal contamination on shrimps and water at the great Kwa river, Calabar Cross River, Nigeria revealed pollution of both the shrimps and water from the Great Kwa River by a plethora of heavy metals, which in turn poses a health risk to aquatic ecosystem and humans. Amongst the heavy metals studied in this research in Calabar, Copper had the highest concentrations in shrimps (33.17 ± 0.79 ppm) and chromium water (27.68 ± 0.34ppm). The heavy metals were found in higher concentrations in the shrimp than in water, except for manganese which had a significantly (p<0.05) higher concentration in water (15.05 ± 0.67ppm) as against 14.02 ± 0.93ppm in shrimp).\n\nThe results of the research indicate significant Lead, Cadmium, Nickel, Chromium, Copper and Manganese content in shrimps and water from the Great Kwa River. It is a matter of great concern for both the environment and public health. Heavy metals are known to be toxic and can cause a range of health problems in humans, including neurological disorders, cancer, and kidney damage. Lead, Cadmium, Nickel and Chromium are particularly dangerous because they can accumulate in the body over time and cause chronic health effects. Moreover exposure to these heavy metals is associated with an increased risk of cardiovascular diseases, hypertension, and impaired cognitive function, neurological and behavioral changes, leading to decreased mobility, altered swimming behavior, and reduced foraging abilities. Moreover, lead can accumulate in the tissues of shrimps over time, leading to chronic exposure and bioaccumulation. This can result in bio magnification, a process where the concentration of lead increases as it moves up the food chain, ultimately affecting humans who consume contaminated seafood. Lead contamination in water can also have significant environmental and public health impacts. High levels of lead in water can cause a range of health problems in humans, including developmental delays in children, decreased intelligence quotient, and an increased risk of cardiovascular disease in adults. Taken together, for this case study, heavy metal concentration was present more in Fish than water at the great Kwa river, and this may cause deleterious effect to the humans consuming shrimps and periwinkle in that area.\n\nFollowing a report on 6th November 2009, the Zamfara State Ministry of Health confirmed an unprecedented outbreak of child mortality in eight of the fourteen local government areas of the Shinkafi and Bakura communities in Zamfara State, Northern Nigeria. Affected communities were predominantly peasant farmers. (Augusto et al., 2021). The mortality affected 34.6% of the population, with a case fatality rate of 30.5%. Over 52% of those who died were children less than five years old (Augusto et al., 2021). It was further reported that the cause of the deaths was that the children had excessively high levels of lead in their blood. Four to five months later, two sister communities in the Gusau local government area of the state became afflicted as well. These two affected communities are situated away from the six contaminated villages in Bukuyyum and Anka local government areas of Zamfara State (Abdullahi and Lasisi, 2024).\n\nThe Ogoni land is an oil-rich region located in the Niger Delta region of Nigeria. The land and its ethnic group, the Ogoni people, shot to worldwide attention in 1992 when the Nigerian military dictator suppressed a demonstration by the Ogoni people. The Ogoni land can best be described as the treasure or scrap of Nigeria (Amosu and Adeosun, 2021). The authorities ordered the arrest and subsequently the trial and execution of nine of the movement’s leaders, including the most prominent and their offense was murder (Okpebenyo et al., 2023). They had been convicted on what are generally considered to be false testimony and mishandled evidence. The movement fought against the disregard of environmental best practices by oil prospecting companies that held sway in the Ogoni land (Okpebenyo et al., 2023). Companies developing the area were particularly criticized. Areas were inadequately treated after drilling had been completed, and the local people received little or no benefits from oil prospecting (Sam et al., 2022).\n\nMany lives have been lost indirectly and directly from the activities of the oil and gas explorers in Ogoni land and other inhabitants near these wells and rigs (Nwoma and Anyika, 2024). The entire ecological system of Ogoni land is severely compromised, and the future of the people of Ogoni is shaky. Cases of massive standing surface oil pollution are very visible in numerous places in the area. Ogoni oil has gained a bad reputation among heavy metal users. In some cases, just the mention of the origin of the crude oil is enough to lose a sale or a customer (Ben, 2022). Any breakdown of the process control in the industry processing Ogoni crude oil must result in a heavy metal disaster of of world proportions. The Ogoni land can best be described as the treasure or scrap of Nigeria (Idialu, 2021).\n\nThree major goldmines attributed to two distinct lead poisoning epidemics of extraordinary scale and remarkable geological background were recorded in Nigeria in recent history. The first, recorded in Bagega, was in 2010 (Jamilu, 2023). In the aftermath of an episode of acute fatal childhood lead poisoning, with more than 400 elevated blood lead levels. What can be described as the second major goldmine activity occurred in Anka Local Government of Zamfara in 2020, with a similarity to the Bagega contamination (Abu Khatita, 2024). Recorded cases of children with elevated blood lead levels have ranged from 24.3% to 60%; over 350 children were reported to have died, and in both of these cases, (Akinwumi et al., 2023; Ezechukwu, 2023; Wilde et al., 2024) the mining involved grinding and milling of lead-rich ore, exposures from dust inhalation, and other pathways of the soil and water compartments (Mahdi et al., 2023). Yet a third contamination with no epidemic status and of considerably fewer numbers was recorded in the Tsafe area in 2020, and the 2020 official status alone still pins both it and the 2020 exceedance incidences as being among the largest recorded in research that examined this throughout the world (Kasongo et al., 2024). A characteristic that has generally defined gold mining in Nigeria is that the mining and grinding of ore releases airborne dust that contains lead, cadmium, mercury, cyanide, and/or other substances used in the process (Escobedo-Monge et al., 2024).\n\nAnother incident of heavy metal contamination with conditions similar to the case described above occurred at the Itakpe iron ore mine in Nigeria in 1985 (Akande et al., 2020). Geologically, there are suspicions that manganese was present in heavy metal concentrations, both as an oxide and as a carbonate (Barde et al., 2024). The incident affected over 10 km of creeks lying near the exploration mine. The river contained high concentrations of iron and manganese deriving from the presence of iron ore on the plateau (Isinkaye et al., 2023).\n\n\n7. Heavy metal pollution mitigation strategies\n\nMitigation of heavy metal bioaccumulation, contamination and pollution is very much imperative in terms of the environment, as widespread pollution increases human exposure and will definitely cause debilitating effects on the human body. Several strategies exist for the decontamination and removal of heavy metals from both the environment and the human body (Wang et al., 2022a; Kowalczyk et al., 2021).\n\nSince the discovery of the problem of environmentally accumulated heavy metals, various technologies have been developed to reduce or eliminate the concentration of heavy metals that have polluted the soil and water. The three main technologies are in situ stabilization and phytoremediation in the environment and chelation therapy to reduce metal-induced oxidative stress, signal transduction, and organ-specific physiology within human beings (Kumar et al., 2023). ’In situ’ refers to on-site or on-area-site and can be accomplished without removing soil from contaminated sites. Chelation is a demure and direct strategy for scavenging the excess metal ions in vital organs of the body, which shows excellent results in flu treatment. In the environmental field, research focusing on bioaccumulation of metals by plants led to the development of technologies to extract heavy metals from the environment, so-called phytoremediation. Phytoremediation is a green technology and is a site-specific technology, which can ultimately reduce the risk of human exposure to toxic substances and environmental remediation costs. Phytoremediation technology includes phytoextraction, phytodegradation, phytostabilization, rhizofiltration, phytovolatilization, phytostimulation, rhizodegradation, rhizofiltration, and hyperaccumulation (Lee and Lee, 2024; Ali, 2023; Chen and Costa, 2021).\n\nThe term phytoremediation is used to describe a set of processes involving the ability of certain plants to remove, degrade, or immobilize a variety of contaminants present in the environment so they are no longer harmful (Yaashikaa et al., 2022). In the case of heavy metals, the term was coined by the US EPA in the early 90s to define the “use of green plants to remove pollutants from the environment or render them harmless”. Phytoremediation is being envisaged as a sustainable approach for in situ remediation of contaminated soils, sediments, and groundwater, due to economic and environmental considerations. This technology can be used to reduce the level of metals in a toxic range for human health and greatly reduce the uptake of these contaminants by plants. In fact, it seems to be effective in plant-only systems, where metals do not accumulate in the food chain, and whenever proper disposal procedures for the harvested material are followed. Since the steel industry is a primary source of contamination by metals and metalloids like chromium, lead, and zinc, good results in terms of removal, stabilization, or reduction can be of interest. In particular, phytoremediation technology appears to be particularly suitable for agricultural substrates or in regions with a view to re-cultivation. Taken together it is very much imperative that safe phytoremediation technology is used to avoid potential harm.\n\nChelation therapy is a therapeutic intervention in which chelating agents are administered to individuals for the removal of toxic heavy metals from the body (Bjørklund et al., 2020). Chelating agents are essentially metal binders and remove them from their sites of deposition in the tissues, in this way, the heavy metal toxins are eliminated in the urine (Gerhardsson, 2022). There are two routes of administration, namely by the oral and parenteral routes, of which the parenteral route is the most effective. Chelation therapy is of benefit in cases of lead and mercury poisoning (Angle, 2023). Chelation could prevent various toxicological manifestations of heavy metals, thus markedly improving various pathophysiological functions. Chelation therapy has been shown to have successful outcomes in cases of lead overload in patients such as children and pregnant women (Singh et al., 2021). However, chelation therapy is ineffective in treating advanced malignancies (Kontoghiorghes, 2022). Despite such knowledge, chelation therapy has also been reported to be effective in the treatment of other heavy metals in the environmental setting (Glicklich et al., 2020).\n\nAnother most common use of chelation therapy is in the treatment of cardiac and cerebral vascular ailments (Ravalli et al., 2022). This therapy is aimed at removing the vascular oxidative injury caused by superoxide and hydroxyl anions by binding these mobilized metal ions (Fe2+ and Ca2+) (Kontoghiorghes et al., 2020). Lead poisoning is the most common cause of neuropathy, and it usually requires an individual to undergo chelation therapy to excrete lead out (Bhasin et al., 2023).\n\n\n8. Conclusion\n\nIn conclusion, heavy metals are major sources of contamination and have adverse effects on human health when their levels exceed the regulatory standards (Mishra et al., 2019). According to the available literature data, if direct human exposure to heavy metal residues in food, water, and/or air occurs, it can lead to severe health problems, e.g., anemia, cancer, or kidney disease (Briffa et al., 2020; Balali-Mood et al., 2021). The data in the literature reviewed for this article have shown that there are multiple sources and pathways of exposure to toxic heavy metals in our environment and identifying the exact causes and adverse effects of contamination on human health is very difficult (Briffa et al., 2020; Bhardwaj et al., 2021; Mitra et al., 2022). Moreover, the removal of metals from the body appears to be limited and slow and may depend on age, sex, and individual genetic variation. In this regard, additional studies are required to find an effective, quick, and safe method for their removal.\n\nIndeed, the need to address heavy metal contamination is very much imperative for a healthy environment and public health. The elements that are classified as heavy metals are difficult to degrade or decompose with time. Additionally, these toxic heavy metals can also flow through the food web and bioaccumulate in various tissues of humans and animals over time due to dietary habits (Nkwunonwo et al., 2020: Sonone et al., 2020). Overall, several challenges, including health risk assessments to determine potential health risks associated with heavy metals, bioavailability assessment to predict the potential for heavy metal bioaccumulation and toxicity in humans, and reducing heavy metal intake, overclocking through legislations to ensure enforcement of existing and future regulatory methods, and encouraging food production in uncontaminated areas, must be addressed by scientists, regulatory authorities, and stakeholders in order to protect human health. In view of these analyses, further research studies should focus on tracing the sources of heavy metals in the environment to find effective ways to overcome this contamination. Moreover, future practices and policies should focus on the development and implementation of economic strategies to reduce or control contamination with toxic heavy metals.\n\nEthics and consent were not required.", "appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nAbd Elnabi MK, Elkaliny NE, Elyazied MM, et al.: Toxicity of heavy metals and recent advances in their removal: a review. Toxics. 2023; 11: 580. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAbdullahi A, Lasisi NO: Assessment of Effects of Maternal Age and Other Factors on Risk of Birth Defects in Zamfara State, Nigeria. J. Appl. Sci. Environ. Manag. 2024; 28: 3877–3881.\n\nAbdullahi IL, Sani A: Welding Fumes Composition and Their Effects on Blood Heavy Metals In Albino Rats. Toxicol. 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PubMed Abstract \| Publisher Full Text \| Free Full Text" }	[ { "id": "363027", "date": "08 Feb 2025", "name": "Rupesh Kumar", "expertise": [ "Reviewer Expertise Same area" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nFew important observations needs to be addressed for improving the quality of work: 1) What is the novelty of study? Is there any existing work supporting or motivating to do this study? Please explain in Introduction part. 2) Author should also mention some other existing technologies may be considered or used instead of AI predictive. 3) I unable to see the research gaps and objectives. Please include latest references which will give you an idea of work in different sectors. Few important papers needs to be added: i. Kumar R et al. (2014 [Ref-1]) ii. Rajani R et al. (2022 [Ref-2]) iii. Kumar R (2017 [Ref-3]) 4) Methodology: Please check for proper citation of figures and tables in the text. In addition, there is no source given for figure and tables. If it is self then author should cite as “Source: Author Composition” or similar. 5) Implications should be added in this (Political, Practical and Social if any). 6) Conclusion part is written in very short. Compare your study with other authors and write in conclusion and extend a bit more. 7) Limitations and future work should be included as a separate heading or may be a part of conclusion also in the last para. 8) Please make a proper structure of your manuscript like aligning with Introduction, LR, Gaps, Objectives, Methods and Materials, Analysis, Results and Discussion, Implications, Conclusion, Limitations and Future Scope and References. 9) Authors may proof read before submitting the revision.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes", "responses": [] } ]	1	https://f1000research.com/articles/14-134
https://f1000research.com/articles/13-627/v1	12 Jun 24	{ "type": "Research Article", "title": "Psychometric properties of an instrument measuring monkeypox knowledge, perception, and beliefs of health threat in health science students in a middle-income country", "authors": [ "Oriana Rivera-Lozada", "Miguel Ipanaqué-Zapata", "Isabel Cristina Rivera-Lozada", "Elvis Siprian Castro-Alzate", "Hebe Hernández-Romero", "Mariana Gómez-Rivera", "César Antonio Bonilla-Asalde", "Miguel Ipanaqué-Zapata", "Isabel Cristina Rivera-Lozada", "Elvis Siprian Castro-Alzate", "Hebe Hernández-Romero", "Mariana Gómez-Rivera" ], "abstract": "Objective This study aimed to establish the factor structure and reliability of the evaluation instrument measuring monkeypox (Mpox) knowledge, perception and beliefs of health threat in students of the health area in two universities of Peru during 2022.\n\nMethods The methodology used was psychometric in nature. The study variable on knowledge of monkeypox was based on the instrument made by Ricco et al., carried out with health professionals, adjusted to Peru and administered to 416 students.\n\nResults The results showed adequate goodness-of-fit indicators with RMSEA and SRMR coefficients lower than 0.08 and a TLI lower than 0.90 and adequate reliability values for knowledge of monkeypox (KR20=0.70 and α=0.73), with the perception of health threats being the one with the highest reliability (α=0.88 and Ω=0.89).\n\nConclusions Having instruments that accurately reflect the knowledge, perception and beliefs of health students will make it possible to contribute significantly to the prevention, control and management of this disease and, at the same time, be prepared to address other challenges of public health in the future.", "keywords": [ "Monkeypox", "Knowledge", "Perception", "Beliefs" ], "content": "1. Introduction\n\nThe disease caused by the monkeypox (Mpox) is considered, after the eradication of smallpox in 1979, the most important infection caused by a virus of the Poxviridae family of the Orthopoxvirus genus.1,2 During the period 2017–2021, outbreaks of cases were reported in Nigeria and other regions that received travelers from this origin. The last outbreak of cases recorded occurred in May 2022 in the United Kingdom, during the COVID-19 virus pandemic.3 In July 2022, Mpox was declared a public health emergency of international concern by the World Health Organization due to the simultaneous record of cases in more than 70 countries.4\n\nManifestations of the disease range from fever, lymphadenopathy, and a typical skin rash to systemic symptoms or even death,5 which is self-limiting in most cases. However, there are more severe forms associated with immunosuppressed populations and vulnerable groups of children, pregnant women, and older men.6,7 Mpox was initially considered a zoonotic disease; however, it currently incorporates contagion through human-human contact, where the main transmission route is direct contact between mucous membranes and skin in sexual activity,8 and secondary routes are respiratory droplets and vertical transmission.8,9\n\nThere have been 86,173 cases and 89 deaths confirmed in the world until February 24, 2023. The Americas accounts for 86% of the cases and includes six of the ten countries with the highest number of confirmed cases globally.10 In the case of Peru, it is in the fourth place and accounts for 17% of the deaths caused by Mpox.11,12 Compared to 2022, a significant decrease in cases was observed compared to other regions of the world. In Latin America, concern about Mpox remains latent since, in addition to the frequency of cases, there are barriers such as social inequality, misinformation, a shortage of human and health resources, and political crises.13\n\nOne aspect of interest is related to the level of knowledge of health personnel concerning Mpox,14 where health professionals in training become relevant in outbreak contexts. For example, we can mention similar cases such as what occurred with the COVID-19 pandemic, which has highlighted the role of learning during university life, proposing strategies for a preventive approach to the healthcare profession, and providing bases for managing the perception of possible contagion.15\n\nThe re-emergence of the disease caused by the monkeypox (Mpox) generated epidemiological alerts worldwide and required health services to implement effective responses that guarantee effective prevention strategies based on mastering the conditions that led to the current state of this problem.16,17 This situation invites us to explore the degree of knowledge as well as the characteristics, attitudes, perceptions and beliefs that influence the practices present during the interaction with users of health services.\n\nThe stated situation added to the Peruvian context in contrast to the literature review carried out allows us to identify the small number of studies related to the degree of knowledge, attitudes and perceptions in health students concerning Mpox, a situation that motivated this study to establish the factor structure and reliability of the evaluation of knowledge, perceptions, and beliefs of health threats in students of the health area in regard to monkeypox (Mpox) infection. Through the review and validation of the psychometric properties of this instrument, the aim is to promote high-quality education in health sciences that not only stays current with medical knowledge but also accurately reflects students’ perceptions and readiness to address emerging health challenges, such as monkeypox and other epidemiological threats.\n\n\n2. Methods\n\nThis research is a psychometric study carried out in two universities in the capital of Peru during the months of August to December 2022.\n\nA total of 436 students enrolled in the universities during the period of interest for this research were surveyed using non-probability convenience sampling. The exclusion criteria were as follows: not being enrolled at the time of administration of the instruments; being under 18 years of age; not accepting informed consent; and not having completed more than 50% of the questionnaires. Twenty of these students (4.5%) did not answer more than 50% of the questionnaires; for this reason, they were excluded from the study, which meant a final sample of 416 students.\n\nThe study variable on knowledge of monkeypox was taken from the instrument created by Ricco et al.18 and carried out with health professionals. From the original instrument, 17 items on knowledge of monkeypox were extracted, organized into three response categories: “True”, “False” and “Don’t know”. The questions have a correct and incorrect question structure; for this reason, after collection, they were transformed into dichotomous items (correct answer=1 point and incorrect answer=0 points). The total score of the questionnaire ranges from 0 to 17 points. Following the recommendations of Lira and Caballero,19 the instrument was translated by professionals and evaluated by expert judgment to maintain agreement and coherence with the Peruvian social context.\n\nRegarding the variable of perception and belief of health threats, the instrument from Ricco et al.’s study18 was also used. It comprised 11 items presented on a Likert scale with five response categories (1=strongly disagree, 5=strongly agree), while the items of threat to health due to other diseases transmitted through the virus used a threat perception magnitude scale with ten response categories reduced to five (1=least threat perception, 2=maximum threat perception), with a total score between 11 and 55 points.\n\nThe instrument was validated by Ricco et al. (2022) and adjusted to Peru through a pilot test that allowed impertinent practices to be excluded. The collection of information received the approval of the university authorities and the informed consent of the students. The students were invited to participate voluntarily and contacted by email and WhatsApp to access the instrument through a Google form.\n\nThe psychometric analysis of the study was exploratory, using the weighted least squares means and variance-adjusted estimation (WLMSV) and polychoric matrix, as well as oblique rotation (quatrimin) to obtain the factor loadings of the dimensions of the study instruments. Additionally, it included the calculation of explained variance to understand the total variation in the data explained by the factors identified in the exploratory factor analysis. Bartlett ’s sphericity was also evaluated to determine if there is sufficient correlation between the variables and the Kaiser-Meyer-Olkin (KMO) adequacy index, which provides a measure of the adequacy of the data for factor analysis.\n\nAfter that, the confirmatory factor analysis was obtained to show the goodness-of-fit indicators. The indicators considered were the Tucker-Lewis index (TLI), appropriate when it is greater than or equal to 0.9020; the standardized root mean squared residual index (SRMR) and the root mean square errors of approximation (RMSEA), appropriate when they are lower than or equal to 0.08.20\n\nFinally, the reliability of the instrument was obtained through the KR-20, Cronbach’s Alpha and Omega indicators, with values greater than 0.50, which are acceptable. R Studio software was used for the analyses of psychometric properties, along with the“lavaan”,“semTools” and “semPlot” packages (Rstudio®, Boston, MA, USA). whose license belongs to the Universidad del Cauca.\n\nThe students who participated in the study did so voluntarily and gave their informed consent in the research instrument form (questionnaire).\n\nThe research considered the Declaration of Helsinki and the protocol was approved by the ethics committee of the Norbert Wiener University, file 1787-2022. dated October 2022 where the investigation has been considered a minimal risk investigation.\n\n\n3. Results\n\nOf the 416 participants, the majority were women (78.61%), belonging to the age group of 18 to 20 years (39.90%), students in the second year of studies (48.32%), nursing professionals (61.78%), and belonging to a private university (90.87%) (Table 1).\n\nRegarding the exploratory analysis of the study questionnaires, the polychoric matrix was used, and the weighted least squares means and variance adjusted (WLMSV) was applied. Each of the items in the questionnaires is based on the dimensions, given that the factor loadings are greater than 0.40. The items that best respond to the knowledge instrument are: yes, they know that monkeypox can be transmitted through direct contact (0.76) and respiratory secretions (0.73), in addition to knowing that monkeypox infections are mainly associated with typical skin lesions (0.75). While for the questionnaire on perception and beliefs about health threats of monkeypox and other diseases transmitted through viruses, it was shown that the items that responded best were the following: perception of monkeypox infection according to its severity (0.93); perception that monkeypox will occur and affect their daily activities (0.87). Likewise, the explained variance for the variables of knowledge and perception and beliefs about monkeypox was reported at 84.6% and 87.1%. The Kaiser-Meyer- Olkin index for the variables of knowledge and perception and beliefs in regard to monkeypox reported 0.93 and 0.95, respectively, taking into account that the appropriate limit is 0.60 and Bartlett ’s sphericity index turned out to be significant (p<0.05) for both variables (Table 2).\n\nRegarding the confirmatory factor analysis, the goodness-of-fit indicators were evaluated for each of the study questionnaires. It is important to mention that the appropriate values for indicators such as RMSEA and SRMR must be lower than 0.08 and TLI must be lower than 0.90. For this reason, the goodness-of-fit indicators for knowledge about monkeypox were adequate given that RMSEA and SRMR were 0.065 and 0.075, respectively, while TLI reported a value equal to 0.92. Additionally, the questionnaire on perceptions and beliefs of health threats posed by monkeypox and other diseases transmitted through viruses reported adequate goodness-of-fit indicators, with RMSEA and SRMR less than 0.08 and the TLI reporting 0.97.\n\nFinally, Table 3 shows that the reliability results were adequate, taking into account that they are reliable with values greater than 0.50. The reliability of the monkeypox knowledge questionnaire was adequate (KR20=0.70 and α=0.73). The reliability of the questionnaire on monkeypox was adequate for each of the dimensions of the instrument, with the perception of threat to health from other contagious viral diseases being the one with the greatest response (α=0.88 and Ω=0.89).\n\n\n4. Discussion\n\nThe second decade of the 21st century has been characterized by the challenge of offering efficient health responses to emerging conditions that involve changes in lifestyles. In the face of infectious conditions such as monkeypox, there is a growing need for tools that account for underlying factors that allow us to understand the complexity of the phenomenon and thus guide decision-making in areas such as public health and clinical practice. This perspective, according to the National Institute of Health of Peru, requires coordinated actions that link surveillance and risk assessment approaches and involve actors from society, the media, and academia.21\n\nThe research allowed us to establish that the instrument subjected to the validation process in a sample of Peruvian students retains a similar factor structure based on the characteristics of the original instrument used by Ricco et al. (2018; 2022) in a sample of Italian physicians.18 The two factors incorporated in the instrument were characterized by offering information related to knowledge through a unidimensional configuration, while in the second factor it was possible to identify a configuration based on three dimensions.22–24 In both cases, when performing the reliability analysis using Cronbach’s alpha, Omega and KR 20 criteria, it was evident that the factors were highly reliable with values greater than 0.70.22,24\n\nIn the local context, no similar studies were identified that used this instrument; however, in a validation experience carried out by Yupari-Azabache et al., where knowledge, attitudes and practices were measured, a factor structure comprised of four dimensions was reported for knowledge, three dimensions for attitudes and two dimensions for practices, with optimal reliability criteria (Cronbach α between 0.81 and 0.91; McDonald ω between 0.82 and 0.92), similar to those of the present one.25\n\nThe study carried out by Caycho -Rodríguez et al., established a strategy for the development and initial validation of a scale of fear of monkeypox, a dimension that could be considered a proxy variable for the attitude factor of this study. The authors reported scale reliability criteria based on a psychological dimension (ω McDonald=0.91) and another affective dimension (ω McDonald=0.71). Additionally, they reported high values of goodness of fit, reliability, and invariance when making comparisons between men (CFI=.99; TLI=.99; RMSEA=.066 [90%CI .004–.111]) and women (CFI=.99; TLI=.99; RMSEA=.067 [90% CI.032–.101]).26\n\nThe approach to this zoonotic disease raises the need to incorporate a complex perspective that links knowledge of aspects such as infection mechanisms, close contact with people with the disease, topical lesions, vulnerable groups and the need for vaccination. The above shows the gap in existing knowledge and the needs of the country when considering the experience of the COVID-19 health emergency and the low levels of knowledge reported in recent studies.17,27\n\nThe items related to attitudes suggest the existence of various manifestations that involve the ability to determine the impact on the reality of the country, which corresponds to a macro-systemic perspective towards a transition that involves daily life25 and includes academic work. The above is based on the need to close gaps in knowledge by health professionals, including those in training, and thus improve communication in care processes with a preventive scope.\n\nA study on the level of advanced knowledge and practices in the general population developed in Peru concluded on the need to guarantee the use of validated instruments that respond to sociodemographic and occupational characteristics28; however, given the conditions in which the investigations were developed, the results obtained give an account of the criteria to deepen the mechanisms of situational analysis that involve, in addition to the natural history of the disease, the incubation periods, geospatial characteristics of the most frequent regions, and strategies to avoid the national health emergency.17 Studies in Europe, North America and some in Latin America reported similar needs and raised conditions that require valid mechanisms to approximate a reliable measure in processes of estimating the occurrence of problems associated with the presence of infectious diseases, considering the high emotional burden and the need to promote decision-making based on evidence related to the experience of providing health services, including academic practice settings.21,29–34\n\nThe results of the present study should be analyzed with caution, considering the sampling method, a condition that limits the ability to generalize the findings. Additionally, it is necessary to consider that the analysis plan did not consider criteria of temporal stability and invariance of the factors based on criteria such as gender, age or academic program, conditions that would increase the scope of establishing the psychometric properties of the instrument.\n\n\n5. Conclusions\n\nThe evaluation of knowledge, perceptions and beliefs about the health threats of infectious diseases such as monkeypox, becomes relevant in all areas of daily life, including university education. Having instruments that accurately reflect the knowledge, perception and beliefs of health students will make it possible to contribute significantly to the prevention, control and management of this disease and, at the same time, be prepared to address other challenges of public health in the future.\n\nThe students who participated in the study did so voluntarily and gave informed consent. The research considered the Declaration of Helsinki, and the protocol was approved by the ethics committee of the Norbert Wiener University, file 1787-2022 dated October 2022 and where it has been considered as a minimum risk research.", "appendix": "Data availability\n\nZenodo: Psychometric Properties of an Instrument Measuring Mon-keypox Knowledge, Perception, and Beliefs of Health Threat in Health Science Students in a Middle-Income Country [Data set]. Zenodo. https://doi.org/10.5281/zenodo.10149774. 34\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nSklenovská N, Van Ranst M: Emergence of Monkeypox as the Most Important Orthopoxvirus Infection in Humans. Front. Public Health. 2018; 6. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMartín Martín S, Morató Agustí M, Javierre Miranda A, et al.: Prevención de las enfermedades infecciosas. Actualización en vacunas PAPPS 2022. Aten. Primaria. 2022; 54: 102462. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCenters for Disease Control and Prevention: cartographer 2022-2023 Mpox Outbreak Global Map. Washington. D.C: 2022.\n\nWorld Health Organization (WHO): WHO Director-General declares the ongoing monkeypox outbreak a Public Health Emergency of International Concern 2022.Reference Source\n\nReda A, Dhama K: Mpox impact on different organ systems: Complications, mechanisms, and management. Int. J. Emerg. Med. 2023; 33(4): 1–13.\n\nPetersen E, Kantele A, Koopmans M, et al.: Human Monkeypox: Epidemiologic and Clinical Characteristics, Diagnosis, and Prevention. Infect. Dis. Clin. N. Am. 2019; 33(4): 1027–1043. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nDu M, Sun H, Zhang S, et al.: Global Epidemiological Features of Human Monkeypox Cases and Their Associations With Social-Economic Level and International Travel Arrivals: A Systematic Review and Ecological Study. Int. J. Public Health. 2023; 68: 1605426. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSharma A, Prasad H, Kaeley N, et al.: Monkeypox epidemiology, clinical presentation, and transmission: a systematic review. Int. J. Emerg. Med. 2023; 16(1): 20. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHuang YA, Howard-Jones AR, Durrani S, et al.: Monkeypox: A clinical update for paediatricians. J. Paediatr. Child Health. 2022; 58(9): 1532–1538. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nDe la Rosa RJG, Hernandez JPR: Una nueva alerta mundial en salud causada por la viruela del simio. Interdiscip. J. Epidemiol. Public Health. 2022; 5(2).\n\nRamírez-Soto MC: Monkeypox Outbreak in Peru. Medicina. 2023; 59(6): 1096. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAl-kassab-Córdova A, Ulloque-Badaracco JR, Benites-Zapata VA, et al.: Facing Mpox (Former Monkeypox) in Latin America: The Example of Peru and Its Vulnerable Healthcare System. MDPI; 2022; 10.\n\nThe Lancet Regional H-A: The cycle of neglect: the mpox emergency in the Americas is far from ending. Lancet Reg. Health Am. 2023; 17: 100429.\n\nStumbar SE, Nusynowitz J, Jamneshan L, et al.: The Need for Emerging Diseases Curricula: A Case Study of Mpox.6.\n\nMartin A, Blom IM, Whyatt G, et al.: A Rapid Systematic Review Exploring the Involvement of Medical Students in Pandemics and Other Global Health Emergencies. Disaster Med. Public Health Prep. 2022; 16(1): 360–372. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nShi A, El Haddad J, Cai P, et al.: Mpox (monkeypox) information on TikTok: analysis of quality and audience engagement. BMJ Glob. Health. 2023; 8(3): e011138. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nRegalado Chamorro M, Hurtado Letona L, Puma Quispe L, et al.: Viruela del mono: a un paso de que la historia se repita. Atención Primaria Práctica. 2022; 4(4): 100151. Publisher Full Text\n\nRiccò M, Ferraro P, Camisa V, et al.: When a Neglected Tropical Disease Goes Global: Knowledge, Attitudes and Practices of Italian Physicians towards Monkeypox, Preliminary Results. Trop. Med. Infect. Dis. 2022; 7(7).\n\nLira M, Caballero E: Adaptación transcultural de instrumentos de evaluación en salud: Historia y reflexiones del por qué, cómo y cuándo. Rev. Méd. Clín. Las. Condes. 2020; 31(1): 85–94. Publisher Full Text\n\nBrown TA: Confirmatory factor analysis for applied research. Guilford Publications; 2015.\n\nSuárez V, Cabezas C: Amenazas a la salud pública en el Perú y la respuesta del Instituto Nacional de Salud. Rev. Peru Med. Exp. Salud Publica. 2022; 39: 140–142. PubMed Abstract \| Publisher Full Text\n\nRaykov T, Hancock GR: Examining change in maximal reliability for multiple-component measuring instruments. Br. J. Math. Stat. Psychol. 2005; 58(Pt 1): 65–82. PubMed Abstract \| Publisher Full Text\n\nTrizano-Hermosilla I, Alvarado JM: Best Alternatives to Cronbach’s Alpha Reliability in Realistic Conditions: Congeneric and Asymmetrical Measurements. Front. Psychol. 2016; 7: 769.\n\nStreiner D, Norman GR, Cairney J: Health measurement scales: a practical guide to their development and use. Aust NZJ Public Health; 2016.\n\nYupari-Azabache IL, Díaz-Ortega JL, Bardales-Aguirre LB, et al.: Validity and Reliability of the Knowledge, Attitudes and Practices Instrument Regarding Monkey Pox in Peru. Risk Manag. Healthc. Policy. 2023; 16: 1509–1520. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCaycho-Rodríguez T, Vilca LW, Carbajal-León C, et al.: The Monkeypox Fear Scale: development and initial validation in a Peruvian sample. BMC Psychol. 2022; 10(1): 280. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nNavarrete-Mejía PJ, Velasco-Guerrero JC, Sullcahuamán-Valdiglesias E: Conocimiento sobre viruela del mono en profesionales de la salud, Lima-Perú. Revista del Cuerpo Médico Hospital Nacional Almanzor Aguinaga Asenjo. 2022; 15: 252–255. Publisher Full Text\n\nMamani-Benito O, Carranza Esteban R, Fernández J, et al.: Adaptation and Validation of a Monkeypox Concern Instrument in Peruvian Adults. Sustainability. 2022; 14: 12354. Publisher Full Text\n\nPatiño LH, Guerra S, Muñoz M, et al.: Phylogenetic landscape of Monkeypox Virus (MPV) during the early outbreak in New York City, 2022. Emerg. Microbes Infect. 2023; 12(1): e2192830. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nChakraborty C, Bhattacharya M, Saikumar G, et al.: A European perspective of phylogenomics, sublineages, geographical distribution, epidemiology, and mutational landscape of mpox virus: Emergence pattern may help to fight the next public health emergency in Europe. J. Infect. Public Health. 2023; 16(7): 1004–1014. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHatmal MM, Al-Hatamleh MAI, Olaimat AN, et al.: Comprehensive literature review of monkeypox. Emerg. Microbes Infect. 2022; 11(1): 2600–2631. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHuaire Inacio EJ, Herrera Álvarez AM, Sifuentes De la Cruz LE, et al.: Retorno a la presencialidad: Actitudes de los universitarios peruanos hacia el aprendizaje y pos-crisis sanitaria. Revista de Ciencias Sociales. 2023; 13159518: 29.\n\nCarreño-Moreno SP, Chaparro-Díaz L, Cifuentes-Tinjaca CD, et al.: Conocimientos, actitudes, prácticas, temor y estrés ante el Covid-19 en estudiantes y recién egresados de Enfermería en Colombia. Revista Cuidarte. 2021; 12(3).\n\nRivera-Lozada O, Rivera Lozada IC, Castro-Alzate ES, et al.: Psychometric Properties of an Instrument Measuring Mon-keypox Knowledge, Perception, and Beliefs of Health Threat in Health Science Students in a Middle-Income Country. [Data set]. Zenodo. 2023. Publisher Full Text" }	[ { "id": "323813", "date": "09 Oct 2024", "name": "Alysa Pomer", "expertise": [ "Reviewer Expertise Biological Anthropology", "infectious diseases", "survey design and research" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary: In this study, the authors seek to validate a psychometric instrument measuring mpox knowledge, perceptions, and beliefs of health threats in a new context—namely, among healthcare students at two universities in Peru. This is a valuable contribution in Peru (and potentially other Spanish-speaking populations of the Americas) where mpox rates have been high. Understanding the knowledge base and biases of medical trainees around this disease can help ensure education of those future medical providers is adapted so mpox patients are getting the best care possible.\nThe methods should be expanded to ensure replication is possible. This should include information about the specific items included as well as the translation procedures.\nThe specific statistical analyses used are outside of my area of familiarity, so I can’t comment on the statistical analyses specifically. However, some information does seem to be missing from the tables that would have made it easier for me to understand these analyses.\nMy greatest concern with this manuscript is that the specific results of this study are not clearly shown in the Results, which means the Discussion does not have a thorough exploration of what this particular study found in relation to other studies, leading to a vague Conclusion that doesn’t say anything specific about this study. If the Results can be more clearly and thoroughly explained, I believe this would cascade to a more robust Discussion section and clear, concise Conclusion.\nIt is worth noting that the nomenclature around this disease changed fairly recently; I strongly suggest changing “monkeypox” to “mpox” throughout the manuscript. The literature is otherwise current.\nFinally, the manuscript would benefit from proofreading for grammar and syntax.\n\nGeneral comments: 1. I strongly suggest changing “monkeypox” to “mpox” to align with updated WHO nomenclature guidelines (https://www.who.int/news/item/28-11-2022-who-recommends-new-name-for-monkeypox-disease and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9901940/).\nIntroduction: 2. Update your first sentence to note that “monkeypox” is the previous name for the disease that is currently known as “mpox” and that this disease is caused by the monkeypox virus (MPXV). 3. Did the last outbreak start in May 2022 in the UK, or was it confined to May 2022 in the UK? The current language makes it sound like the latter, but that’s contradicted in the following line when it’s stated that a PHE was declared two months later. Please clarify. 4. Compared to 2022…”—is this referring to case rates in 2023 being compared to 2022 case rates? Please clarify.\nMethods: 5. Population: I suggest presenting the inclusion criteria rather than the exclusion criteria. 6. Variables and instruments: “The study variable on knowledge of [mpox] was taken from the instrument…and carried out with health professionals.” How are the health professionals involved with the survey? I understood the survey to be conducted online and given to students. Please clarify. 7. Variables and instruments: Which 17 knowledge items and 11 perception/belief items were included? Why were these items included but not the others? Consider including the survey used in this study as a supplementary file (Spanish and English translations). 8. Variables and instruments: Considering the importance of translation in the validation of survey instruments in new contexts, the information about the translation procedure should be expanded. For example, what does it mean that the instrument was “translated by professionals and evaluated by expert judgment”? How many people translated the survey? Were the translators from the medical field? Were any of the translators part of the study team? Did a second set of translators back-translate? 9. Procedure: “Irrelevant” would be a more accurate word than “impertinent” in the first sentence.\nResults: 10. A table showing the knowledge items, correct answer, and response distribution for each item would be helpful (similar to table A3 in the Ricco et al., 2022, paper). 11. The results of the perception and belief of health threats variables should also be presented in a table.\nDiscussion: 12. Clarification—If the first sentence is referring to the 2020s, this is actually the third decade of the 21st century (2000s is the first decade, 2010s is the second decade, 2020s is the third decade).\nConclusions: 13. This is a very vague statement that doesn’t say anything about what this particular study actually found. Clarify the findings through the Results and Discussion sections to create a more specific Conclusions section.\nReferences: 14. #14 is an incomplete reference and should be as follows: [ ref 1 ]\nTables: 15. Table 1 should include the total number of participants. 16. Tables 2 and 3 include “D1, D2, D3” in the header but don’t define what these mean. Please define this terminology as a footnote in the tables and consider adding the information to the text. 17. Table 3 shows RMSEA with bracketed ranges, but no other indicators show these ranges. Please explain what these ranges are and why the other indicators do not include ranges.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [] }, { "id": "338479", "date": "14 Nov 2024", "name": "Mona Gamal Mohamed", "expertise": [ "Reviewer Expertise Infectious disease", "Meta-analysis", "qualitative and quantitative research" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntroduction:\nThe introduction lacks a comprehensive discussion of the psychometric framework and the significance of the study. While the disease context is briefly mentioned, the foundational importance of this work in advancing measurement science is not adequately addressed. Contrary to the claim of limited research in this area, a substantial body of literature exists, providing critical insights into similar psychometric developments. These references should be acknowledged to contextualize the study and highlight its relevance within the broader research landscape.\nMethods:\nThe methodology section is underdeveloped and lacks clarity, making it difficult to follow the process. Only one reference is cited for the instrument's development, despite the wealth of existing literature on similar psychometric tools, which I have included in the included citations. Furthermore, the translation process is entirely omitted, and the critical phases of tool validation—such as content validation, construct validation, and reliability testing—are not detailed. These omissions significantly undermine the credibility and reproducibility of the study.\nResults:\nThe results section requires substantial improvement through advanced statistical analysis. The current presentation appears overly simplistic, offering only a fundamental analysis that does not provide a nuanced understanding of the tool's psychometric properties. Enhanced analysis is necessary to give the reader a clearer and more comprehensive perspective on the validity and reliability of the instrument. Such improvements would significantly elevate the quality and usefulness of the findings.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [] } ]	1	https://f1000research.com/articles/13-627
https://f1000research.com/articles/13-1544/v1	20 Dec 24	{ "type": "Genome Note", "title": "A reference genome for the eastern bettong (Bettongia gaimardi)", "authors": [ "Luke W Silver", "Richard J Edwards", "Linda Neaves", "Adrian D. Manning", "Carolyn J Hogg", "Sam Banks", "Richard J Edwards", "Linda Neaves", "Adrian D. Manning", "Carolyn J Hogg", "Sam Banks" ], "abstract": "Abstract* The eastern or Tasmanian bettong (Bettongia gaimardi) is one of four extant bettong species and is listed as ‘Near Threatened’ by the IUCN. We sequenced short read data on the 10x system to generate a reference genome 3.46Gb in size and contig N50 of 87.36Kb. Additionally, we used GeMoMa to provide and accompanying annotation for the reference genome. The generation of a reference genome for the eastern bettong provides a vital resource for the conservation of the species.", "keywords": [ "Genome annotation", "reference genome", "bettong", "marsupial" ], "content": "Introduction\n\nThe eastern or Tasmanian bettong (Bettongia gaimardi) is a small nocturnal Australian marsupial in the potoroid family and is considered an important ecosystem engineer due to its habit of digging and feeding on fungi (Munro et al. 2019, Ross et al. 2019a, 2019b). Eastern bettongs were once widespread across south-eastern Australia but are reported to have gone extinct on mainland Australia around the 1920’s due to predation from introduced carnivores and land clearing (Short 1998). Eastern bettongs are now confined to the eastern half of Tasmania where they are listed as ‘Near Threatened’ by the IUCN Red List (Burbidge et al. 2016).\n\nAustralia has experienced the highest extinction rate of mammals on any continent over the past 200 years, accounting for 28% of the world’s mammal extinctions since the year 1600 (McKenzie et al. 2007). Nationwide, a number of reintroduction programs are being implemented for the conservation of locally-extinct mammals, typically in the ‘critical weight range’ of 35 – 5500g (Burbidge and McKenzie 1989). In the case of the eastern bettong, the species was reintroduced from the state of Tasmania to two fenced reserves in the Australian Capital Territory (ACT) between 2011 and 2012 (Batson et al. 2016).\n\nThe generation of a reference genome will provide a valuable resource in the management of the two reintroduced populations of eastern bettongs and contribute to the global effort to sequence all eukaryotic life on Earth (Lewin et al. 2022). To generate a reference genome, we sequenced DNA with 10x short reads and used GeMoMa to produce a genome annotation.\n\n\nMethods\n\nWe used muscle tissue from a deceased male pouch young (B. gaimardi) individual collected from Mulligan’s Flat Woodland Sanctuary during population monitoring in 2014 and was frozen immediately after collection. The Sample was collected under Australian National University Animal Experimentation Ethics Committee ethics protocol A2011/017. DNA extraction used the QIAGEN Genomic Tips kit (Qiagen Catalogue # 10223) yielding 170ng/μl of DNA. Sequencing used the KAPA HyperPrep PCR free library kits (Roche Catalogue # KK8503) and two lanes of HiSeq Xten 150 bp PE sequencing (Illumina) at the Ramaciotti Centre for Genomics (UNSW, Sydney). Further sequencing using the 10X Chromium Genomics library prep with >50 kb size selection was sequenced with 2 lanes of HiSeq Xten (150 bp PE) (Illumina) was undertaken. The sample was accessioned to the Australia Museum Accession number AM M.56404.\n\nRaw 10x data was assembled using Supernova v2.0.0 (RRID:SCR_016756) (Weisenfeld et al. 2017) with pseudohaplotype output. Haplotypes were tidied and filtered using Diploidocus v0.3.0 (RRID:SCR_021231) (Stuart et al. 2022), which filtered redundant and 100% unresolved scaffolds, and assigned the longest version of each scaffold to haplotype 1 [bettong.v1.0]. Scaffolds flagged as diploid (identical in both haplotypes) were then added back to haplotype 2 and each haplotype ran through Telociraptor v0.9.0 (https://github.com/slimsuite/telociraptor) to length-sort and rename scaffolds after modifying the ends to reveal telomeres, where appropriate [bettong.v1.1]. Scaffolds identified by Tiara v1.0.3 (Karlicki et al. 2022) as being from archaea, bacteria, prokarya or organelle were filtered, along with scaffolds flagged for exclusion or review by FCS-GX [bettong.v1.2] (Astashyn et al. 2023).\n\nCompleteness was estimated using Benchmarking Universal Single-Copy Orthologues (BUSCO, RRID:SCR_015008) v5.4.3 (Simao et al. 2015) using the mammalia_odb10 (n:9226) and vertebrata_odb10 datasets (n:3354).\n\nRepetitive elements of the genome were identified, classified and masked using a Pawsey Supercomputing Centre Nimbus cloud machine (256GB RAM, 64 vCPU, 3 TB storage) by building a database using RepeatModeler v2.0.1 (RRID:SCR_015027) (Flynn et al. 2020); repeats were then masked using RepeatMasker v4.0.9 (RRID:SCR_012954) (Smit et al. 2013-2015).\n\nA homology-based annotation was created independently for each haplotype using GeMoMa v1.9 (RRID:SCR_012954) (Keilwagen et al. 2019) using the annotation from nine Ensembl mammalian genomes (cow [Bos taurus], human [Homo sapiens], opossum [Monodelphis domestica], mouse [Mus musculus], Tammar wallaby [Macropus eugenii], platypus [Ornithorhynchus anatinus], koala [Phascolarctos cinereus], Tasmanian devil [Sarcophilus harrisii], wombat [Vombatus ursinus]) ( Table 1). SAAGA v0.7.9 (https://github.com/slimsuite/saaga.git) was used to map annotated proteins onto a combined dataset of SwissProt (Edwards and Palopoli 2015, UniProt 2023) and Quest for Orthologues reference proteomes (Nevers et al. 2022) to add descriptions and extract the longest isoform per gene for completeness estimation using BUSCO v.5.4.3 (RRID:SCR_015008) in protein mode against the vertebrata_obd10 (n:3354) and mammalia_obd10 lineages (n:9226) (Simao et al. 2015).\n\nThe ‘genestats’ script (https://github.com/darencard/GenomeAnnotation) was used to obtain the average number of exons and introns and the average exon and intron length.\n\n\nResults\n\nGenome assembly with Supernova estimated a 3.79 Gb genome size (46.88X raw coverage) and assembled a 3.57 Gb genome in 38,249 scaffolds (scaffold N50=2.77 Mb) (Silver 2024). Following Diploidocus cleanup, there were 27,408 primary scaffolds (3.46 Gb) with 1,681 alternative scaffolds (3.01 Gb). Telociraptor made five inversions and trimmed one contig. Contamination removal filtered 786 scaffolds (2.00 Mb) from each haplotype. This gave a final genome size of 3.46 Gb with 26,663 scaffolds ( Table 2). The genome size is comparable to that of other marsupial genomes, including that of the closely related woylie (Bettongia penicillate ogilbyi) (Haouchar et al. 2016, Peel et al. 2021). BUSCO completeness of the final genome was 92.2% for mammalia_odb10 and over 96.9% for vertebrata_odb10 (96.8% for haplotype two) ( Table 2). Additionally, 53.08% of the genome was identified as repeats, which is similar to other marsupials, including the closely related woylie (53.05%) (Peel et al. 2021) ( Table 3).\n\nGenome annotation with GeMoMa predicted 36,068 and 36,015 protein coding genes for haplotype one and two, respectively, which is a large over-estimation with other marsupials having around 20,000 protein coding genes (Johnson et al. 2018, Brandies et al. 2020). The annotation is highly complete with 94.1% of mammalian protein BUSCOs complete ( Table 4). The average protein length was 384.3 and 384.7 amino acids for haplotype one and two, respectively, with an average of 6.52 exons per gene ( Table 4). On average, predicted proteins were 87.8% the length of their best SwissProt/QFO hit, suggesting some fragmentation of the annotation, which might be inflating the numbers of annotated genes.\n\nSamples were collected under Australian National University Animal Experimentation Ethics Committee ethics protocol A2011/017 (Approved 2011, expired Dec 2014). The sample was collected in during trapping in 2014.", "appendix": "Data availability\n\nThe raw are publicly available through the Bioplatforms Australia Oz Mammals Genomes: https://data.bioplatforms.com/organization/bpa-omg . The assembled and annotated genome herein is hosted on the Australasian Genomes site (https://awgg-lab.github.io/australasiangenomes/) in addition to NCBI.\n\nRaw genome sequences are available on:\n\nNCBI’s Short Read Archive (SRA): Raw DNA data for generation of genome. SRX26311185 and SRX26311186 (https://www.ncbi.nlm.nih.gov/sra/PRJNA1095660) (Silver et al. 2024).\n\nThe data produced as part of this study are stored on NCBI under BioProjects PRJNA1095660 (Silver et al. 2024). Databases of molecular data on the NCBI Web site include such examples as nucleotide sequences (GenBank), protein sequences, macromolecular structures, molecular variation, gene expression, and mapping data. They are designed to provide and encourage access within the scientific community to sources of current and comprehensive information. Therefore, NCBI itself places no restrictions on the use or distribution of the data contained therein.\n\nFigshare: ARRIVE checklist for A reference genome for the eastern bettong (Bettongia gaimardi), DOI: https://doi.org/10.6084/m9.figshare.27144360.v1 (Silver 2024).\n\nThe project contains the following reporting guidelines:\n\n• Author Checklist – ARRIVE\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgements\n\nThe authors would like to acknowledge computational resource support from: Galaxy Australia, a service provided by the Australian Biocommons and its partners; the University of Sydney’s High Performance Computing facility Artemis provided by the Sydney Informatics Hub; the University of New South Wales Katana High Performance Computing (doi:10.26190/669X-A286). Support for DNA sequencing was provided through the Oz Mammals Genomics (OMG) Initiative consortium (https://ozmammalsgenomics.com/consortium/), which was funded by Bioplatforms Australia through the Australian Government National Collaborative Research Infrastructure Strategy.\n\nThe eastern bettong reintroduction was conducted as part of and with support of the “Mulligans Flat – Goorooyarroo Woodland Experiment” (https://www.coexistenceconservationlab.org/mulligans-flat-goorooyarroo-woodland-experiment). Thanks to the ACT Government and Woodlands and Wetlands Trust and their staff for their support for the eastern bettong reintroduction project at Mulligans Flat Woodland Sanctuary. Thanks to Brittany Brocket for the initial DNA extraction.\n\n\nReferences\n\nAstashyn A, Tvedte ES, Sweeney D, et al.: Rapid and sensitive detection of genome contamination at scale with FCS-GX. bioRxiv. 2023. Publisher Full Text\n\nBatson W, Fletcher D, Portas T, et al.: Re-introduction of eastern bettong to a critically endangered woodland habitat in the Australian Capital Territory, Australia. Global Re-introduction Perspectives. 2016; pp. 172–177.\n\nBrandies PA, Tang S, Johnson RSP, et al.: The first Antechinus reference genome provides a resource for investigating the genetic basis of semelparity and age-related neuropathologies. GigaByte. 2020; 2020: gigabyte7–gigabyte22. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBurbidge AA, McKenzie N: Patterns in the modern decline of Western Australia’s vertebrate fauna: Causes and conservation implications. Biol. Conserv. 1989; 50(1-4): 143–198. Publisher Full Text\n\nBurbidge AA, Woinarski J, Johnson CN: Bettongia giamardi. The IUCN Red List of Threatened Species. 2016. Publisher Full Text\n\nEdwards RJ, Palopoli N: Computational prediction of short linear motifs from protein sequences. Methods Mol. Biol. 2015; 1268: 89–141. Publisher Full Text\n\nFlynn JM, Hubley R, Goubert C, et al.: RepeatModeler2 for automated genomic discovery of transposable element families. Proc. Natl. Acad. Sci. USA. 2020; 117(17): 9451–9457. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHaouchar D, Pacioni C, Haile J, et al.: Ancient DNA reveals complexity in the evolutionary history and taxonomy of the endangered Australian brush-tailed bettongs (Bettongia: Marsupialia: Macropodidae: Potoroinae). Biodivers. Conserv. 2016; 25(14): 2907–2927. Publisher Full Text\n\nJohnson RN, O’Meally D, Chen Z, et al.: Adaptation and conservation insights from the koala genome. Nat. Genet. 2018; 50(8): 1102–1111. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKarlicki M, Antonowicz S, Karnkowska A, et al.: Tiara: Deep learning-based classification system for eukaryotic sequences. Bioinformatics. 2022; 38(2): 344–350. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKeilwagen J, Hartung F, Grau J: GeMoMa: Homology-based gene prediction utilizing intron position conservation and RNA-seq data. Methods Mol. Biol. 2019; 1962: 161–177. PubMed Abstract \| Publisher Full Text\n\nLewin HA, Richards S, Lieberman Aiden E, et al.: The Earth BioGenome Project 2020: Starting the clock. Proc. Natl. Acad. Sci. USA. 2022; 119(4): e2115635118. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMcKenzie N, Burbidge A, Baynes A, et al.: Analysis of factors implicated in the recent decline of Australia’s mammal fauna. J. Biogeogr. 2007; 34(4): 597–611. Publisher Full Text\n\nMikkelsen TS, Wakefield MJ, Aken B, et al.: Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences. Nature. 2007; 447(7141): 167–177. PubMed Abstract \| Publisher Full Text\n\nMunro NT, McIntyre S, Macdonald B, et al.: Returning a lost process by reintroducing a locally extinct digging marsupial. PeerJ. 2019; 7: e6622. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nNevers Y, Jones TEM, Jyothi D, et al.: The Quest for orthologs orthology benchmark service in 2022. Nucleic Acids Res. 2022; 50(W1): W623–W632. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPeel E, Silver L, Brandies P, et al.: A reference genome for the critically endangered woylie, Bettongia penicillata ogilbyi. GigaByte. 2021; 2021: gigabyte35–gigabyte15. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nRenfree MB, Papenfuss AT, Deakin JE, et al.: Genome sequence of an Australian kangaroo, Macropus eugenii, provides insight into the evolution of mammalian reproduction and development. Genome Biol. 2011; 12(8): R81. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nRosen BD, Bickhart DM, Schnabel RD, et al.: De novo assembly of the cattle reference genome with single-molecule sequencing. Gigascience. 2020; 9(3). PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nRoss CE, McIntyre S, Barton PS, et al.: A reintroduced ecosystem engineer provides a germination niche for native plant species. Biodivers. Conserv. 2019a; 29(3): 817–837. Publisher Full Text\n\nRoss CE, Munro NT, Barton PS, et al.: Effects of digging by a native and introduced ecosystem engineer on soil physical and chemical properties in temperate grassy woodland. PeerJ. 2019b; 7: e7506. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nShort J: The extinction of rat-kangaroos (Marsupialia:Potoroidae) in New South Wales, Australia. Biol. Conserv. 1998; 86(3): 365–377. Publisher Full Text\n\nSilver L: ARRIVE checklist for A reference genome for the eastern bettong (Bettongia gaimardi). Dataset. figshare. 2024. Publisher Full Text\n\nSilver LW, Edwards EJ, Neaves L, et al.: Bettongia gaimardi genome sequencing and assembly. National Centre for Biotechnology Information: Sequence Read Archive; 2024.\n\nSimao FA, Waterhouse RM, Ioannidis P, et al.: BUSCO: Assessing genome assembly and annotation completeness with single-copy orthologs. Bioinformatics. 2015; 31(19): 3210–3212. Publisher Full Text\n\nSmit A, Hubley R, Green P: RepeatMasker Open-4.0.2013-2015. Retrieved 19 December 2019. Reference Source\n\nStammnitz MR, Gori K, Kwon YM, et al.: The evolution of two transmissible cancers in Tasmanian devils. Science. 2023; 380(6642): 283–293. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nStuart KC, Edwards RJ, Cheng Y, et al.: Transcript and annotation-guided genome assembly of the European starling. Mol. Ecol. Resour. 2022; 22(8): 3141–3160. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nUniProt C: UniProt: the Universal Protein Knowledgebase in 2023. Nucleic Acids Res. 2023; 51(D1): D523–D531. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWeisenfeld NI, Kumar V, Shah P, et al.: Direct determination of diploid genome sequences. Genome Res. 2017; 27(5): 757–767. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nZhou Y, Shearwin-Whyatt L, Li J, et al.: Platypus and echidna genomes reveal mammalian biology and evolution. Nature. 2021; 592(7856): 756–762. PubMed Abstract \| Publisher Full Text \| Free Full Text" }	[ { "id": "351903", "date": "08 Jan 2025", "name": "Naoki Osada", "expertise": [ "Reviewer Expertise Population genetics", "molecular evolution", "genomics" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript presents the results of whole-genome sequencing and assembly of Bettongia gaimardi. The authors conducted genome assembly, quality evaluation, and annotation, including repetitive sequence annotation. I have verified that the assembled genome sequence and raw data are publicly available. Overall, this dataset is valuable for future research, and I have only some minor comments:\n\nIn the abstract, showing scaffold N50 would be helpful. In the Introduction section, the phrase “10x short reads” might be misleading, as it could imply a 10-fold coverage of short reads. I suggest using “10x Genomics short reads” or a similar term for clarity. In the Method section, the sentence \"Further sequencing using ... was sequenced with 2 lanes ...\" requires rephrasing for better readability. It would be helpful if the authors provided additional details about the amount of sequencing data obtained, such as the number of reads or total bases. I assume the authors used default settings for running the software, but it should be stated in the Method section. In the Data availability section, the first sentence would be to: “The raw data are …”.\n\nAre the rationale for sequencing the genome and the species significance clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of the sequencing and extraction, software used, and materials provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a usable and accessible format, and the assembly and annotation available in an appropriate subject-specific repository? Yes", "responses": [ { "c_id": "13171", "date": "27 Jan 2025", "name": "Luke Silver", "role": "Author Response", "response": "Reviewer Comment: In the abstract, showing scaffold N50 would be helpful. Author Response: We have added in the scaffold N50 value to the abstract Reviewer Comment: In the Introduction section, the phrase “10x short reads” might be misleading, as it could imply a 10-fold coverage of short reads. I suggest using “10x Genomics short reads” or a similar term for clarity. Author Response: We have rephrased as suggested Reviewer Comment: In the Method section, the sentence \"Further sequencing using ... was sequenced with 2 lanes ...\" requires rephrasing for better readability. Author Response: We have rephrased the sentence to “Additional sequencing using the 10X Chromium Genomics library prep with >50 kb size selection was performed using 2 lanes of HiSeq Xten (150 bp PE) (Illumina).” for clarity Reviewer Comment: It would be helpful if the authors provided additional details about the amount of sequencing data obtained, such as the number of reads or total bases Author Response: We have added the amount of reads produced in the first sentence of the results “Sequencing generated 185M reads of short read data and 149M reads of 10x Genomics data” Reviewer Comment: I assume the authors used default settings for running the software, but it should be stated in the Method section. Author Response: We have stated in the methods the settings used for running the software Reviewer Comment: In the Data availability section, the first sentence would be to: “The raw data are …”. Author Response: We have updated the data availability section as suggested" } ] }, { "id": "351899", "date": "14 Jan 2025", "name": "Jonathan J Hughes", "expertise": [ "Reviewer Expertise Genomics", "phylogenetics", "mammalogy" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors describe a whole-genome assembly generated with 10X sequencing for the eastern bettong, an ecologically important marsupial of conservation concern. They report their protocols for extraction, sequencing, QC, and annotation. The manuscript is clearly written and the methodology is both appropriate and reasonably detailed. I have a few small concerns that could be addressed:\nState the parameters used when running any given software. If only default parameters were used for all software, then state that. In Table 2, use commas consistently for reporting large numbers. The number of scaffolds reported in the results (26,663) is different to that reported in Table 2 (26,623). I have been able to locate most of the raw data and the assembled genome through NCBI, but the genome does not appear to be currently hosted on the Australian Genomes website as stated.\n\nAre the rationale for sequencing the genome and the species significance clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of the sequencing and extraction, software used, and materials provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a usable and accessible format, and the assembly and annotation available in an appropriate subject-specific repository? Yes", "responses": [ { "c_id": "13172", "date": "27 Jan 2025", "name": "Luke Silver", "role": "Author Response", "response": "State the parameters used when running any given software. If only default parameters were used for all software, then state that. We have stated in the methods the settings used for running the software In Table 2, use commas consistently for reporting large numbers. We have used comma’s consistently throughout the manuscript The number of scaffolds reported in the results (26,663) is different to that reported in Table 2 (26,623). We have updated the results to correctly report 26,623 as the number of scaffolds I have been able to locate most of the raw data and the assembled genome through NCBI, but the genome does not appear to be currently hosted on the Australian Genomes website as stated. We have uploaded the genome and annotation onto the Australian Genomes website" } ] }, { "id": "351906", "date": "17 Jan 2025", "name": "Németh Attila", "expertise": [ "Reviewer Expertise molecular phylogentics", "phylogeography", "(molecular) taxonomy", "conservation genetics" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear Editor(s), Dear Authors,\nI am sending below my comments on Manuscript, entitled \"A reference genome for the eastern bettong (Bettongia gaimardi),\" which was submitted for publication in the journal F1000Research.\nI find the article important, of scientific value and interest, because it is the first to provide information on the genome of an animal species, a reference genome, as the authors say, for which we have no such information.\nNevertheless, some concerns have been raised that make me unsure whether the genomic data provided can be considered a true reference genome.\nWhy was the reference genome based on a sample from only one individual? It is not an endangered species, so what was the reasoning behind this choice? Why were only short reads performed? The length of repetitive regions is typically much greater than that of short reads, which raises questions about the methodology used. How accurate do the authors estimate their chosen method is?\n\nAlthough I am not a real expert on genome assembly, I recommend that the authors add a brief section in the manuscript discussing the limitations of their findings. This section could explain the rationale behind their decision to work with a single individual and the reasons for choosing this particular method, such as the use of short reads.\nI also think it is important to briefly discuss what the authors think might explain why this animal has one and a half times as many protein-coding regions as the known marsupial genome. Could there be a biological or evolutionary reason for this?\nOverall, I believe the manuscript is valuable and I support its indexing. While I am uncertain if the results can truly be classified as a reference genome, I am convinced that indexing them will greatly benefit the scientific community. At the same time, I feel that the suggested enhancements could significantly improve the quality of the manuscript and ensure the correct perception and subsequent further use of the results.\nBest regards,\n\nAre the rationale for sequencing the genome and the species significance clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Partly\n\nAre sufficient details of the sequencing and extraction, software used, and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a usable and accessible format, and the assembly and annotation available in an appropriate subject-specific repository? Partly", "responses": [ { "c_id": "13173", "date": "27 Jan 2025", "name": "Luke Silver", "role": "Author Response", "response": "Why was the reference genome based on a sample from only one individual? It is not an endangered species, so what was the reasoning behind this choice? Response: A single individual was used as this is still the current best practice in wildlife for generating reference assemblies, we agree that in the near term future it will become more feasible to generate a pangenome for wildlife species to truly capture the entire variation of a species. Why were only short reads performed? The length of repetitive regions is typically much greater than that of short reads, which raises questions about the methodology used. Response: The authors agree that long read sequencing would be more preferable to cover the entire length of repetitive regions, however, at the time sequencing was undertaken (~2017) short reads and 10x were the technologies most accessible to conservation researchers. How accurate do the authors estimate their chosen method is? Response: Based of the similarity of the size of the genome assembly and repeat content we can be confident that the genome is highly complete. Additionally our BUSCO analysis suggests a highly complete genome assembly (BUSCO completeness >95%). We agree that utilising long read sequencing would result in an increase in contiguity of the assembly. Although I am not a real expert on genome assembly, I recommend that the authors add a brief section in the manuscript discussing the limitations of their findings. This section could explain the rationale behind their decision to work with a single individual and the reasons for choosing this particular method, such as the use of short reads. Response: We have added a sentence into the results of the improvements that could be realised with the use of a long read technology. “Whilst the BUSCO scores suggest a highly complete genome, the use of long read data such as PacBio or Oxford Nanopore would assist in increasing the contiguity of the assembly” I also think it is important to briefly discuss what the authors think might explain why this animal has one and a half times as many protein-coding regions as the known marsupial genome. Could there be a biological or evolutionary reason for this? Response: The increase in the number of protein coding genes could be due to the unavailability of transcriptome data for the species. Which would provide increased support for which of the predicted genes are actually expressed in the species. We have added a sentence in the results stating this. “In the future, generating transcriptomes for a variety of eastern bettong tissues would likely improve the accuracy of the annotation.”" } ] } ]	1	https://f1000research.com/articles/13-1544
https://f1000research.com/articles/13-1060/v1	17 Sep 24	{ "type": "Opinion Article", "title": "Zero-dose children in Latin America: analysis of the problem and possible solutions", "authors": [ "Maria L. Avila-Aguero", "Helena Brenes-Chacon", "Mario Melgar", "Francisco Becerra-Posada", "Enrique Chacon-Cruz", "Angela Gentile", "Martha Ospina", "Nancy Sandoval", "Jennifer Sanwogou", "Analia Urena", "Maria T. Valenzuela", "Ana Morice", "Helena Brenes-Chacon", "Mario Melgar", "Francisco Becerra-Posada", "Enrique Chacon-Cruz", "Angela Gentile", "Martha Ospina", "Nancy Sandoval", "Jennifer Sanwogou", "Analia Urena", "Maria T. Valenzuela", "Ana Morice" ], "abstract": "Introduction Zero-dose children (ZDC) are defined as those that have never been reached by routine immunization services. In Latin America, almost 2.7 million infants younger than 1 year of age, have incomplete vaccination schedules, and vaccine preventable diseases such as measles or polio have increase worldwide. ZDC are reported to reside in high risk and fragile settings, including remote-rural areas, urban slums, and conflict-affected areas. Identifying the problem and settings in each country is mandatory to propose possible solutions to the immunization coverage situation.\n\nAreas covered In November 2023, a group of experts of the Latin America Society of Pediatric Infectious Diseases (SLIPE) analyzed the global and regional reality of ZDC, and present in this document an updated reality of the Latin American region and the weight of the possible interventions to overcome this problem.\n\nExpert commentary Communication is a key element to improve vaccination coverage, as it is quality and use of vaccination data. Campaigns that deliver targeted and effective messages to communities and families, provide education about vaccination, avoid missed vaccination opportunities, and coordinate efforts across different sectors and communities, among other strategies, could improve the current immunization situation.", "keywords": [ "dose-zero children", "DTP1", "immunization", "vaccination", "National Immunization Technical Advisory Groups", "NITAGs" ], "content": "Article highlights\n\n\n\n- Zero-dose children (ZDC) is a worldwide issue that could lead to reemergence of vaccine preventable diseases. Latin America is not foreign to this problem.\n\n- The challenges of implementing strategies to address this problem is difficult, especially because there is not only one cause for this problem. Nevertheless, the measures used to this purpose could lead to adequate immunization coverage in the Latin American region.\n\n- Communication in immunization is a key element to improve vaccination coverage, as it is quality and use of vaccination data. Campaigns that deliver targeted and effective messages to communities and families, provide education about vaccination, avoid missed vaccination opportunities, and coordinate efforts across different sectors and communities, among other strategies, could improve the current immunization situation.\n\n- We sought to review the situation around the increase of ZDC in our region, and to present possible interventions to address this problem.\n\n\n1. Introduction\n\nAs of January 2023, research in vaccines and vaccine development has evolved, with almost 966 new vaccine candidates.1 Even though this number of these new candidates is significantly higher than 5 years ago, the use of already approved vaccines is not adequate, and the number of zero-dose children (ZDC) has also increased.2 In Latin America, UNICEF reports that almost 2.7 million infants younger than 1 year of age, have incomplete vaccination schedules, and that vaccine preventable diseases such as measles or polio have increased worldwide in the last years.3\n\nThe strategic plan of the Pan American Health Organization (PAHO) highlights the importance of vaccine accessibility to generate an impact and reduce disease burden.4 By 2022, vaccine coverage around the world improved, and the number of children with no DTP1 dose went from 18 to 14 million children. Nevertheless, disparities among countries is evident, with just ten countries accounting for 58% of the world’s unvaccinated infants.5 The World Health Organization’s (WHO) Immunization Agenda 2030 details the steps to accomplish better immunization coverage.6\n\nLatin America and the Caribbean is not foreign to this reality. In November 2023, a group of experts of the Latin American Society of Pediatric Infectious Diseases (SLIPE) analyzed the global and regional reality of ZDC. This document presents an updated reality of the Latin American region and the potential impact of various interventions to address this problem.\n\n\n2. Current situation of zero-dose children in Latin America\n\nZDC are defined as those that have never been reached by routine immunization services. They are operationally measured as those who do not have their first dose of a vaccine containing diphtheria-tetanus-pertussis components (DTP1). Nevertheless, the problem does not stop with susceptible children; it also involves the lack of healthcare access for their families. This population also faces several barriers that separates them from adequate medical access, such as: socioeconomic vulnerability, inadequate access to medical services, gender, ideologic, and ethnic barriers, lack of prenatal care access, hard-to-reach communities, and regions in conflict, among others.7,8 Africa, South-East Asia, and Eastern Mediterranean are among the regions with the most ZDC. Within the Americas, Mexico and Brazil were mentioned as high-risk countries during 2021 and 2022 respectively.7 However, the Americas region achieved a 14% reduction in the number of children receiving zero doses from 2021 to 2022, dropping from 1.85 million to 1.31 million.9\n\nAccording to UNICEF estimates, by 2030 a decrease of 50% in ZDC is expected. Latin America has shown promising reduction in 2022, and a considerate reduction is possible if the problem is stipulated as a priority in the region.5\n\nIssues around vaccination are documented for Latin America in a PAHO evaluation of risk,10,11 where they identify the implication of several diseases in the Americas, and the special situation and challenges after the COVID-19 pandemic.\n\nBefore the pandemic, cases of diphtheria were sporadically reported, mainly in Venezuela and Haiti. With vaccination coverage decrease during 2020-22, reported cases of diphtheria increased in other countries in the regions. For measles, a considerable increase of cases started to be reported in Latin American countries in 2018. With the COVID-19 pandemic and restriction measures implemented, these cases decreased, but a new increase was documented in 2023, with almost 177 suspected cases in the region. For polio, the situation is different since most reported cases in Latin America are related to vaccination. Wild polio cases primarily occur in Asian countries, but in 2019, Guatemala reported three vaccine related polio cases. Nevertheless, risk of wild polio disease based on vaccine coverage is reported, and according to the WHO, Brazil, Haiti, Dominican Republic, and Peru are considered very high-risk countries, while Argentina, Bahamas, Bolivia, Ecuador, Guatemala, Panama, Suriname, and Venezuela are classified as high-risk countries. For yellow fever, a decrease of cases has been reported by 2022.12\n\nIdentifying and characterizing the problem in each country is mandatory to understand the number of ZDC and undervaccinated communities, who and where they are, and why they have not been reached. Based on those answers, the country can make decisions and implement effective and sustainable interventions. There are countries where vaccines supply deficiency is identified, making the solution in these regions complex. On the other hand, there are countries where the access to population is difficult due to distrust, poverty, lower socioeconomical status, discrimination, or religious beliefs, and their approach may differ from others.13\n\nConfidence in vaccination is a determinant for vaccine acceptance, a concept severely damaged during the COVID-19 pandemic. Involvement of health care workers in shaping public perception of vaccination and education about vaccines play a major role and can help prevent vaccine hesitancy.14\n\n\n3. Risk focus evaluation of decision-making interventions for dose-zero children in Latin America\n\nVaccine coverage can be calculated differently in various regions. Administrative forecasts of vaccine coverage may not give a correct estimation of a country’s reality, and the real impact of vaccination may not be accurate. For example, home births in remote regions or children with an irregular migration status may not be quantified as undervaccinated or ZDC. Nominalization of immunization coverage is a strategy to geographically localize ZDC allowing for more targeted actions in affected regions. Homogeneity of vaccine coverage within each country and at regional level is also a strategy to decrease susceptible populations. For example, one of the challenges is not only to identify and vaccinate ZDC but also to keep them in the system to complete their vaccination schedules. In these cases, the “dropout” indicator, which shows how many children received DPT1 but did not receive DPT3, is crucial for monitoring if children are completing their vaccination schedule.\n\nThe lack of a unified easy-to-access system on which vaccines are updated will improve immunization report. Having an Electronic Immunization Registry (EIR) globally accessible in all countries for all vaccines and healthcare subsectors would contribute to the availability of real-time information and the development of strategies to catch up on delayed vaccination schedules and reach underserved populations.15 The usefulness of a robust EIR was clearly showed during the COVID-19 pandemic when countries had to vaccinate almost their entire populations in record time. The availability of relevant, reliable, and timely information was key to designing the campaigns, generating real world evidence on vaccine effectiveness, and issuing vaccination certificates.\n\nActive search of vaccine preventable diseases cases is an important tool to identify high-risk regions. Improvement of communication and surveillance systems could enhance national active search of reportable diseases. Effective, rapid, transparent, and clear communication and dialogue is recommended to improve trust in health systems.16,17\n\nTo mitigate risk of vaccine preventable diseases, each country needs to fulfill a series of criteria such as: subnational evaluation of risk, systematic evaluation of risk contributors, mitigation plan development, including at least 80% of communities and regions of very high-risk and high-risk of disease reintroduction, and prioritize evaluation and development of risk evaluation processes. Intensive work in and with communities is necessary to avoid missed opportunities for interventions.11 Interventions should not be limited to ZDC but should also include other infants at high risk due to delayed vaccine schedules. Measuring the time to complete updated immunization calendars for those younger than one year of age could be useful as an indicator.\n\nInformed decision-making interventions are based on the best possible evidence generated from better quality tools, triangulation to improve data analysis, and use of information, considering equity, security, sustainability, and acceptability of interested parties,18 while providing active work in the field to identify at-risk populations. Evidence-based decisions will contribute to prioritize interventions, evaluate situations, and implement actions. Low and middle-income countries can evaluate immunization options according to necessity and priorities using different available tools.19\n\nFor example, a survey among Argentinean pediatricians evaluating vaccination practices and barriers was conducted among 1,696 responders.20 Results showed that participants considered limited capacity to explain vaccination related topics to users, coupled with limited training in the topic. False contraindications of vaccinations were commonly transmitted to families, resulting in missed vaccination opportunities for children. Temporary vaccine supply issues were also reported as barriers.\n\n\n4. Advances in National Immunization Technical Advisory Groups (NITAGs) and their role in Latin America\n\nImmunization has been essential in preventing thousands of deaths among children in the region. The use of evidence-based information has allowed the introduction of new vaccines in immunization programs in Latin America based on local burden of disease in each country. Re-emerging diseases in the region due to different factors highlights the importance of operational NITAGs to help improve vaccination status in our countries.\n\nIn Latin America and the Caribbean, 21 out of 42 countries in the region have a NITAG, with the most recent groups formed in Haiti in 2019, Belize in 2021, and Suriname in 2022. The Caribbean region, trough the Caribbean Community, uses a unified NITAG. According to international standards, a NITAG must have an administrative or legislative base, formal Terms of References, at least five areas of expertise represented among its members (epidemiology, immunology, pediatrics, infectious diseases, and public health), have one or more meetings per year, circulated agendas, and background documents available at least one week prior to meetings, and disclosure of conflicts of interests when present. In 2022, two additional process indicators were introduced to include whether NITAGs have issued recommendations and whether any of these recommendations have been adopted by their respective health institutions and Ministries of Health. Autonomy of NITAGs should be sought trough independence from ministries of health, nevertheless, this is not always accomplished in their established structures.\n\nDuring the pandemic, in 2022, measures to improve NITAG performance were developed. One of the measures included the creation of a Regional NITAG Network of the Americas (RNA), with the aim to be the main communication channel for NITAGs in the countries of the Americas; to improve the capacity of NITAGs to efficiently formulate evidence-based recommendations on immunization through collaboration; and to facilitate NITAG exchanges.\n\nNITAGs are essential for the success of immunization programs in countries. They base their recommendations on WHO’s Strategic Advisory Groups of Experts (SAGE), and PAHO’s Regional Technical Advisory Group (TAG), as well as their own national data, among others. NITAG objectives consist in providing evidence-based recommendations on new immunization priorities, updated vaccination schedules, surveillance of vaccine preventable diseases, and the impact of immunization in different settings.\n\nAccording to NITAG assessments conducted in 2020 and 2021, NITAGs in the Americas have limitations. For example, some of the advisory groups lack the presence of different experts in expected areas. In some cases, the president of the NITAG is also the representative of the Ministry of Health, making it difficult to separate both roles and creating potential conflict of interests. Also, NITAG member selection is not always uniform creating bias in opinions generated in these groups. Finally, considering that NITAG’s role is solely advisory, they face the challenge of their recommendation being rejected or simply ignored by their Ministries of Health, without the need for clear explanation for its refusal.\n\nNITAGs have a significant role in immunization programs in the region, from experience observations, evidence-based recommendations, and valuable information that could change the development of vaccination policies in different countries. Unfortunately, several Ministries of Health do not fully value NITAG recommendations. Regarding transparency, in many countries where there is a NITAG, their recommendations are not publicly and routinely disseminated. In those cases, lack of adherence by health authorities remains hidden. In many cases, they are not perceived as essential components of immunization systems in their country. It is important to establish, reactivate, and keep NITAGs contribution in Latin America, as their participation is key in the reduction of ZDC in the Region.\n\n\n5. Expert opinion\n\nIn November 2023, the expert group of SLIPE gathered in Costa Rica to analyze the regional situation of ZDC. A series of situations that could impact immunization coverage in the region were identified and are presented in this section.\n\nEfficiency of vaccination systems in Latin America is influenced by different situations that can have an impact in social and communal behavior towards vaccination.8 Adapted and sustainable measures to overcome barriers presented in vaccination practices can be approached using integrative strategies in health systems among different countries. Identify, reach, monitor, measure, and advocate should be used as steps to analyze the situation of ZDC.\n\nVaccination coverage improvement objectives are not targeted to avoid reintroduction of vaccine preventable diseases in the region, -a very difficult task-, but to overcome the number of ZDC and undervaccinated communities in the region and prevent disease in vaccinated individuals and communities through herd protection of vaccine preventable diseases.\n\nIrregular migration is a reality in the Americas and countries should adapt to these situations. For example, among the proposed strategies, the development of a Pan-American unique immunization card could be considered to give continuity to immunization schedules of migrants regardless of the country.\n\nLatin American countries should move from evaluation of the situation only, to the implementation of strategies and communication of those successful measures with other countries. This could be accomplished by taking a broader look at the reality of the Latin American situation.\n\nThe role of NITAGs in this path is crucial. Besides the technical role of this advisory group, they are referral groups that review the global situation analysis performed yearly by the WHO and UNICEF. Data on vaccine preventable diseases are reported by country each year to the joint reporting form, providing a wide analysis for NITAGs to consider.21 Recommendations provided by NITAGs should be carefully reviewed by their Ministries of Health. In the event that the Ministry of Health refuses a NITAG recommendation, a clear explanation for its refusal should be provided in writing. The NITAG should then be able to identify a new policy question to address the issue and follow up with the Ministry of Health for further discussion. A broader understanding of epidemiological realities in every country is necessary for the success of implemented strategies to decrease the number of ZDC in our region.\n\nTo reduce the number of ZDC and unvaccionated communities in Latin America, a comprehensive strategy should be implemented. Here are some key components of such a strategy:\n\n1. Improve vaccine accessibility ensuring vaccines are readily available and accessible to all children, even in remote or underserved areas. This can be achieved through mobile vaccination units, extended clinic hours, or outreach programs to reach marginalized populations.\n\n2. Increase awareness, education and collaboration with communities and stakeholders to implement awareness campaigns to educate parents, caregivers, and communities about the importance of vaccines in preventing diseases. Education should start early in school programs using awareness activities among children and families. Also, incorporating education regarding vaccines and their policies during medical education could improve caregivers’ knowledge. Address myths and misinformation about vaccines through evidence-based information campaigns could help engage with community leaders, religious groups, healthcare providers, and other stakeholders to build trust in vaccination programs. Foster partnerships to address cultural, social, and economic barriers to vaccine uptake.\n\n3. Robust monitoring and evaluation of vaccination coverage to track vaccination coverage rates at national, regional, and local levels. Use data to identify underserved areas and populations in need of targeted interventions. Adopt relevant recommendations to support, strengthen, report, and monitor vaccine preventable diseases in each country, could improve quality and use of data.22 Standard coverage estimates are based on the distributive-administrative method, which is practical, nonetheless, it does not give information related to incomplete courses neither on vaccine recipients, and it relies heavily on quality of reporting.23\n\n4. Address equity and inequalities ensuring that vaccination programs are equitable and reach all children, regardless of their socio-economic status, ethnicity, or geographic location. Target resources towards vulnerable populations to bridge existing gaps in access. Modernize vaccination schedules, by offering similar vaccines in both the public and private sectors, the use of combined vaccines, such as pentavalent or hexavalent vaccines, has been shown to be safe, effective, and well-received by the population. Their use would help prevent missed vaccination opportunities.\n\n5. Improve vaccination registries in the region. Implementing an electronic vaccination registry could ensure accurate tracking of immunization data, optimizing vaccine distribution, enhancing public health monitoring, and ultimately improving the region’s overall health outcomes by facilitating timely and effective vaccination strategies. Although there are validated technologies to implement electronic registry of health, they have not been validated in newborns and children.24 The Pan American Health Organization have been developing a methodology to assess electronic immunization registries in low- and middle-income countries in Latin America to evaluate health information systems, framework, and strategies to assess information systems.25 Moving towards EIR should be a priority for countries that have not implemented this tool yet.\n\n\n6. Conclusions\n\nZDC is a worldwide situation that could result in a reemergence of vaccine preventable diseases. Latin America and the Caribbean are not exempt of this reality, and the associated health impact makes it a priority concern. Understanding the challenges around ZDC and implementing strategies to address this problem are the next steps in reaching adequate immunization coverage.\n\nCommunication in immunization is a key element to improve vaccination coverage, as it is quality and use of vaccination data. Campaigns that deliver targeted and effective messages to communities and families, provide education about vaccination, avoid missed vaccination opportunities, and coordinate efforts across different sectors and communities, among other strategies, could improve the current immunization situation.\n\nThe field of vaccine development has advanced in the last years, including research for better antigenic affinity, broader antigenic efficacy and effectiveness, easier and faster manufacturing, and lower costs. However, vaccine technology must be integrated with comprehensive public health policies to reduce the number of ZDC in Latin America. This integration should encompass not only the development and distribution of vaccines but also the implementation of educational programs, community outreach, and robust healthcare infrastructure. By ensuring that technological advancements in vaccination are supported by strong policy frameworks, we can enhance access to vaccines, improve immunization rates, and ultimately protect more children from preventable diseases.\n\n\nAuthor contributions\n\nAll authors contributed equally to the conception, design, information, manuscript preparation, and edition.", "appendix": "Data availability statement\n\nNo data are associated with this article.\n\n\nAcknowledgments\n\nWe thank the Latin America Society of Pediatric Infectious Diseases (SLIPE) for providing the space to conduct this meeting during their international medical congress in San José, Costa Rica.\n\n\nReferences\n\nYue J, Liu Y, Zhao M, et al.: The R&D landscape for infectious disease vaccines. Nat. Rev. Drug Discov. 2023 Nov; 22(11): 867–868. Publisher Full Text\n\nZero-dose: The children missing out on life-saving vaccines. UNICEF; 2023 [June 24th, 2024]. Reference Source\n\nImmunization. UNICEF; 2023 [cited 2024 January 10th, 2024]. Reference Source\n\nPlan Estratégico de la OPS (2020-2025). 2019 [cited 2024 May 10th, 2024]. Pan American Health Organization; Reference Source\n\nHoja informativa: Estimación OMS/UNICEF de la cobertura nacional de inmunización en 2022. Pan American Health Organization; 2022 [cited 2023 November, 15th, 2023]. Reference Source\n\nImmunization Agenda 2030: A Global Strategy to Leave No One Behind. World Health Organization; 2020 [June 09th, 2024]. Reference Source\n\nKaur G, Danovaro-Holliday MC, Mwinnyaa G, et al.: Routine Vaccination Coverage - Worldwide, 2022. MMWR Morb. Mortal Wkly. Rep. 2023 Oct 27; 72(43): 1155–1161. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBehavioural and social drivers of vaccination: tools and practical guidance for achieving high uptake. World Health Organization; 2022 [cited 2024 January 10th, 2024]. Reference Source\n\nImpact Global 2: Promote equity: Leave no child behinds. Number of zero-dose children-WHO Region of the Americas. World Health Organization; 2024 [June 25th, 2024]. Reference Source\n\nEvaluación de Riesgos sobre enfermedades prevenibles por vacunación (difteria, sarampión, fiebre amarilla y poliomielitis): implicaciones para la Región de las Américas. Pan American Health Organization; 2023 [cited 2024 February 15th, 2024]. Reference Source\n\nMethodology for the evaluation of missed opportunities for vaccination. Pan American Health Organization; 2013 [cited 2024 May 10th, 2024]. Reference Source\n\nBoletín Epidemiológico Nacional 657 SE 23. Ministerio de Salud Republica Argentina; 2023 [cited 2024 February 15th, 2024]. Reference Source\n\nOzawa S, Yemeke TT, Evans DR, et al.: Defining hard-to-reach populations for vaccination. Vaccine. 2019 Sep 3; 37(37): 5525–5534. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nGuzman-Holst A, DeAntonio R, Prado-Cohrs D, et al.: Barriers to vaccination in Latin America: A systematic literature review. Vaccine. 2020 Jan 16; 38(3): 470–481. PubMed Abstract \| Publisher Full Text\n\nLandscape Analysis of Health Information Systems and Data Tools for Identifying, Reaching, and Monitoring Zero-Dose and Under-Immunized Children. USAID; 2022 [June 13th, 2024]. Reference Source\n\nComunicación de riesgos y brotes. Pan American Health Organization; 2023 [cited 2023 December 22nd, 2023]. Reference Source\n\nImmunization coverage. World Health Organization; 2023 [cited 2023 January 10th, 2023]. Reference Source\n\nA Guide for Evidence-Informed Decision-Making, Including in Health Emergencies. Pan American Health Organization; 2022 [cited 2023 December 2nd, 2023]. Reference Source\n\nBotwright S, Giersing BK, Meltzer MI, et al.: The CAPACITI Decision-Support Tool for National Immunization Programs. Value Health. 2021 Aug; 24(8): 1150–1157. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nGentile A, Castellano VE, Juarez MDV, et al.: National survey for pediatricians in Argentina: Vaccination in daily practice, perception of knowledge and barriers. Arch. Argent. Pediatr. 2024 Jun 1; 122(3): e202310204. PubMed Abstract \| Publisher Full Text\n\nWHO/UNICEF Joint Reporting Process. World Health Organization; 2024 [June 9th, 2024]. Reference Source\n\nScobie HM, Edelstein M, Nicol E, et al.: Improving the quality and use of immunization and surveillance data: Summary report of the Working Group of the Strategic Advisory Group of Experts on Immunization. Vaccine. 2020 Oct 27; 38(46): 7183–7197. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHoshaw-Woodard S: Description and comparison of the methods of cluster sampling and lot quality assurance sampling to assess immunization coverage. World Health Organization; 2021 [June 9th, 2024]. Reference Source\n\nKalisky T, Saggese S, Zhao Y, et al.: Biometric recognition of newborns and young children for vaccinations and health care: a non-randomized prospective clinical trial. Sci. Rep. 2022 Dec 29; 12(1): 22520. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAssessing electronic immunization registries: the Pan American Health Organization experience. Pan American Health Organization; 2019 [June 9th, 2024]. Reference Source" }	[ { "id": "325745", "date": "01 Oct 2024", "name": "Anne Eudes Jean Baptiste", "expertise": [ "Reviewer Expertise Immunization", "epidemiology", "surveillance", "measles", "polio", "diphtheria", "tetanus", "pertussis and zero-doses." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nTo strengthen the article, several key areas require attention: 1- More quantitative data on immunization coverage rates, ZDC prevalence, and relevant metrics would enhance the analysis and identification of specific areas of concern. 2- Acknowledging limitations, such as potential bias in data analysis, and outlining areas for future research is essential. This will enhance the article's credibility. 3- Emphasizing in the conclusion the importance of political will and commitment is critical.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Partly\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Partly", "responses": [ { "c_id": "12866", "date": "27 Jan 2025", "name": "Helena Brenes", "role": "Author Response", "response": "Thank you for the observations. We appreciate every comment that was done ot improve our manuscript. The objective of this article was not to analyze the reality in every country of the region, but to analyze the general problem and give general possible solutions to this issue. We emphasize our results in the available information and included more data of the countries that participated in this review. Changes are highlighted in red." }, { "c_id": "12868", "date": "27 Jan 2025", "name": "Helena Brenes", "role": "Author Response", "response": "Reviewer Comments: 1. More quantitative data on immunization coverage rates, ZDC prevalence, and relevant metrics would enhance the analysis and identification of specific areas of concern. Author Response: We added available information of the regions where information is available, and including countries that participate in this review. 2. Acknowledging limitations, such as potential bias in data analysis, and outlining areas for future research is essential. This will enhance the article's credibility. Author Response: Thank you, we added a limitation section to clarify this aspects. 3. Emphasizing in the conclusion the importance of political will and commitment is critical. Author Response: Thank you, we added a sentence with this comment at the conclusion section." } ] }, { "id": "329401", "date": "10 Oct 2024", "name": "Chelsea Marie", "expertise": [ "Reviewer Expertise Microbiology", "immunology and clinical research." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis review entitled \"Zero-dose children in Latin America: analysis of the problem and possible solutions\" seeks to describe the problem of Zero Dose Children (defined as those that have never been reached by routine immunization services), describe how interventions can be targeted, and suggest solutions. The review also includes a discussion on the importance and role of National Immunization Technical Advisory Groups (NITAGs).\nThe topic is highly significant as ZDC are vulnerable to preventable diseases and the number of ZDC in a country is a key indicator of barriers to vaccination. Analysis of vaccination is particularly topical in the wake of the covid-19 pandemic which resulted in structural barriers to vaccination as well as an increase in vaccine hesitancy in some populations.\n\nWhile the title suggests an analysis of ZDC in Latin America the content presented herein is more editorial in nature, with a mixture of global, regional and country-wide statistics presented throughout that while illustrative of some specific points, do not leave the reader with a comprehensive understanding of the problem or it's associated impacts.\n\nIf within the scope, I believe this review has the unique opportunity to include such an analysis by including an analysis of ZDC in Latin America in a country by country manner from the WHO and UNICEF Estimates of National Immunization Coverage (WUENIC), 2023 revision report. . Approaching the evaluation of ZDC in Latin America in the way could highlight not only the countries where interventions are most needed, but also highlight countries that have effectively reduced the proportion of ZDC which could in turn suggest or inform the section on possible solutions. While the estimates in this report come with limitations, the authors appear to be well-qualified to offer an expert interpretation and discussion of such limitations.\n\nThe prevalence of vaccine preventable diseases in Latin America is mentioned in several places throughout the review and similar to the comment above, including a comprehensive analysis of prevalence estimates of vaccine preventable diseases would strengthen this review and offers the opportunity to examine how ZDC rates and vaccine preventable disease rates intersect.\n\nIn the section entitled \"Risk focus evaluation of decision-making interventions for dose-zero children in Latin America\". I believe the goal of this section is to summarize how data can be used to prioritize and target interventions for ZDC across Latin America. I agree that the discussion of drop-out is very important and a key factor beyond ZDC that should be included. This could be analyzed by looking at the rates DPT1 and DPT3 by country in the WUENIC report and would be a fascinating adjunct that has the potential to highlight distinct barriers by country.\n\nThere is a brief mention of the impact of the covid-19 pandemic on vaccination rates, that is also apparent in the data on vaccine rates. It would be interesting to discuss the impact in terms the decrease in vaccination rates during the pandemic, as well as the rate of catch-up by country. The important topic of vaccine hesitancy is also mentioned and is interesting as it contradicts the assumption that ZDC is largely driven by lack of access. Is vaccine hesitancy thought to be a driver of ZDC in Latin America?\n\nThe authors highlight the key role of Advances in National Immunization Technical Advisory Groups (NITAGs) in Latin America. As well as barriers faced by NITAGs. This is an important topic and offers useful information. This section could be strengthened by including more detailed information on the countries with and without NITAGs, as well as include references for some of the statements in this section. The final section highlights broad recommendations of the SLIPE to improve immunization rates and decrease the number of ZDC in Latin America. These recommendations are fairly common-sense and apply to vaccination efforts throughout the world. This impact of this section could be increased by placing these recommendations in the context of the existing landscape of ZDC in Latin America and highlighting region specific or country specific barriers.\n\nOverall, this review offers information on a crucial public health issue of ZDC in Latin America. My recommendations for approval would be to include a more comprehensive analysis of the problem leveraging the UNCEIF and WHO data and to provide more focused recommendations on the particular barriers facing Latin American countries.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Partly\n\nAre all factual statements correct and adequately supported by citations? No\n\nAre arguments sufficiently supported by evidence from the published literature? Partly\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Partly", "responses": [ { "c_id": "12867", "date": "27 Jan 2025", "name": "Helena Brenes", "role": "Author Response", "response": "Thank you for the observations. We appreciate every comment that was done to improve our manuscript. The objective of this article was not to analyze the reality in every country of the region, but to analyze the general problem and give general possible solutions to this issue. We emphasize our results in the available information and included more data of the countries that participated in this review. Changes are highlighted in red." } ] } ]	1	https://f1000research.com/articles/13-1060
https://f1000research.com/articles/13-1343/v1	08 Nov 24	{ "type": "Research Article", "title": "Does Brand Attitude Complement Influencer Credibility in Shaping Purchase Intention of Indian GenZ Consumers?", "authors": [ "Pranav Vilas Chavare", "Smitha Nayak", "Ramona Birau", "Varalakshmi Alapati", "Pranav Vilas Chavare", "Ramona Birau", "Varalakshmi Alapati" ], "abstract": "Introduction The social media landscape has undergone radical changes and has revolutionized consumer perspectives, purchasing habits, and behaviors. Amidst this emerging trend is the rise of influencer marketing and its impact on the purchase intentions of followers. The objective is to explore the characteristics of influencers that contribute to their credibility. This research aims to explore the role of consumers’ attitude toward brands on their intention to adopt brands endorsed by influencers.\n\nMethods This cross-sectional research was undertaken among GenZ in the urban landscape of India. Data collected was analyzed using SmartPLS4 software.\n\nFindings Trust, expertise, and similarity were the significant antecedents of the formation of influencer credibility. Attractiveness did not have a significant influence on influencer credibility. A complementary partial mediation of Attitude towards a brand is observed in the association between influencer credibility and the purchase intention of followers. Attitude towards the video also had a significant positive influence on purchase intention.\n\nConclusion The study found that Gen Z places little importance on an influencer’s attractiveness, as it has no significant impact on credibility. However, attitude toward the brand strongly influenced purchase intention and partially mediated the relationship between influencer credibility and purchase intention.", "keywords": [ "influencer credibility", "purchase intention", "attitude towards brand", "India" ], "content": "1. Introduction\n\nThe social media landscape has undergone radical changes over the past few years. It has become an important part of people’s everyday routines and significantly influences cultural aspects of society. It has revolutionized consumer perspectives, purchasing habits, and behaviors (Y. Dwivedi, 2021). In today’s technology-driven world, social networking platforms have become an avenue where brands can extend their marketing campaigns to a wider range of consumers. Social media has transformed the way businesses connect with their audience, and India is no exception to this digital revolution Social media platforms such as Facebook, YouTube, Instagram, and Twitter have become the grounds for brands to engage with customers, build relationships, and drive sales. India has embraced the Internet, and its digital population has grown rapidly over the past decade, reaching 600 million active Internet users (www.statista.com/, n.d.). Access to social media has also enhanced the time spent by users on social media daily. A report published by The Indian Institute of Management Ahmedabad on “New Age Digital Media Consumption: A survey of Social Media, OTT Content Online Gaming” reported that Indians, on average, spent 194 minutes daily on social media platforms (The Esya Centre and IIM Ahmedabad, 2023) and most of them were in the age group of 18 to 34 years of age (GWI, 2023). This forms a strong foothold for brands to emphasize digital marketing strategies to this specific age group. Amidst this emerging trend is the growth of a concept called marketing influencers. Marketing Influencers are defined as “people who have the power to affect the purchase decisions of others due to their real or perceived authority, knowledge, position, or relationship” (Mavrck, 2014). A further classification of influencers based on the number of followers they have helps different businesses choose which influencers to partner with. While macro-influencers can claim millions of followers, micro-influencers usually have less than 100,000. Micro-influencers are everyday people who post meaningful content with a significant impact on social media sites such as Facebook, Instagram, and YouTube. Social media organizations and celebrities are examples of macro-influencers. In the present digital landscape, consumers seek opinions from their peers (other consumers) and marketing influencers to make informed purchase decisions. Thus, influencers play a major role in shaping consumer purchase decisions and brand choices (Anjali Chopra and Jaju, 2020).\n\nInfluencer marketing has been used more recently, but there hasn’t been a single scholarly definition of it—especially when it comes to India (Johansen and Guldvik, n.d.). Based on the number of followers they have, around 4 million influencers in India are divided into four categories: elite, mega, macro, and micro as of June 2023 (Katya Naydu, 2023). About 118 million Indians have purchased goods or services that influencers have promoted, according to Roshan Behera (2023). The authors decided to look into the influencer marketing scene in India, specifically from the perspective of Generation Z (those born between 1997 and 2012), given the growing importance of influencers in the country and the paucity of scholarly research on the subject. Further, on social media, Gen Z users are more likely to be drawn to content about fashion, travel, and movies. According to a demographic comparison, millennials follow 52% of Instagram influencers, whereas Gen Z members follow about 97.9% of them (BrandWagon Online, 2023). This highlights the importance of influencer marketing, especially when aimed at the Gen Z demographic in India. Although the influencers themselves have a charm factor, an important question is what makes their content truly appealing. The answer to this question is perhaps the relationship between the influencer’s credibility, the audience’s views towards the brand, and their attitude toward the content. This study aims to understand the connection between these factors and how the audiences’ attitudes mediate the influencers’ credibility and purchase intention. The objective is to analyze the influencer marketing sector in India and find insights into the characteristics of influencers that contribute to their credibility. Furthermore, study the mediating effect of the audiences’ attitude toward the brand on the relationship between influencer credibility and purchase intention. The proposed conceptual framework is presented in Figure 1.\n\nThe subsequent sections of the manuscript are structured as follows: the hypothesis development section presents literature related to the context of the present research endeavor and aids in conceptualizing the proposed conceptual model. The methodology section highlights the study setting, sampling procedure, and the research instrument development process. The results section presents the data analysis, followed by the discussion section and theoretical and managerial implications. The last section of the manuscript presents directions for future research and the limitations of the study.\n\n\n2. Literature review & hypotheses development\n\nResearch reveals a positive link between the perceived attractiveness of a social media influencer and consumers’ likelihood to purchase the advertised cosmetic product. This attractiveness-purchase intention connection likely stems from several factors: grabbing attention, triggering positive emotions, creating social influence, and boosting perceived trust in the influencer’s opinion. However, the strength of this link can vary. Younger consumers or those who highly value physical appearance might be more susceptible to attractiveness pull. Hence it would be worth exploring this association between the attractiveness of the influencer and\n\nAttractiveness of the social media influencers has a significant positive impact on the credibility of the influencer.\n\nThe capacity of a communicator to make accurate representations in a certain field of knowledge is referred to as expertise (Anthony R. Pratkanis, 2011). It includes knowledge, understanding, and experience gained from ongoing work in the same profession. A communicator must have in-depth knowledge, applicable abilities, or a respectable title that establishes credibility in their chosen field to be acknowledged as an expert (Teresa Borges-Tiago et al., 2023). Consumers are more likely to buy a product endorsed by an influencer they perceive as knowledgeable and experienced, suggesting expertise builds trust and guides informed buying decisions. This knowledge-driven trust stems from several factors: reduced purchase risk due to the influencer’s proven experience, empowered decision-making through clear product explanations, and a boost in overall credibility based on their expertise (Ashraf et al., 2023; Masuda et al., 2022). However, the strength of this connection can vary depending on factors like product type (expertise’s impact is stronger for complex products), target audience (consumers valuing knowledge are more influenced), and influencer niche (expertise relevant to the product matters most) (Saima & Khan, 2020). So, expertise strengthens influencer credibility thereby converting likings into purchases. Understanding these dynamics among the GenZ followers would be worth exploring as GenZ is believed to be significantly influenced by peer reviews (Costa E Silva et al., 2017).\n\nThe expertise of the Influencer has a significant impact on the Credibility of the Influencer.\n\nSimilarity implies the extent to which the audience resembles the communicator (McCracken, 1989). A study was undertaken by Naderer et al. (2021) Documented that similarity with the influencer had a direct positive effect on the purchase intention of the promoted brand. This means that when the influencer showed a brand and a disclosure, it increased the participants’ intention to buy the product compared to not seeing any brand presentation. Furthermore, the researchers found that the trustworthiness of the influencer played a significant role in mediating the relationship between similarity and purchase intention. This is because brand information from someone similar to you is usually regarded as more genuine and credible than, say, a message from the business itself (Willemsen et al., 2012).\n\nSimilarity of the Influencer with the target audience has a significant positive influence on the credibility of the influencer.\n\nTrust represents an individual’s belief or willingness to depend upon, an attitude-related object or phenomenon (Ki et al., 2023). Trust in the context of influencer marketing can be defined as the influencer’s audience’s belief that the influencer is honest, transparent and genuinely supports the endorsed brand. An influencer can enhance their trust in the audience by being authentic in their content and interactions. In the absence of physical interaction, trust becomes a cornerstone for customers to establish trust in online activities (Gibreel et al., 2018; Ventre & Kolbe, 2020). The audience is more likely to engage and show an enhanced purchase intention when they trust the parties involved. This is applicable in social media, e-commerce, online reviews, etc. (Ventre & Kolbe, 2020). Confirmed the positive relationship between trust and purchase intention in the context of online reviews. Overall, trust is an important factor contributing to the success of influencer marketing (Sokolova & Kefi, 2020).\n\nTrust is a significant positive antecedent of Influencer credibility.\n\nGreer (2003) found that people’s opinions about the stories they read are influenced by their perception of the reliability of the material they get online. When it comes to health communication, people’s opinions on online health information are greatly influenced by the websites’ perceived legitimacy (Wang et al., 2008). In the case of advertising, the literature currently in publication indicates a favorable relationship between customer perceptions of the trustworthiness of endorsers and their endorsements (Goldsmith et al., 2000). It was established that a favorable correlation between attitudes toward website sponsors and their perceived credibility. According to research by Long and Chiagouris (2006), website users’ opinions of a nonprofit organization are greatly influenced by their perception of the website’s legitimacy. Hence in the digital space, it would be worthwhile to explore if the attitude towards the video of the social media influencer influences the purchase intention of their followers.\n\nAttitude towards the video has a positive influence on purchase intention.\n\nAn attitude-towards-the-ad model was developed by McCracken (1989). These factors influence consumers’ perceptions of advertisements. The empirical study’s conclusions imply that consumers’ perceptions of advertisers and advertising are positively impacted by their perceived believability (Aaker et al., 2012). Established that admired brands motivate consumers to purchase more from the brand. According to Roberts (2005) Brands gain the respect of consumers by performing well, which eventually leads to the development of a positive reputation. According to a research project by Trivedi & Sama (2020), consumer-favorite brands enjoy favorable relationships with their customers. Therefore, it may be necessary to investigate the extent to which brand attitude influences followers of social media influencers’ purchase intentions directly and through mediation.\n\nInfluencer credibility has a positive influence on Attitude toward the brand.\n\nAttitude toward the brand positively influences purchase intention.\n\nAttitude toward brand mediates the association between influencer credibility and purchase intention.\n\nInfluencers on social media are essential for improving marketing campaigns in the digital era. Choosing influencers wisely about the target market can have a big impact on audience purchase intentions and increase brand recognition. Purchase intention, according to J. P. Trivedi (2018) and Shah and Pillai (2012), arises from consumers’ comprehension of the thinking behind the choices they make regarding brands (Ki et al., 2023). Claim that it illustrates a scenario in which consumers are likely to purchase a product in a given setting. By using influencers in their marketing campaigns, marketers can positively affect the brand by strengthening the image the influencers have established and enhancing product recognition. Customers are more likely to purchase the promoted products when influencers with a strong connection to the target market are used (Lim et al., 2017). This finding aligns with a study by Singh and Banerjee (2018). Which emphasizes the ability of influencers to attract clients and stimulate purchase intentions through effective communication with their audience. Hence, this research endeavor intends to explore the effect of influencer credibility on the purchase intention of the followers.\n\nInfluencer Credibility has a significant positive influence on the purchase intention of followers.\n\nSource: Author’s own.\n\n\n3. Methods\n\nThe quantitative research methodology used in this study is called “cross-sectional research design.” “Post-positivism,” which emphasizes the development of empirical tools to interpret and evaluate human behavior, is the fundamental research philosophy. The goal of the inquiry is to investigate the links that are described in the conceptual framework between independent, dependent, and mediating factors. This marketing study was exempt from submission to the Institutional Ethics Committee of Manipal Academy of Higher Education, by clause 6 of the circular titled “Project Exemption from Submission to IEC,” issued by the Institutional Ethics Committee on 14/01/2021.\n\nA study undertaken by BrandWagon Online (2023) indicated that the Indian social media landscape, especially on Instagram, is cluttered by the Gen Z segment of the population, and 97.9 percent of them follow influencers. Hence, respondents for this study are restricted to Gen Z of the Indian Population. Additionally, results reported by Statista on “Use of social media platforms in India” read that 59 percent of the rural population in India did not use social media platforms and the same figure stood at 33 percent for the urban population. It is also revealed that 28 percent of the urban regions accessed at least 6 social media applications. Hence, this study is restricted to respondents from the urban regions of India only. The third inclusion criterion to respond to the questionnaire was that they had to follow influencers on social media platforms and have purchased at least one brand in the last 6 months endorsed by the influencer. These three inclusion criteria ensured that the response was obtained from a well-focused segment. A Google form was created to capture data from respondents. The respondents were contacted directly by the researchers, who additionally on the study’s objectives and guaranteed that their information would only be used for academic purposes. As a result, the participants were given access to the Google form, which they were asked to fill out and submit online. Data collection was undertaken from November 2023 to January 2024.\n\nA structured questionnaire was designed to collect data from the respondents. Scales to measure the underlying constructs {Purchase Intention (Mahrous & Abdelmaaboud, 2017); Expertise (Spake & Megehee, 2010); Attractiveness (A. Dwivedi et al., 2015); Similarity (Casaló et al., 2020); Trust (Mahrous & Abdelmaaboud, 2017); Credibility (Xiao et al., 2018); Attitude towards Brand (Spears & Singh, 2004); Attitude Toward Advertisement (Voss et al., 2003)} were adapted and measured on 5 5-point Likert scale. The questionnaire consisted of 29 questions including the inclusion criteria & demographic details. A Google form was generated and circulated to capture their response from the identified segment of respondents. It was informed to them that the data collected would be kept confidential and would be utilized only for academic purposes.\n\nThis study adopted a purposive sampling technique. Data was collected from students of Manipal Academy of Higher Education, and the students are the most representative of the target audience for this research. The sample size was estimated based on the number of indicators in the study by ten (Sarstedt et al., 2017) ie: 29 10 = 280. It further rounded off to 300. Finally, data was collected from 300 respondents.\n\nMicrosoft Excel (RRID:SCR_016137 available at https://www.microsoft.com/en-gb/) was used to undertake descriptive analysis and Smart PLS software (SmartPLS, RRID: SCR_022040) was used to analyze the underlying constructs of the study and assess the mediation analysis. The Partial Least Square Structural Equation Modelling technique was used to test the additive and linear models.\n\nBefore the completed questionnaire was sent out to participants to undertake a pilot study, two experienced researchers reviewed it to ensure face validity. The input gathered in this approach helped to improve the instrument’s readability. Further, to ensure the internal consistency of the scales, a pilot study was undertaken with 40sample response data. Cronbach alpha of all constructs of the study was above o.7 (Attitude towards brand = 0.956; Attitude towards video 0.938; Purchase Intention = 0.845; Attractiveness of Influencer = 0.777; Credibility = 0.934; Influencer Experience = 0.882; trust = 0.826) except of Similarity with the Influencer was below the threshold value of 0.7. In social science research, a construct with a Cronbach alpha above 0.6 in a pilot study could be retained as it is expected the increase with an increment in sample size. Hence the research team decided to retain the construct and explore it further during the final data analysis phase.\n\n\n4. Results\n\nTo investigate the proposed correlations, we used maximum-likelihood estimation in structural equation modeling (SEM). According to Hair (2009) SEM was selected because of its capacity to evaluate the relationships between latent and observable variables directly.\n\nThe construct’s reliability and validity were established by assessing Cronbach’s alpha, rhoa, and composite reliability, as outlined in Table 1. The computed rhoa value surpassing the 0.7 cutoffs indicates (Hair et al., 2010) robust reliability. Composite reliability is adopted to examine the internal consistency of the constructs and all values are above the threshold limit (Werts et al., 1974). Cronbach alpha estimates reveal reliability of the all the indicators as all figures were above the threshold value of 0.7 (Ken Kwong-Kay Wong, 2013). Convergent validity was established using Average Variance Extracted (AVE). All constructs have an AVE above the threshold of 0.5 (Richard P. Bagozzi and Youjae Yi, 1988). Collinearity among the indicators was examined in the VIF estimates of the constructs. All the VIF values were less than 0.5 (Sarstedt et al., 2017) no collinearity among the constructs of the study. Similarly, the absence of collinearity among the constructs of the study was established where the VIF values of the inner model of all the exogenous constructs were less than 3.3 (Joseph F. Hair et al., 2017). This also ensures the absence of common method bias impacting the data (Kock, 2015). Evaluation of the Structure Model is presented in Figure 2. Indicating Discriminant validity was confirmed using the Fornell and Larcker methodology, as depicted in Table 2.\n\n p<0.01.\n\nSubsequently, the structural model was assessed by the bootstrapping technique and the hypothesis was tested. The structural wall was further evaluated with the help of the path coefficients (Table 3). R2 and Q2 were obtained from the structural model. R2 indicates that a model’s prediction ability should be more than 0.1 (Falk and Miller, 1992). Trust, Expertise, Attractiveness, and similarity explained 48.7 percent of the variance for Influencer credibility. The credibility of the influencer explained a 20.9 percent variance of Attitude towards Brand and both these constructs explained a 36.6 percent variance of the outcome construct Purchase Intention. Furthermore, Q2, which assesses the model’s predictive usefulness, ought to be greater than 0. The efficiency of the model was confirmed in the current investigation when both R2 and Q2 values were above the designated thresholds, thus the model’s predictive relevance was justified.\n\nAbbreviation: BI = bias-corrected.\n\n* p<0.01.\n\n** p<0.05.\n\n* p<0.1.\n\nThe results revealed that two exogenous constructs, Expertise (β = 0.342, t = 7.007 p = 0.000) & Trust (β = 0.353, t = 6.549, p = 0.000) had a significant positive impact on the credibility of the influencer. However, Similarity (β = 0.123, t = 2.095, p = 0.036) partially influenced the influencer credibility. Hypothesis 5 (Attitude towards Brand on Purchase Intention) and Credibility of Influencer on Attitude towards Brand were supported revealing two dimensions. Firstly, Attitude towards the Video (β = 0.167, t = 2.771, p = 0.006) has a significant positive association with to Purchase Intention of the followers and secondly, Credibility of the Influencer (β = 0.458, t = 9.063, p = 0.000) had a significant positive influence on the Followers Attitude towards the Brand. Attitude towards Brand (β = 0.208, t = 3.697, p = 0.000) and Credibility of the Influencer (β = 0.370, t = 6.134, p = 0.000) had a significant positive impact on the Purchase intention of the follower. Thus, H7 and H8 were also supported.\n\nA mediation analysis was performed to assess the mediating effect of ATB on the linkage between Credibility and PI of the followers. The results (Table 4) revealed that the total effect of Credibility on PI was significant (β = 0.524, t = 10.305, p = 0.000). With the inclusion of the mediating variable.\n\nThe Standard Root Mean Square Residual (SRMR), with a suggested threshold of <0.8, was used to assess model fitness. (Sarstedt et al., 2017). The model’s SRMR rating of 0.055 indicated that it suited the data quite well. Additionally, Q2 was calculated to determine predictive relevance when the endogenous construct was greater than zero.\n\nIPMA’s result is presented as bootstrapping with 5,000 subsamples, demonstrating that all requirements for applying the IPMA approach are met and that some path coefficients are statistically significant. IPMA clarifies the comparative importance and effectiveness of exogenous (Trust, Expertise, Similarity, Attractiveness, Attitude towards Brand, Attitude towards the video, Influencers Credibility) on the endogenous construct (Purchase Intention). Their significance and efficacy are shown by their aggregate impacts and index values. The impact on the endogenous variables is significant. The intrinsic potential of the latent variable scores is demonstrated through effectiveness (Table 5, Figure 3).\n\n\n5. Discussion\n\nInfluencer marketing has become a potent catalyst propelling brands’ social media investment in the ever-changing world of digital marketing. Influencers provide organizations with a means of accessing pre-existing communities and fostering genuine interactions with their target audiences. Influencers are frequently people with sizable and devoted online followings. Upholding the model proposed by Hovland et al. (1953) on Communication and persuasion, trust in the influencer significantly influences the credibility of the influencer. Similarity with the influencer and Expertise of the influencer is explored to have a significant role in determining the influencer’s Credibility. These findings are in line with the previously published literature on the construct of trust in the marketing influencer (Johnsson, 2023; Saima & Khan, 2020; Trivedi & Sama, 2020; Patmawati & Miswanto, 2022). Digital media platforms provide internet users with substantial control over the information they share, which fosters a climate even conducive to the spread of misleading information, such as fake news. Internet users now place more emphasis on original information and reliable sources, highlighting the significance of real and honest information sources in the digital sphere.\n\nFurther Naderer et al., (2021) documented that similarity with the influencer had a direct positive effect on the purchase intention of the promoted brand. Additionally, a qualitative study undertaken by Johnsson (2023). Among GenZ of Bangladesh, it was documented that most of the followers compared themselves with celebrity influencers and tried to imitate them. This is not justified in our research context as attractiveness did not significantly influence the credibility of the influencer. Another study was undertaken by Trivedi (2018) revealed a higher efficacy of attractiveness the social media influencers. Although the findings contradict the research findings of Johnsson (2023) and Trivedi (2018) revealed, it is noteworthy to observe that these studies are undertaken in different contexts. Trivedi (2018) documented research in the context of fashion influencers. However, it is also documented by Masuda et al. (2022) that the strength of this association can vary depending on the age group of the followers and the product category under consideration. Younger consumers or those who highly value physical appearance might be more susceptible to attractiveness pull. Similarly, luxury or aspirational products can have a stronger effect.\n\nAttitude towards the Video content is documented to have a significant direct positive influence on purchase intention by the followers, leading to acceptance of H5. This finding is also affirmed by Trivedi (2018) that attitude towards the brand endorsed plays a significant role in determining the consumers’ purchase intention. This finding was significantly endorsed in the fashion marketing landscape. This strongly affirms the Theory of Reasoned Action (Icek Ajzen, 1980).\n\nAttitude towards the brand significantly influenced Purchase Intention and it partially mediated the association between influencer credibility and purchase intention leading to acceptance of H7 and H9. The result is consistent with previous research, supporting the important role that attitudes are shaped by perceived information credibility, as has been shown in studies by Masuda et al. (2022); Naderer et al., (2021) and Wang et al. (2008). This finding also raises questions about the possible value of using YouTube videos’ perceived legitimacy to forecast viewers’ purchase intentions for the products they showcase. The substantial correlation between attitudes and behavioral intentions, a link that Ajzen and Fishbein (1977). Thoroughly examined gives rise to this assumption.\n\n\n6. Theoretical and managerial implications\n\nThis study is meaningful in its input to the theoretical understanding of using the Theory of Reasoned Action and the Tri Component Attitude Model in explaining the impact of relevant cues on influencer credibility and purchase intention. This research attempts to deepen knowledge of how GenZ influencer marketing in the context of the Indian market. This study closes a gap in the literature by examining the influence of social media influencers on purchase intentions in India, a topic that has not been well studied. By providing a thorough framework that clarifies the role of influencer qualities in influencing customer purchase intentions through the mediation of credibility, it advances our understanding of the subject. The importance of antecedents of the credibility of the influencer, namely expertise, trust, and similarity, has emerged in this research endeavor. The impact of influencer credibility on purchase intention is well documented and resonates outcomes of previous researchers. This study establishes the significance of the truthfulness and resemblance of the influencer to be effective with his or her followers. It is observed that the target segment (GenZ) gives less importance to the Attractiveness of the influencer and it was insignificant in influencing the credibility. In the backdrop of the Tri Component Attitude Model (Rosenberg et al., 1960), this finding emphasizes the cognitive component of attitude formation. The Tripartite model, also recognized as the three components of attitude, encompasses affective, behavioral, and cognitive elements. Collectively, these elements create attitudes, with one element usually predominating over the others at any one time. The findings revealed that Attitude towards the brand has a significant positive influence on Purchase intention. The IPMA results also indicate that Attitude towards the brand is the second most important factor determining the purchase intention of followers. Similar previous studies (J. P. Trivedi, 2018; J. Trivedi & Sama, 2020) have also highlighted the importance of attitude towards the brand in followers’ purchase intention. This strengthens our understanding of the need to build brands and consider influencers as mere enablers of decision-making. This is further validated by the mediation analysis performed in this study. A partial mediation is proved (Table 4) which indicates that both the antecedents (attitude towards brand and influencer Credibility) have an important role to play in shaping followers’ purchase intention. The significant and positive impact of trustworthiness, similarity, and expertise on influencer credibility should inform advertisers or marketers to use trustworthiness as a criterion to evaluate the power of a social media influencer as a potential advertising partner. This project is also among one of the few studies to analyze the follower’s attitude towards video content on purchase intention. It indicates marketers to take special cognizance of this fact and encourages them to create defined standard operating procedures to be necessarily followed by the influencers. If social media influencer intends to continue their collaborations with advertisers, or wish to expand their followers they must connect with the followers.\n\n\n7. Future directions and limitations\n\nThere are certain drawbacks to this study. It doesn’t distinguish between different kinds of videos or brands/products; instead, it concentrates on social media influencers and brands/products in a general way. Subsequent investigations ought to improve the accuracy of influencer marketing theories by examining particular video categories (e.g., office supplies, alcoholic beverages, gaming videos), alternative content formats (e.g., blog posts, audio podcasts, Instagram/Facebook photos), or product genres (e.g., product reviews, how-to tutorials, gaming videos). Furthermore, examining particular groups of micro or macro influencers may reveal differences in the ways that trustworthiness is influenced. Additionally, this study uses a single survey instrument and depends on a single source of consumers, which could introduce a single-source bias. To get over this restriction, future research should think about selecting participants from a variety of sources and using a range of techniques to look more deeply into the dynamics of social media influencer marketing and how consumers perceive the reliability of information.\n\nThis marketing study was exempt from submission to the Institutional Ethics Committee of Manipal Academy of Higher Education, by clause 6 of the circular titled “Project Exemption from Submission to IEC,” issued by the Institutional Ethics Committee on 14/01/2021.\n\nNo minors were included in the study. It clearly states that while collecting data, respondents were briefed, and then handed over the Google form. The first section of the Google form briefed the respondent again and only if they consent, they clicked the link and presented their consent.\n\nConsent was taken Verbally and while filling questionnaire the following text was displayed first:\n\nDear Respondent, Marketing Influencers have become a part of our digital ecosystem.\n\nIn light of this pervasive influencer content that you actively follow, please address the following questions, reflecting on your exposure to these influencers and their messages. Your responses will be kept confidential. If you consent to provide data on your experience with marketing influencer content, click on the link below to proceed. Thank You\"\n\nThe respondent has to consent before clicking on the questionnaire link. This is now has to be how consent was captured from each respondent.\n\n\nAuthor contributions\n\n\n\n• Study conception and design: Prof Smitha Nayak, Pranav Chavare, Dr Ramon Birau\n\n• Data collection: Prof Smitha Nayak, Pranav Chavare,\n\n• Analysis and interpretation of results: Prof Smitha Nayak, Pranav Chavare, Dr Varalakshmi Alapati\n\n• Manuscript preparation. Prof Smitha Nayak, Pranav Chavare, Dr Ramona Birau, Dr Varalakshmi Alapati", "appendix": "Data availability\n\nFigshare: [Influencer Marketing [https://doi.org/10.6084/m9.figshare.27094330.v1]\n\nThe project contains the following underlying data:\n\n• Impact of Marketing Influencers Dataset\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAaker JL, Garbinsky EN, Vohs KD: Cultivating admiration in brands: Warmth, competence, and landing in the “golden quadrant.”. J. Consum. Psychol. 2012; 22(2): 191–194. 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Stud. 2018; 15(3): 188–213. Publisher Full Text" }	[ { "id": "339092", "date": "27 Nov 2024", "name": "Yoesoep Edhie Rachmad", "expertise": [ "Reviewer Expertise Yes", "I consider aspects of this article to be of major significance.Justification:The study provides critical insights into the mechanisms by which influencer credibility and brand attitude shape purchase intentions", "particularly among Gen Z consumers in a rapidly digitizing market like India. This demographic and geographical focus offers unique value in understanding emerging consumer behaviors.Why It Is Significant:Practical Implications:The findings can guide brands and marketers in designing more effective influencer strategies", "especially in leveraging trust and expertise over attractiveness.Theoretical Contribution:By identifying the mediating role of brand attitude", "the study advances existing frameworks like the Theory of Reasoned Action", "adding depth to literature on influencer marketing and consumer behavior.Emerging Market Focus:The focus on Gen Z in India highlights evolving trends in an underrepresented region", "providing valuable insights that could inform both academic and industry strategies globally.The work bridges theoretical and practical gaps", "making it a substantial addition to the field of marketing research." ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSubmission ID\n\n: 2024_IJWOE-237645 Title\n\n: Does Brand Attitude Complement Influencer Credibility in Shaping Purchase Intention of Indian GenZ Consumers? Authors\n\n: Pranav Vilas Chavare, Smitha Nayak, Ramona Birau, Varalakshmi Alapati. Journal\n\n: F1000Research 2024, 13:1343 Last updated: 13 NOV 2024\nDear Authors, Thank you for your submission of the manuscript titled \"Does Brand Attitude Complement Influencer Credibility in Shaping Purchase Intention of Indian GenZ Consumers?\" This study offers a valuable and timely contribution to the field of influencer marketing, particularly in the context of Generation Z consumers in India. The research methodology, findings, and theoretical implications are well-articulated. However, I would like to suggest a few areas for improvement to further enhance the manuscript’s clarity, impact, and contribution. Feedback and Suggestions Clarity in Presentation\nDetailed Explanations:\nWhile the methodology section is robust, additional explanations regarding the choice of a five-point Likert scale and its appropriateness in this context would enhance understanding. Consider including a justification for its use over other scales.\nFigures and Tables:\nSome figures and tables, such as the structural model and hypothesis testing results, could benefit from clearer captions or legends. For example, explicitly defining significance levels (e.g., p values) directly in the table or figure notes would improve readability. Data Accessibility and Reproducibility\nData Sharing:\nIt is commendable that the dataset is available on Figshare under a Creative Commons license. However, it may be beneficial to provide an appendix or a supplementary section with detailed instructions on how to access and use the dataset for replication studies. Discussion and Implications\nComparative Context:\nThe discussion section could be expanded to include comparisons with similar studies in other regions or demographic groups. This would contextualize the findings and highlight their generalizability.\nPractical Applications:\nIncluding examples of how brands or marketers can apply these findings to develop effective influencer strategies would increase the manuscript's practical utility. Future Research Directions\nContent and Product Categories:\nThe study would benefit from a clearer acknowledgment of its limitations regarding generalizations across different content types or product categories. Suggestions for future research in these areas could provide valuable guidance for subsequent studies. Minor Corrections\nConsistency in Terms:\nEnsure all technical terms are consistently defined throughout the manuscript. For instance, maintaining uniform terminology for constructs like “trust,” “expertise,” and “credibility” will aid comprehension.\nGrammar and Typographical Errors:\nA few minor typographical errors were noted. A careful review of the manuscript will help ensure overall accuracy and readability. Overall, this manuscript represents a significant contribution to the literature on influencer marketing and consumer behavior. The innovative approach and detailed analysis are commendable, and I am confident that with these refinements, the paper will achieve even greater impact. Thank you for the opportunity to review this work. I look forward to the revised version. Best regards, Prof. Dr. Yoesoep Edhie Rachmad Reviewer\nSubmission ID\n\n: 2024_IJWOE-237645 Title\n\n: Does Brand Attitude Complement Influencer Credibility in Shaping Purchase Intention of Indian GenZ Consumers? Authors\n\n: Pranav Vilas Chavare, Smitha Nayak, Ramona Birau, Varalakshmi Alapati. Journal\n\n: F1000Research 2024, 13:1343 Last updated: 13 NOV 2024\n\nDear Editor, The manuscript titled \"Does Brand Attitude Complement Influencer Credibility in Shaping Purchase Intention of Indian GenZ Consumers?\" presents a compelling study that contributes significantly to the growing field of influencer marketing and its impact on consumer behavior, specifically within the context of Generation Z in India. While the research demonstrates robust methodology and meaningful findings, there are a few areas that I would recommend addressing to enhance the overall clarity and impact of the manuscript:\nKey Points for Consideration\nClarity and Accessibility in Methodology:\nThe study employs PLS-SEM to test hypotheses effectively. However, for a broader audience, providing additional context or illustrative examples regarding the structural model and key metrics (e.g., significance thresholds) would increase clarity and accessibility.\n\nData Availability and Reproducibility:\nWhile the authors commendably provide access to the dataset on Figshare, it may be beneficial to suggest including explicit guidance or links in an appendix to facilitate easier replication by future researchers.\n\nDiscussion of Findings and Generalizability:\nThe discussion section could be expanded to compare the findings with similar research across different demographics or industries. Highlighting potential applications of the study's insights in other regions or sectors would underscore its broader relevance.\n\nPractical Implications:\nThe paper makes significant theoretical contributions. To balance this, elaborating on how brands can implement these findings to design effective influencer campaigns could enhance the manuscript’s practical utility.\n\nFuture Research Directions:\nThe limitations section briefly mentions opportunities for future work. However, more detailed suggestions, such as examining content types or distinguishing between macro- and micro-influencers, would provide valuable guidance for subsequent research in this field.\nOverall Recommendation The manuscript offers a valuable addition to the literature on influencer marketing and consumer behavior. Addressing the points above through minor revisions would further strengthen its impact and readability.\nThank you for the opportunity to review this manuscript. I look forward to seeing its refined version.\nBest regards, Prof. Dr. Yoesoep Edhie Rachmad Reviewer\n\nSubmission ID\n\n: 2024_IJWOE-237645 Title\n\n: Does Brand Attitude Complement Influencer Credibility in Shaping Purchase Intention of Indian GenZ Consumers? Authors\n\n: Pranav Vilas Chavare, Smitha Nayak, Ramona Birau, Varalakshmi Alapati. Journal\n\n: F1000Research 2024, 13:1343 Last updated: 13 NOV 2024\n\nI recommend Minor Revisions for the manuscript titled \" Does Brand Attitude Complement Influencer Credibility in Shaping Purchase Intention of Indian GenZ Consumers?\".\nJustification for Recommendation:\n\nInnovative Approach:\nThe manuscript provides an insightful examination of influencer credibility and its impact on purchase intention, particularly in the context of Generation Z in India. The integration of trust, expertise, and similarity in assessing influencer credibility adds a significant contribution to the literature on consumer behavior.\n\nClarity and Detail:\nThe study uses advanced methodologies such as PLS-SEM, which are well-documented. However, the manuscript would benefit from additional intuitive examples or explanations for readers less familiar with this approach. Adding more visuals or diagrams, particularly in the methodology section, could enhance clarity.\n\nData Accessibility:\nWhile the dataset is made publicly available through Figshare, the authors should provide additional guidance or references for accessing and utilizing the data to support reproducibility.\n\nDiscussion and Practical Implications:\nThe discussion section is thorough but could be expanded with a stronger emphasis on practical applications. For instance, the authors could elaborate on how brands can leverage the findings to design effective influencer marketing campaigns.\n\nMinor Corrections:\nSome typographical errors and inconsistencies in the use of technical terms were noted. Ensuring uniformity in terminology and addressing these minor errors will improve the manuscript's readability.\nConclusion:\nThis manuscript is a valuable contribution to the understanding of influencer marketing and consumer behavior. The proposed revisions are minor and intended to enhance the manuscript's clarity, practical relevance, and broader impact.\nI look forward to reviewing the revised version.\nBest regards, Prof. Dr. Yoesoep Edhie Rachmad Reviewer\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "12904", "date": "09 Dec 2024", "name": "smitha nayak", "role": "Author Response", "response": "1. While the methodology section is robust, additional explanations regarding the choice of a five point likert scale. Response : Changes have been incorporated. As these scales were originally developed and designed to be measured on 5 point likert scale, the same has been adopted in the manuscript. 2. Data Sharing: It is commendable that the dataset is available on Figshare under a Creative Commons license. However, it may be beneficial to provide an appendix or a supplementary section with detailed instructions on how to access and use the dataset for replication studies. Response: This statement has been included in the “Underlying Data“ section of the. The underlying data of the manuscript can be accessed on Figshare by clicking on this link 3. Including examples of how brands or marketers can apply these findings to develop effective influencer strategies would increase the manuscript's practical utility. Response: The same has already been addressed in the theoretical and managerial implication sections of the manuscript. 4. Content and Product Categories: The study would benefit from a clearer acknowledgment of its limitations regarding generalizations across different content types or product categories. Suggestions for future research in these areas could provide valuable guidance for subsequent studies. Response has been incorporated. 5. Manuscript has been rechecked for Consistency, Typographical errors and Grammatical errors." } ] }, { "id": "339089", "date": "17 Dec 2024", "name": "Meenakshi Sharma", "expertise": [ "Reviewer Expertise Marketing", "Green banking", "Sensory marketing" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDetailed Explanation: The narrative style of the paper is scientific. The paper has a high degree of clarity and is focused. It contributes to the body of knowledge in the marketing domain, especially in the context of GenZ. It has been clearly articulated. Figures and Tables: All figures and tables are in order and have an intext mentioned at appropriate places. Consistent with the paper's objective, the tables provide an overview of major findings. Methodology: The methodology section is well drafted and captures the process appropriately. However, the authors are advised to explain the sample size estimation process in detail. This will strengthen the methodology section. There appears to be an error in the data measurement section. Relook at the “5-5 point likert scale”. In the pilot testing section “Similarity with the Influencer was below the threshold value of 0.7. In social science research, a construct with a Cronbach alpha above 0.6 in a pilot study could be retained as it is expected the increase with an increment in sample size. Hence the research team decided to retain the construct and explore it further during the final data analysis phase.” Authors are advised to include a citation for this. Data sharing: data is shared on Figshare and incorporated in the manuscript. Discussion and Directions for future direction: The discussion section is well drafted and provides a comparison to previously published literature at appropriate places. A few grammatical errors are observed, Authors are advised to relook and incorporate corrections. Eg.. A sentence starts with “To address ……..”; Typo errors like 3.6….Cronbach alpha of all constructs of the study was above o.7 etc.\nAuthors are advised to take a relook at the paper and incorporate the suggestions presented above. The paper maybe accepted for indexing as it is written well and contributes to the body of knowledge of management science.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13198", "date": "27 Jan 2025", "name": "smitha nayak", "role": "Author Response", "response": "Dear Reviewer, Thank you for your observations and feedback on the manuscript. I acknowledge the typo errors in the document and have included the corrections in the new version of the manuscript. As far as the Cronbach Alpha goes, in social science research if the values are in the range of 0.5 to 0.7, it is still recommended to proceed with the scale as the assumption is that a bigger sample size will normalize this when the final data collection is undertaken. I am uploading a new version of the manuscript after refining it with your suggestions. Thank you again." } ] } ]	1	https://f1000research.com/articles/13-1343
https://f1000research.com/articles/13-857/v1	01 Aug 24	{ "type": "Systematic Review", "title": "Hormonal Influences on ADC Values in Breast Tissues: A Scoping Review of DWI in Pre- and Post-menopausal Women", "authors": [ "Winniecia Dkhar", "Rajagopal Kadavigere", "Sneha Ravichandran", "Abhimanyu Pradhan", "Suresh Sukumar", "Neil Barnes Abraham", "Rajagopal Kadavigere", "Abhimanyu Pradhan", "Suresh Sukumar", "Neil Barnes Abraham" ], "abstract": "Background Breast cancer remains a significant global health concern, with early diagnosis and risk factor identification crucial for improving outcomes. Diffusion-Weighted Imaging (DWI) and Apparent Diffusion Coefficient (ADC) measurements have emerged as promising tools in breast cancer diagnostics. However, the influence of hormonal status on these measurements remains unclear.\n\nObjective This scoping review aims to synthesize current evidence on how hormonal changes in pre- and post-menopausal women influence ADC values of benign, malignant, and fibroglandular breast tissues.\n\nMethod Following the Arksey and O'Malley framework, we conducted a comprehensive search of Scopus, Embase, and PubMed databases for relevant studies published between January 2000 and 2021. Inclusion criteria encompassed 1.5 Tesla MRI studies reporting ADC values in female subjects, considering menopausal status.\n\nResults Six studies meeting the inclusion criteria, involving 612 patients, were analyzed. Findings suggest that menopausal status may influence ADC values, with postmenopausal women generally showing lower ADC values in both normal fibroglandular tissue and breast lesions. The impact of menstrual cycle phases on ADC values was less consistent across studies.\n\nConclusions This review highlights the potential influence of hormonal status on ADC values in breast tissues. While DWI with ADC mapping shows promise as a reliable diagnostic tool across different hormonal states, further research is needed to fully understand and account for hormonal influences on ADC measurements. Future studies should focus on longitudinal designs, standardization of DWI protocols, and integration of hormonal status information into breast cancer risk assessment models.", "keywords": [ "Breast cancer", "Diffusion-Weighted Imaging", "Apparent Diffusion Coefficient", "hormonal influence", "menopause", "scoping review" ], "content": "1. Introduction\n\nBreast cancer continues to be one of the most prevalent and deadly diseases affecting women worldwide. According to the World Health Organization, breast cancer is the most common cancer in women, with an estimated 2.3 million new cases diagnosed globally in 2020.1 The incidence of breast cancer has been steadily increasing over the past decades, partly due to improved screening methods and increased life expectancy.2 However, this rising incidence underscores the critical importance of early detection and accurate diagnosis in reducing mortality rates and improving patient outcomes.3–6\n\nIn recent years, significant advancements have been made in breast cancer diagnostics, with imaging techniques playing a pivotal role. Among these, Magnetic Resonance Imaging (MRI) has emerged as a powerful tool, offering high sensitivity in detecting breast lesions. Within the realm of MRI, Diffusion-Weighted Imaging (DWI) has gained particular attention for its ability to provide functional information about tissue microstructure without the need for contrast agents.\n\nDWI is based on the principle of measuring the random Brownian motion of water molecules within tissues.7 The degree of water diffusion can be quantified using the Apparent Diffusion Coefficient (ADC), which provides a numerical value reflecting tissue cellularity and integrity of cell membranes. In the context of breast imaging, ADC values have shown promise in differentiating between benign and malignant lesions, as malignant tissues typically demonstrate restricted diffusion due to increased cellularity, resulting in lower ADC values.7\n\nHowever, the interpretation of ADC values in breast tissue is complex, as these values can be influenced by various factors beyond the presence or absence of malignancy. One crucial factor that has garnered increasing attention is the potential influence of hormonal status on ADC measurements. The female breast undergoes significant physiological changes throughout a woman's lifetime, largely driven by hormonal fluctuations.8 These changes are particularly pronounced during the menstrual cycle, pregnancy, and the transition to menopause.\n\nThe hormonal milieu plays a vital role in breast tissue composition and structure. Estrogen and progesterone, the primary female sex hormones, influence the growth and development of breast tissue, affecting both the glandular and stromal components. During the menstrual cycle, fluctuations in these hormones lead to cyclic changes in breast tissue, including variations in water content, vascularity, and cellular proliferation. Similarly, the transition to menopause is marked by a significant decline in ovarian hormone production, leading to involution of glandular tissue and an increase in adipose tissue within the breast.8\n\nGiven these hormone-driven changes in breast tissue composition and microstructure, it is plausible that hormonal status could influence DWI measurements and, consequently, ADC values. Understanding these potential influences is crucial for several reasons:\n\n1. Diagnostic Accuracy: If hormonal status significantly affects ADC values, it could impact the accuracy of DWI in differentiating between benign and malignant lesions. Establishing hormone-specific reference ranges or correction factors might be necessary to optimize diagnostic performance.\n\n2. Risk Assessment: Hormonal exposure is a known risk factor for breast cancer. If ADC values reliably reflect hormone-induced changes in breast tissue, they could potentially serve as imaging biomarkers for assessing breast cancer risk.\n\n3. Treatment Monitoring: For patients undergoing hormonal therapies (e.g., hormone replacement therapy or endocrine therapy for breast cancer), understanding how these treatments affect ADC values could be valuable for monitoring treatment response and tissue changes.\n\n4. Personalized Screening: Knowledge of how hormonal status influences ADC values could inform more personalized screening protocols, potentially optimizing the timing of MRI examinations based on a woman's menstrual cycle or menopausal status.\n\nDespite the potential importance of this topic, the relationship between hormonal status and ADC values in breast tissue remains incompletely understood. While several studies have investigated this relationship, results have been inconsistent, and a comprehensive synthesis of the available evidence is lacking. This scoping review aims to address this gap by systematically exploring and synthesizing the current literature on how hormonal changes in pre- and post-menopausal women influence the ADC values of benign, malignant, and fibroglandular breast tissues. By mapping the existing evidence, identifying key concepts, and highlighting knowledge gaps, this review seeks to provide a foundation for future research and clinical applications of DWI in breast imaging.\n\nThe specific objectives of this scoping review are:\n\n• To summarize the current evidence on the relationship between hormonal status (including menstrual cycle phases and menopausal status) and ADC values in breast tissues.\n\n• To identify patterns or trends in how ADC values vary with hormonal changes across different studies.\n\n• To explore the potential implications of hormonal influences on ADC values for breast cancer diagnosis, risk assessment, and treatment monitoring.\n\n• To highlight gaps in the current knowledge and propose directions for future research.\n\nBy addressing these objectives, this scoping review aims to contribute to a more nuanced understanding of DWI in breast imaging and to inform future studies and clinical practices in this rapidly evolving field.\n\n\n2. Methods\n\nThis scoping review was conducted following the methodological framework proposed by Arksey and O'Malley (2005) and further refined by Levac et al. (2010). This framework consists of five key stages:1 identifying the research question,2 identifying relevant studies,3 study selection,4 charting the data, and5 collating, summarizing, and reporting the results. Additionally, we incorporated the optional sixth stage of consultation with stakeholders to enhance the review's relevance and uptake.\n\nThe primary research question guiding this scoping review was: “How do hormonal changes in pre- and post-menopausal women influence the ADC values of benign, malignant, and fibroglandular breast tissues as measured by Diffusion-Weighted Imaging?”\n\nThis question was developed through an iterative process involving discussions among the research team and preliminary literature searches. The question was designed to be broad enough to capture the range of relevant literature while maintaining a clear focus on the relationship between hormonal status and ADC values in breast tissues.\n\nA comprehensive search strategy was developed in consultation with an experienced medical librarian. The following electronic databases were searched: Scopus, Embase, and PubMed. The search was limited to studies published between January 2000 and December 2021, reflecting the period during which DWI became increasingly used in breast imaging.\n\nThe search strategy included a combination of controlled vocabulary (MeSH terms) and free-text terms. Key search terms included:\n\n- “Diffusion Weighted Imaging” OR “DWI” OR “Diffusion Weighted MR Imaging”\n\n- “Apparent Diffusion Coefficient” OR “ADC”\n\n- “Magnetic Resonance Imaging” OR “MRI”\n\n- “Breast cancer” OR “breast” OR “fibroglandular tissue”\n\n- “Premenopausal” OR “postmenopausal” OR “menstrual cycle”\n\nInclusion criteria\n\nThe inclusion criteria for this study encompassed several specific requirements. Only studies utilizing 1.5 Tesla MRI scanners and focusing exclusively on female subjects were considered. Additionally, the research had to employ Diffusion-Weighted Imaging sequences and report Apparent Diffusion Coefficient (ADC) values for benign and/or malignant lesions and/or fibroglandular tissue. Studies that took into account pre- and/or post-menopausal status were also included. Lastly, the review was limited to peer-reviewed articles published in English. These criteria were designed to ensure a focused and relevant selection of studies for analysis.\n\nExclusion criteria:\n\nStudies using 3 Tesla MRI scanners were excluded to maintain consistency in imaging parameters across the reviewed research. Any studies involving subjects undergoing neoadjuvant treatment were also omitted from consideration. The review excluded studies that did not report separate mean ADC values for benign and malignant lesions, as well as those not directly related to the diagnostic performance of Diffusion-Weighted Imaging (DWI). To focus on primary research findings, the review also excluded preclinical studies, case reports, letters, review articles, and unpublished articles. These exclusion criteria were implemented to ensure a more homogeneous and relevant dataset for analysis, focusing on studies that directly addressed the research question using comparable methodologies.\n\nThe study selection process was conducted in two phases. In the first phase, two reviewers independently screened the titles and abstracts of all retrieved articles against the inclusion and exclusion criteria. In the second phase, the full texts of potentially eligible articles were obtained and independently reviewed by the same two reviewers. Any disagreements were resolved through discussion, with a third reviewer consulted when necessary.\n\nA standardized data charting form was developed in Microsoft Excel to systematically extract relevant information from the included studies. This form was initially piloted on a sample of five studies and subsequently refined based on team discussions to ensure its effectiveness and comprehensiveness.\n\nThe data extraction process captured a wide range of information, including study characteristics (author, year, country, and study design), participant characteristics (sample size, age range, and menopausal status), and MRI characteristics (scanner manufacturer and b-values used). Detailed information about ADC measurement techniques, such as regions of interest and measurement methods, was also collected.\n\nImportantly, the form captured quantitative data on ADC values, including mean and standard deviation for benign lesions, malignant lesions, and normal fibroglandular tissue. Any reported relationships between hormonal status and ADC values were noted, along with key findings and conclusions from each study.\n\nTo ensure accuracy and completeness, two reviewers independently extracted data from each included study. The extracted data were then cross-checked, providing a robust and reliable dataset for subsequent analysis.\n\nThe extracted data were analysed using a narrative synthesis approach. We organized the findings according to key themes and concepts that emerged from the data. Quantitative data (e.g., ADC values) were summarized using descriptive statistics where appropriate. We also created tables and figures to present the key characteristics and findings of the included studies.\n\nIn synthesizing the results, we focused on identifying patterns and trends in the relationship between hormonal status and ADC values, as well as highlighting any inconsistencies or gaps in the current evidence base. The PRISMA-ScR check list was used for reporting the data.15\n\n\n3. Results\n\nThe initial database search yielded a total of 487 articles. After removing duplicates, 342 unique articles remained for title and abstract screening. Based on the screening, 28 articles were selected for full-text review. After applying the inclusion and exclusion criteria to the full texts, 5 studies were ultimately included in this scoping review. The study selection process is illustrated in Figure 1 (PRISMA flow diagram).\n\nThe six included studies were published between 2001 and 2018, representing a span of nearly two decades of research in this area. All studies used 1.5 Tesla MRI scanners, as per our inclusion criteria. The studies were conducted in various countries: two from the United States, two from South Korea, one from Italy, and one from the United Kingdom. The total number of participants across all studies was 612, with individual study sample sizes ranging from 6 to 288 participants. Table 1 provides the summary of the articles reviewed for this study.\n\n3.2.1 Menopausal Status and ADC Values\n\nAll these studies examined the relationship between menopausal status and ADC values. The findings across these studies showed some consistencies but also notable variations:\n\nHorvat et al. (2018) found no significant difference in ADC sensitivity or specificity between pre- and post-menopausal groups, with mean ADC values for benign lesions being 1.541 ± 0.256 × 10−3 mm2/s in premenopausal women and 1.515 ± 0.272 × 10−3 mm2/s in postmenopausal women. Kim et al. (2016) reported significantly lower ADC values in postmenopausal women compared to premenopausal women for both normal fibroglandular tissue (1.60 ± 0.30 vs. 1.75 ± 0.27 × 10−3 mm2/s, p < 0.05) and malignant lesions (0.91 ± 0.18 vs. 1.06 ± 0.35 × 10−3 mm2/s, p < 0.05). Similarly, Shin et al. (2015) observed lower ADC values in postmenopausal women for normal fibroglandular tissue (1.480 vs. 1.640 × 10−3 mm2/s, p < 0.001) and malignant lesions (0.648 vs. 0.644 × 10−3 mm2/s, p = 0.031). Additionally, O’Flynn et al. (2012) reported significantly lower mean ADC values in postmenopausal breasts compared to premenopausal breasts for normal fibroglandular tissue (1.46 ± 0.3 vs. 1.84 ± 0.26 × 10−3 mm2/s, p < 0.001). While Iacconi et al. (2014) primarily focused on premenopausal women, they also noted that postmenopausal status was associated with lower ADC values in normal breast tissue.\n\nThe consistency in findings across these studies, despite variations in sample sizes and specific ADC values, suggests a trend towards lower ADC values in postmenopausal women, particularly in normal fibroglandular tissue. This trend was observed in both benign and malignant lesions, although the difference was more pronounced and consistent for normal tissue.\n\n3.2.2 Menstrual Cycle and ADC Values\n\nThree studies examined the potential influence of menstrual cycle phases on ADC values:\n\nHorvat et al. (2018) found no significant difference in ADC sensitivity or specificity between pre- and post-menopausal groups, with mean ADC values for benign lesions being 1.541 ± 0.256 × 10−3 mm2/s in premenopausal women and 1.515 ± 0.272 × 10−3 mm2/s in postmenopausal women. Kim et al. (2016) reported significantly lower ADC values in postmenopausal women compared to premenopausal women for both normal fibroglandular tissue (1.60 ± 0.30 vs. 1.75 ± 0.27 × 10−3 mm2/s, p < 0.05) and malignant lesions (0.91 ± 0.18 vs. 1.06 ± 0.35 × 10−3 mm2/s, p < 0.05). Similarly, Shin et al. (2015) observed lower ADC values in postmenopausal women for normal fibroglandular tissue (1.480 vs. 1.640 × 10−3 mm2/s, p < 0.001) and malignant lesions (0.648 vs. 0.644 × 10−3 mm2/s, p = 0.031). Additionally, O’Flynn et al. (2012) reported significantly lower mean ADC values in postmenopausal breasts compared to premenopausal breasts for normal fibroglandular tissue (1.46 ± 0.3 vs. 1.84 ± 0.26 × 10−3 mm2/s, p < 0.001). While Iacconi et al. (2014) primarily focused on premenopausal women, they also noted that postmenopausal status was associated with lower ADC values in normal breast tissue.\n\nSeveral studies investigated additional factors that might influence ADC values in breast tissues:\n\n1. Background Parenchymal Enhancement (BPE): Horvat et al. (2018) investigated the impact of BPE on ADC values and found no significant influence on the sensitivity or specificity of ADC in distinguishing between benign and malignant lesions. This suggests that BPE, despite its known association with hormonal status, may not significantly affect the diagnostic performance of DWI.\n\n2. Fibroglandular Tissue (FGT): Iacconi et al. (2014) reported that the amount of FGT had a significant influence on the quantitative measurement of ADC in normal breast tissue. They found that breasts with higher amounts of FGT tended to have higher ADC values. This relationship was observed in both pre- and post-menopausal women, although the effect was more pronounced in premenopausal subjects.\n\n3. Age: While not directly related to hormonal status, age was found to be a potential confounding factor in several studies. O'Flynn et al. (2012) noted a negative correlation between age and ADC values in normal fibroglandular tissue, which may partly explain the lower ADC values observed in postmenopausal women.\n\n4. Lesion Type: All studies that included both benign and malignant lesions consistently reported lower ADC values for malignant lesions compared to benign ones, regardless of menopausal status. This finding reinforces the potential of ADC as a diagnostic tool in differentiating between benign and malignant breast lesions.\n\nThe review revealed several technical factors that could contribute to variability in ADC measurements across studies:\n\n1. b-values: The studies used different b-values for DWI acquisition, ranging from 0 and 600 s/mm2 (Horvat et al., 2018) to 0 and 1000 s/mm2 (Kim et al., 2016). This variation in b-values could potentially affect the calculated ADC values and their sensitivity to tissue microstructure.\n\n2. Region of Interest (ROI) Selection: The method of ROI selection varied among studies. Some studies used a single ROI (e.g., Partridge et al., 2001), while others used multiple ROIs or whole-lesion measurements (e.g., Shin et al., 2015). This variability in ROI selection could contribute to differences in reported ADC values across studies.\n\n3. Scanner Variability: Although all included studies used 1.5 Tesla MRI scanners, there were differences in scanner manufacturers (e.g., GE, Siemens, Philips). While the impact of scanner variability on ADC measurements was not directly assessed in these studies, it represents a potential source of inconsistency across studies.\n\nDespite the potential influences of hormonal status and other factors on ADC values, several studies reported on the overall diagnostic performance of ADC in differentiating between benign and malignant lesions:\n\n1. Horvat et al. (2018) found that ADC demonstrated high sensitivity (84%) and specificity (84%) in distinguishing between benign and malignant lesions, regardless of BPE, FGT, or menopausal status.\n\n2. Kim et al. (2016) reported that using an ADC cutoff value of 1.23 × 10−3 mm2/s resulted in a sensitivity of 86.7% and specificity of 86.4% for diagnosing malignant lesions in premenopausal women. For postmenopausal women, a cutoff value of 1.12 × 10−3 mm2/s yielded a sensitivity of 92.3% and specificity of 86.7%.\n\n3. Shin et al. (2015) found that the optimal ADC cutoff for differentiating benign from malignant lesions was 1.108 × 10−3 mm2/s in premenopausal women (sensitivity 87.7%, specificity 86.8%) and 1.025 × 10−3 mm2/s in postmenopausal women (sensitivity 80.6%, specificity 82.9%).\n\nThese findings suggest that while hormonal status may influence absolute ADC values, the diagnostic performance of ADC in differentiating between benign and malignant lesions remains robust across different hormonal states when appropriate cutoff values are used.\n\nOnly one study, Partridge et al. (2001), attempted to track longitudinal changes in ADC values across the menstrual cycle. Despite the small sample size, this study provided valuable insights into the potential for cyclic variations in ADC values. The observed minimal fluctuations suggest that the timing of DWI examinations within the menstrual cycle may not significantly impact diagnostic accuracy. However, more extensive longitudinal studies are needed to confirm this finding.\n\nNone of the included studies directly measured hormone levels and correlated them with ADC values. The assessment of hormonal status was primarily based on self-reported menstrual history or menopausal status. This represents a significant gap in the current literature, as direct correlations between specific hormone levels and ADC values could provide more precise insights into the relationship between hormonal status and diffusion properties of breast tissues.\n\nIn summary, the results of this scoping review reveal a complex relationship between hormonal status and ADC values in breast tissues. While there is evidence suggesting lower ADC values in postmenopausal women, particularly in normal fibroglandular tissue, the impact of menstrual cycle phases appears minimal. The influence of other factors such as BPE and FGT on ADC values adds further complexity to the interpretation of DWI results. Despite these variations, the diagnostic performance of ADC in differentiating between benign and malignant lesions appears to remain robust across different hormonal states, suggesting its potential as a valuable tool in breast cancer diagnosis.\n\n\n4. Discussion\n\nThis scoping review synthesizes the current evidence on the influence of hormonal status on Apparent Diffusion Coefficient (ADC) values in breast tissues. The findings reveal a complex interplay between hormonal factors and diffusion properties of breast tissue, with implications for the interpretation and application of Diffusion-Weighted Imaging (DWI) in breast cancer diagnostics.\n\nOne of the most consistent findings across the reviewed studies was the tendency for lower ADC values in postmenopausal women compared to premenopausal women, particularly in normal fibroglandular tissue. This trend was observed in four out of five studies that examined menopausal status,3–6 with only Horvat et al. (2018) reporting no significant difference.\n\nThe lower ADC values in postmenopausal breast tissue can be explained by the physiological changes that occur during menopause. The decline in estrogen levels leads to a reduction in breast tissue vascularity and an increase in fatty tissue replacement of glandular tissue (involution). These changes could result in decreased water diffusivity, manifesting as lower ADC values.\n\nHowever, it's important to note that while the trend was consistent, the magnitude of the difference varied across studies. This variability could be attributed to differences in study populations, imaging protocols, or measurement techniques. Moreover, the study by Horvat et al. (2018), which had the largest sample size, found no significant difference in ADC values between pre- and postmenopausal women. This discrepancy highlights the need for larger, standardized studies to definitively establish the relationship between menopausal status and ADC values.\n\nIn contrast to the findings on menopausal status, the evidence for menstrual cycle-related changes in ADC values was less conclusive. The three studies that examined this relationship (Kim et al., 2016; Partridge et al., 2001; O'Flynn et al., 2012) consistently found minimal or no significant variations in ADC values across different phases of the menstrual cycle.\n\nThis lack of significant menstrual cycle-related changes is somewhat surprising, given the known cyclic changes in breast tissue due to fluctuating levels of estrogen and progesterone. These hormonal fluctuations lead to changes in breast volume, water content, and vascularity throughout the menstrual cycle. The absence of corresponding changes in ADC values suggests that these cyclic variations may not substantially affect water diffusivity at the microstructural level detectable by current DWI techniques.\n\nHowever, it's important to note that the studies examining menstrual cycle effects had relatively small sample sizes and may have lacked the statistical power to detect subtle changes. Furthermore, the timing of MRI examinations in relation to menstrual cycle phases was based on self-reported menstrual history rather than direct hormonal measurements, which could introduce inaccuracies.\n\nDespite the observed variations in ADC values related to menopausal status, the diagnostic performance of ADC in differentiating between benign and malignant lesions appears to remain robust. Several studies (Horvat et al., 2018; Kim et al., 2016; Shin et al., 2015) reported high sensitivity and specificity for ADC in distinguishing malignant from benign lesions, regardless of menopausal status.\n\nThis maintained diagnostic performance suggests that while absolute ADC values may vary with hormonal status, the relative difference between benign and malignant lesions remains sufficiently large for accurate differentiation. However, the optimal ADC cutoff values for diagnosing malignancy may differ between pre- and postmenopausal women, as demonstrated by Kim et al. (2016) and Shin et al. (2015). This finding underscores the importance of considering menopausal status when interpreting ADC values in clinical practice.\n\nThe review highlighted several other factors that may influence ADC values, including the amount of fibroglandular tissue (FGT) and background parenchymal enhancement (BPE). The study by Iacconi et al. (2014) found that breasts with higher amounts of FGT tended to have higher ADC values, an effect that was more pronounced in premenopausal women. This finding suggests that breast composition, which is influenced by hormonal status, can affect ADC measurements independently of the presence or absence of lesions.\n\nInterestingly, Horvat et al. (2018) found that BPE did not significantly impact the diagnostic performance of ADC. This is noteworthy because BPE is known to be influenced by hormonal status and has been associated with breast cancer risk. The lack of significant impact on ADC performance suggests that DWI may offer advantages in terms of consistent diagnostic accuracy across varying levels of BPE.\n\nThe review revealed considerable variability in technical aspects of DWI acquisition and ADC measurement across studies. Differences in b-values, ROI selection methods, and scanner manufacturers could all contribute to variations in reported ADC values. This lack of standardization presents a challenge for comparing results across studies and for establishing universal ADC thresholds for clinical use.\n\nFuture research should aim to standardize DWI protocols and ADC measurement techniques to improve the comparability and reproducibility of results. This standardization should include consensus on optimal b-values, ROI selection methods, and strategies for minimizing the impact of scanner variability.\n\nSeveral limitations in the current body of evidence were identified:\n\n1. Limited direct measurement of hormone levels: None of the reviewed studies directly measured hormone levels and correlated them with ADC values. Future studies incorporating direct hormonal measurements could provide more precise insights into the relationship between specific hormone levels and breast tissue diffusivity.\n\n2. Lack of longitudinal studies: With the exception of Partridge et al. (2001), which had a very small sample size, there was a lack of longitudinal studies tracking ADC changes over time in individual women. Such studies could provide valuable information on intra-individual variations in ADC values across hormonal states.\n\n3. Limited exploration of other hormonal influences: The review focused primarily on menopausal status and menstrual cycle effects. Other hormonal factors, such as the use of hormonal contraceptives or hormone replacement therapy, were not extensively explored in the included studies.\n\n4. Potential selection bias: The inclusion of only English-language publications and the focus on 1.5 Tesla MRI studies may have led to the exclusion of relevant data.\n\nBased on these limitations and the findings of this review, several directions for future research can be proposed:\n\n1. Large-scale, multi-centre studies with standardized protocols to definitively establish the relationship between hormonal status and ADC values.\n\n2. Longitudinal studies tracking ADC changes across the menstrual cycle and through menopausal transition in individual women.\n\n3. Studies incorporating direct measurements of hormone levels to correlate with ADC values.\n\n4. Investigation of the effects of exogenous hormones (e.g., oral contraceptives, hormone replacement therapy) on ADC values.\n\n5. Exploration of advanced DWI techniques, such as intravoxel incoherent motion (IVIM) or diffusion kurtosis imaging, to potentially capture more subtle hormone-related changes in breast tissue microstructure.\n\n6. Development and validation of hormone status-specific ADC thresholds for breast cancer diagnosis.\n\n\n5. Conclusion\n\nThis scoping review provides a comprehensive overview of the current evidence on the influence of hormonal status on ADC values in breast tissues. The findings suggest that menopausal status may significantly impact ADC values, with postmenopausal women generally showing lower ADC values in normal fibroglandular tissue. However, the influence of menstrual cycle phases on ADC values appears to be minimal.\n\nDespite these hormonal influences on absolute ADC values, the diagnostic performance of ADC in differentiating between benign and malignant lesions remains robust across different hormonal states. This suggests that DWI and ADC measurements continue to be valuable tools in breast cancer diagnosis, regardless of a woman's hormonal status.\n\nHowever, the review also highlights significant gaps in the current literature, including a lack of standardization in DWI protocols, limited longitudinal data, and an absence of studies directly correlating hormone levels with ADC values. Addressing these gaps in future research will be crucial for fully understanding the complex relationship between hormonal status and breast tissue diffusivity.\n\nAs DWI continues to gain importance in breast imaging, considering hormonal influences on ADC values will be essential for accurate interpretation of results and optimal clinical application. Future research should focus on large-scale, standardized studies and the development of hormone status-specific reference ranges for ADC values. These efforts will contribute to the refinement of DWI as a powerful tool in personalized breast cancer diagnosis and management.", "appendix": "Data availability statement\n\nNo data are associated with this article.\n\nReporting guidelines\n\nThe checklist is added in the repository in the link: Dkhar, Winniecia, 2024, “Hormonal Influences on ADC Values in Breast Tissues: A Scoping Review of DWI in Pre- and Post-menopausal Women”, https://doi.org/10.7910/DVN/WFX1DQ, Harvard Dataverse, V1 Winniecia et al. (2024)\n\n\nReferences\n\nWHO & World Health Organization: WHO. World Health Organization; 2024 [cited 2024 Jul 16]. Reference Source\n\nRavichandran S, Avantsa R: 3D Tomosynthesis Evaluation of Pixel Intensity Values of Breast Masses. Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics). 2021. Publisher Full Text\n\nO’Flynn EAM, Morgan VA, Giles SL, et al.: Diffusion weighted imaging of the normal breast: reproducibility of apparent diffusion coefficient measurements and variation with menstrual cycle and menopausal status. Eur. Radiol. 2012 Jul 26; 22(7): 1512–1518. PubMed Abstract \| Publisher Full Text\n\nIacconi C, Thakur SB, Dershaw DD, et al.: Impact of fibroglandular tissue and background parenchymal enhancement on diffusion weighted imaging of breast lesions. Eur. J. Radiol. 2014 Dec; 83(12): 2137–2143. PubMed Abstract \| Publisher Full Text\n\nShin S, Ko ES, Kim RB, et al.: Effect of menstrual cycle and menopausal status on apparent diffusion coefficient values and detectability of invasive ductal carcinoma on diffusion-weighted MRI. Breast Cancer Res. Treat. 2015 Feb 1; 149(3): 751–759. PubMed Abstract \| Publisher Full Text\n\nKim JY, Suh HB, Kang HJ, et al.: Apparent diffusion coefficient of breast cancer and normal fibroglandular tissue in diffusion-weighted imaging: the effects of menstrual cycle and menopausal status. Breast Cancer Res. Treat. 2016 May 18; 157(1): 31–40. PubMed Abstract \| Publisher Full Text\n\nFink KRT, Fink JR: Principles of Modern Neuroimaging. Principles of Neurological Surgery. Elsevier; 2018; p. 62–86.e2. Publisher Full Text\n\nJaved A, Lteif A: Development of the Human Breast. Semin. Plast. Surg. 2013 May 23; 27(01): 005–012. Publisher Full Text\n\nHorvat J v, Durando M, Milans S, et al.: Apparent diffusion coefficient mapping using diffusion-weighted mri: Impact of background parenchymal enhancement, amount of fibroglandular tissue and menopausal status on breast cancer diagnosis. Eur. Radiol. 2018 Jan 12; 28(6): 2516–2524. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKim JY, Suh HB, Kang HJ, et al.: Apparent diffusion coefficient of breast cancer and normal fibroglandular tissue in diffusion-weighted imaging: the effects of menstrual cycle and menopausal status. Breast Cancer Res. Treat. 2016 May 1; 157(1): 31–40. PubMed Abstract \| Publisher Full Text\n\nShin S, Ko ES, Kim RB, et al.: Effect of menstrual cycle and menopausal status on apparent diffusion coefficient values and detectability of invasive ductal carcinoma on diffusion-weighted MRI. Breast Cancer Res. Treat. 2015 Feb 1; 149(3): 751–759. PubMed Abstract \| Publisher Full Text\n\nIacconi C, Thakur SB, Dershaw DD, et al.: Impact of fibroglandular tissue and background parenchymal enhancement on diffusion weighted imaging of breast lesions. Eur. J. Radiol. 2014; 83(12): 2137–2143. PubMed Abstract \| Publisher Full Text\n\nO’Flynn EAM, Morgan VA, Giles SL, et al.: Diffusion weighted imaging of the normal breast: Reproducibility of apparent diffusion coefficient measurements and variation with menstrual cycle and menopausal status. Eur. Radiol. 2012 Jul; 22(7): 1512–1518. PubMed Abstract \| Publisher Full Text\n\nPartridge SC, Mckinnon GC, Henry RG, et al.: Menstrual Cycle Variation of Apparent Diffusion Coefficients Measured in the Normal Breast Using MRI. J. Magn. Reson. Imaging. 2001; 14: 433–438. PubMed Abstract \| Publisher Full Text\n\nDkhar W: Hormonal Influences on ADC Values in Breast Tissues: A Scoping Review of DWI in Pre- and Post-menopausal Women. Harvard Dataverse. 2024; V1. Publisher Full Text" }	[ { "id": "310441", "date": "09 Aug 2024", "name": "Manna Debnath", "expertise": [ "Reviewer Expertise Expert in Medical Imaging Technology (MRI)" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a scientifically sound scoping review. The author(s) have written extremely well. However, a few minor changes need to be addressed. Once these are included, the manuscript's quality will improve even further. Reviewers comment: 1. References are needed in the second paragraph of the introduction section. 2. Page No.3 References are needed on the line ‘While several studies have investigated this relationship, results have been inconsistent, and a comprehensive synthesis of the available evidence is lacking.’ 3. The introduction is well-written and properly highlights the research gaps. 4. In the study selection section, I suggest that the author include a statement on including or excluding full-text articles or abstracts. 5. The phases of the selection process are well written. 6. In the result section, paragraph 1, you stated that '5 studies were ultimately included for scoping review', yet in PRISMA flow diagram Figure 1, in the Included Section of the chart, the number of articles included for this scoping review is 6. Please confirm the mismatch between the included articles in the study. 7. In the PRISMA flow chart, please correct the sentence, ‘Study excluded N = 1 *Study was based on 3T MRI.’ 8. Page no. 7, 3.2.1 Menopausal status and ADC values; and Page no. 8, 3.2.2 Mensural cycle and ADC values. Both paragraphs have the same data. Without repeating the data, I suggest you change the heading to Mensural cycle, menopausal status, and ADC values. 9. Page 10, last paragraph: 'Future research'. I suggest fusing these lines on the next page, under the heading ‘Based on these limitations and the findings of this review, several directions for future research can be proposed’. 10. The conclusion is clearly written and shows that the hypothesis was proven correctly.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes", "responses": [ { "c_id": "12203", "date": "30 Aug 2024", "name": "Winniecia Dkhar", "role": "Author Response", "response": "Thank you for your valuable feedback on our scoping review. We appreciate your thoughtful comments and suggestions. Here is our response to each of your points: 1. We agreed and added appropriate references to the second paragraph of the introduction. 2. We included relevant references to support the statement about inconsistent results and lack of comprehensive synthesis. 3. Thank you for your positive feedback on the introduction. 4. We added a clear statement about the inclusion/exclusion of full-text articles and abstracts in the study selection section. 5. We appreciate your positive comment on the description of the selection process phases. 6. Thank you for catching this discrepancy. We corrected the text to match the PRISMA flow diagram, confirming that 6 studies were included in the final review. 7. We revised the sentence in the PRISMA flow chart as suggested. 8. We appreciated this suggestion and merged the two sections under a single heading \"Menstrual cycle, menopausal status, and ADC values\" to avoid repetition. 9. We had already implemented this suggestion by fusing the future research directions with the conclusion section. 10. Thank you for your positive feedback on the conclusion. We made all these revisions to improve the quality and clarity of our manuscript. We appreciate your thorough review and constructive comments, which have undoubtedly enhanced the overall quality of our scoping review." } ] } ]	1	https://f1000research.com/articles/13-857
https://f1000research.com/articles/14-127/v1	27 Jan 25	{ "type": "Research Article", "title": "An extension of Trust and TAM model with TPB in the adoption of digital payment: An empirical study in Vietnam", "authors": [ "Truong Tuan Linh", "Nguyen Thi Thanh Huyen", "Nguyen Thi Thanh Huyen" ], "abstract": "Background Digital payment systems are pivotal in the digital economy, relying on the interplay between internet technology and e-vendors. This study seeks to explore acceptance behaviors regarding digital payments by employing an extended version of the Trust and Technology Acceptance Model (TAM) and incorporating the Theory of Planned Behavior (TPB).\n\nMethods We conducted a qualitative analysis using interview data from 509 respondents and applied Structural Equation Modeling (SEM) to evaluate the relationships between key variables. The extended model allows for a comprehensive examination of both technological and trust-related factors influencing adoption.\n\nResults Our analysis revealed that all standardized path coefficients were positively significant, except for the path from perceived usefulness (PU) to attitude (ATT). The findings confirm that while digital payments are primarily driven by Internet and communication technologies, addressing trust-related issues is essential for enhancing user adoption. The TAM identifies perceived usefulness and perceived ease of use, alongside trust, as critical factors affecting behavioral intention. In the TPB framework, trust significantly impacts digital payment adoption through mediators such as attitude, perceived behavioral control, and subjective norm.\n\nConclusions This study enhances our understanding of the factors influencing digital payment adoption, emphasizing the need to address both technological and trust issues. The insights gained provide valuable recommendations for increasing the use of digital payment systems, particularly in the Northern mountainous regions of Vietnam, thereby fostering greater financial inclusion and economic growth.", "keywords": [ "acceptance behaviors", "C-TAM-TPB", "digital payment", "digital economy", "trust-related issues" ], "content": "1. Introduction\n\nThe transformative power of information technology has reshaped global lifestyles, particularly in communication, the trade of goods and services, and financial transactions. The rise of information and communication technology, along with the increasing online capabilities of devices, has significantly influenced modern life, driving a shift toward greater reliance on machines for decision-making. This transformation is not just a trend but a fundamental shift that is shaping the future of our society (Susanto et al., 2022). This has led to a dynamic transformation of the global payment system. It is evident in the shift from cash-based transactions to digital payment methods (Kabir et al., 2017).\n\nTransforming into a digital economy is both an objective and an urgent necessity for Vietnam as it continues to integrate more deeply into the international economy. A key focus of this transformation is the development of digital payments (DPs), which drives advancements in the national population database, e-government, electronic public services, e-commerce, and non-cash payments. The recent rapid and widespread growth of digital payments is a testament to the success of this digital transformation. However, this development also presents challenges that must be addressed with suitable solutions moving forward (Dao, 2023). As one of the emerging economies in Southeast Asia, Vietnam holds significant potential for the growth of digital payments. In 2021, the total transaction value of digital payments in Vietnam was estimated at $15 billion, with an anticipated annual growth rate of 15.7% through 2025 (PWC Vietnam, 2021).\n\nIn recent years, digital payments have rapidly developed in Vietnam. The COVID-19 pandemic has accelerated this trend, with many Vietnamese consumers increasingly opting for digital payment methods. Digital payments provide greater convenience than traditional payment methods, enabling users to complete transactions quickly, from any location, at any time, and reduce costs (Teng & Khong, 2021; Zhang et al., 2023). The adoption of digital payments is rapidly increasing among individuals, businesses, and public sector organizations (Kabir et al., 2017).\n\nSeveral studies have explored the factors that influence the adoption of digital payments. These studies typically utilize well-established frameworks, including the Theory of Reason of Action (TRA) (L. T. B. Diep, 2021), Technology Acceptance Model (TAM) (Davis,1989), the Unified Theory of Acceptance and Use of Technology (UTAUT), or its successor UTAUT2 (Ramayanti et al., 2024; Venkatesh et al., 2012). Susanto et al. (2022) and Kabir et al. (2017) researched 597 and 223 digital payment articles, respectively, found that TAM theory was the most widely used to analyze factors influencing intent and even the continuity of using digital payments. However, TAM does not include social factors and behavioral control that many studies have shown to influence users’ actual use of new technology significantly (Taylor & Todd, 1995a). Hence, the researchers proposed a C-TAM-TPB model by combining TPB model (Theory of Planned Behavior) and TAM model (Chih Chung, 2013; Lee, 2009; Poon et al., 2024; Taylor & Todd, 1995b; Wu & Chen, 2005).\n\nAs far as we know, there is limited research on digital payment adoption (DPA) in Vietnam. N. N. Dung et al.(2021) combined UTAUT, TAM, and TPB in their research and indicated that mobility, accessibility, compatibility, convenience, and personal innovation have impacted the intention to use mobile payments. Owning accounts with financial intermediaries positively influenced the use of mobile payments by using the logit regression model (Son et al., 2020). Based on the positive determinants from previous studies, L. T. B. Diep (2021) found a solid and conclusive relationship between perceived trust, technical protection, perceived security, and e-payment system retention. ECM (Expectation Confirmation Model) and TAM were employed in the study, and the results indicate that trust, in the context of satisfaction, significantly influences the intention of Vietnamese customers to continue using e-wallets (Thao & Ngoc, 2022).\n\nOur study will utilize an extended version of the Trust and TAM model, incorporating the TPB, to better understand the acceptance behavior toward adopting digital payments. We anticipate that this extension will enhance our ability to analyze the issue more effectively and offer valuable recommendations to boost the usage rate of digital payments in the Northern mountainous regions of Vietnam. The rest of the paper is structured as follows: Section 2 provides theoretical background. Section 3 outlines the methods. Section 4 presents empirical results. Section 5 focuses on discussing the main results and suggesting some implications. Finally, the authors conclude some limitations and raise potential areas for future research in Section 6.\n\n\n2. Theoretical background\n\nAlthough digital payment is a specific component of the digital economy, its adoption fundamentally involves the interplay between internet technology and e-vendors in delivering services. The trust and Technology Acceptance Model (TAM) developed by Gefen et al. (2003) has been extensively studied in online shopping contexts. It demonstrates that comprehending both internet technology and trust issues is crucial for understanding behavioral intentions to use online shopping. Therefore, adopting digital payment can be influenced by various potential antecedents, including individual factors, organizational members, and social systems.\n\nPerceived usefulness\n\nPerceived usefulness, which reflects an individual’s strong belief in the benefits of technology, is considered a critical factor in enhancing performance (Davis, 1989; Taylor & Todd, 1995a). Digital payment systems are deemed useful for customers when they offer substantial services. Despite previous unsatisfactory experiences, customers are likely to continue using digital payment methods if they find them beneficial (Bhattacherjee, 2001; V. Van Diep, 2017). Perceived usefulness is the most frequently utilized independent variable in prior research for assessing people’s readiness to adopt DPs both at individual and organizational levels (Kabir et al., 2017). Therefore, we propose the following hypothesis:\n\nPerceived usefulness (PU) positively influences attitudes (ATT) towards adopting digital payments.\n\nPerceived usefulness (PU) positively influences user digital payments adoption (DPA).\n\nPerceived ease of use\n\nPerceived ease of use is defined as “the degree to which an individual believes that using a particular system would be free of effort” (Davis, 1989). Innovative technology systems that are perceived as easier to use and less complex are more likely to gain acceptance and be adopted by users. Digital payment systems are perceived as easy to use when users find them simple to understand, quick to learn, and straightforward to operate. As a result, perceived ease of use is recognized as a critical factor influencing users’ acceptance and adoption of new technology (V. Van Diep, 2017; Kabir et al., 2017; Tavera-Mesías et al., 2023). Additionally, a more vital perception of ease of use can enhance consumer confidence in the expected benefits of using technological products (Daragmeh et al., 2021; Doanh et al., 2022). Accordingly, we propose the following hypothesis:\n\nPerceived ease of use (PEU) positively influences attitudes (ATT) towards adopting digital payments.\n\nPerceived ease of use (PEU) positively influences perceived usefulness (PU) towards adopting digital payments.\n\n2.2.1 Attitude\n\nAttitude refers to an individual’s favorable or unfavorable feelings about engaging in a particular behavior (Davis, 1989; Taylor & Todd, 1995a). Additionally, a positive or negative attitude directly impacts the strength of behavioral beliefs regarding the anticipated significant outcomes (Wu & Chen, 2005). Therefore, it is more likely for customers to take action to use digital payments if they develop a positive opinion about the adoption of a digital payment method. In line with the above argument, we propose the following hypothesis:\n\nAttitude (ATT) positively influences user digital payments adoption (DPA).\n\n2.2.2 Perceived behavioral control\n\nPerceived behavioral control represents an individual’s perception of the ease or difficulty involved in carrying out a particular behavior. It relates to beliefs about the presence of factors that may either facilitate or obstruct the performance of the behavior (Ajzen, 1991, 2002; Rachmawati & Rahardi, 2023). In the context of digital payments, perceived behavioral control refers to a consumer’s perception of having the necessary resources, knowledge, and opportunities to adopt digital payment methods. We propose the following hypothesis:\n\nPerceived behavioral control (PBC) positively influences user digital payments adoption (DPA).\n\n2.2.3 Subjective norm\n\nSubjective norm refers to an individual’s perception of social pressure to either engage in or refrain from a particular behavior (Ajzen, 1991). In other words, subjective norm relates to an individual’s normative beliefs about the expectations of others (Rachmawati & Rahardi, 2023; Wu & Chen, 2005). In our study, subjective norm is defined as consumers’ beliefs about the influence that someone important to them may have on their decision to adopt digital payment methods. Based on this, we propose the following hypothesis:\n\nSubjective norm (SN) positively influences user digital payments adoption (DPA).\n\nTrust is the confidence one party has in the intentions and actions of the other party (Aldaabseh & Aljarah, 2021; Siagian et al., 2022). Trust often encompasses three key dimensions: ability, integrity, and benevolence (Benamati et al., 2010). Ability refers to the knowledge and skills required of digital payment service providers to fulfill their tasks effectively. Integrity signifies that these providers consistently keep their promises, while benevolence indicates that they genuinely care about the users’ interests, not just their own. Trust will be a crucial potential influencer in examining the adoption of digital payments. In exploring the factors influencing digital payment adoption, we refer to the relationships depicted in Figure 1, which presents the conceptual framework guiding our analysis. This framework emphasizes the interplay between technological acceptance and trust\n\n2.3.1 Trust and TAM relationship\n\nThe relationship between PU, PEU, and trust has been widely discussed in the literature (Gefen, 2004; Gefen et al., 2003; Pavlou, 2003). Wu & Chen (2005) followed Gefen et al. (2003) suggest a model of trust and TAM for the initial adoption of online tax. It shows that trust is an antecedent of PU, and PEU is an antecedent of trust.\n\nIn line with social cognitive theory, perceived ease of use (PEU) can generally be argued to positively impact a person’s favorable expectations regarding accepting innovative technology (Bandura, 1986). This is because cognition-based trust is primarily founded on initial impressions of behavior. In the context of online services, PEU represents the initial feeling or expectation that influences further online transactions (Wu & Chen, 2005). PEU is hypothesized to positively influence trust because it helps foster a favorable impression of e-vendors during the initial adoption of online services. This positive impression can make customers more willing to invest in and commit to the buyer-seller relationship (Gefen et al., 2003; Wu & Chen, 2005). In line with the above argument, we propose the following hypothesis:\n\nPerceived ease of use (PEU) positively influences Trust (TR) towards adopting digital payments.\n\nTrust is a key determinant of perceived usefulness, particularly in the digital payments environment, as it assures consumers that they will experience the expected benefits from service providers. In addition, trust is recognized to positively influence PU because it allows consumers to feel comfortable being vulnerable with e-vendors, ensuring they receive the expected value from their interactions and services (Pavlou, 2003). When consumers initially trust their e-vendors and perceive that adopting an online tax will enhance their job performance, they are more likely to believe that the online tax is beneficial (Wu & Chen, 2005). Hence, we propose the following hypothesis:\n\nTrust (TR) positively influences perceived usefulness (PU) towards adopting digital payments.\n\n2.3.2 Trust and TPB relationship\n\nThe relationship between trust and TPB can be explored from various perspectives. Trust is hypothesized as a common antecedent influencing attitude, perceived behavioral control, and subjective norm.\n\nTrust in an e-vendor is considered a significant behavioral belief that directly influences a customer’s attitude toward purchasing behavior. When an e-vendor is perceived as trustworthy, it increases the likelihood that the consumer will benefit from and avoid potential risks associated with adopting online services (Pavlou, 2003). Many previous studies have shown a positive relationship between trust and attitude (Agag & El-Masry, 2016; Chawla & Joshi, 2019; Wu & Chen, 2005). Trust is clearly a crucial factor influencing attitudes toward adopting digital payment behavior. Thus, the following hypothesis is proposed:\n\nTrust (TR) positively influences attitude (ATT) towards adopting digital payments.\n\nTrust can strengthen perceived behavioral control in online transactions by making the interactions between customers and e-vendors more predictable and consistent (Pavlou, 2003). Trust impacts perceived behavioral control by bolstering self-efficacy and fostering conditions that facilitate successful interactions (Wu & Chen, 2005). When customers trust a digital payment provider that meets their expectations, this trust is likely to enhance their perceived behavioral control over digital payment transactions. Based on the preceding arguments, the hypothesis can be stated as follows:\n\nTrust (TR) positively influences perceived behavioral control (PBC) toward adopting digital payments.\n\nPeer and superior influences shape users’ subjective norms concerning IT usage. Consequently, it can be inferred that trust in peers and superiors concerning their beliefs about IT usage should play a significant role in shaping subjective norms (Taylor & Todd, 1995a). Similarly, trust in e-vendors, particularly regarding their reputation, brand name, and service quality, may positively influence subjective norms related to online transaction behavior (Wu & Chen, 2005). Therefore, whether trust exerts direct or indirect influences on subjective norms remains a crucial antecedent of subjective norms in digital payments. Hence, we propose the following hypothesis:\n\nTrust (TR) positively influences subjective norms (SN) toward adopting digital payments.\n\n\n3. Methods\n\nThis study utilized both quantitative and qualitative research across four phases to explore the factors influencing digital payment adoption in Vietnam’s northern mountainous region. The survey scales were developed based on theoretical frameworks and relevant literature, with input from experts in fintech and e-commerce to ensure content validity. A pilot test with 100 participants from Thai Nguyen and Cao Bang helped refine the questionnaire. The primary survey was conducted in Lang Son and Cao Bang provinces from December 2023 to January 2024. These provinces were chosen to explore the factors limiting digital payment adoption, particularly in rural areas, as part of a broader investigation into the challenges of digital payment adoption in the northern mountainous region of Vietnam.\n\nFollowing the sample size guidelines from Hair et al. (2019), we aimed for at least 140 participants, with the final sample comprising 800 respondents evenly split between the two provinces. Participants were informed about the study and provided consent before the interviews. Each respondent received a small gift valued at approximately $2 to encourage participation. Of the initial surveys, 509 were valid, yielding a 63.63% response rate. Participants provided personal information, including their name, address, age, education, income, and occupation, which interviewers recorded. The interviewees reviewed their responses and confirmed their accuracy by signing the survey form. Afterward, they signed a summary information table and received a gift from the project.\n\nStructural Equation Modeling (SEM) is a second-generation statistical analysis technique designed to examine multidimensional relationships between multiple variables within a model (Anderson et al., 2004). SEM has been widely utilized across various fields, including sociology (Lavee, 1988; Lorence & Mortimer, 1985), psychology (Anderson et al., 2004), and management (Tharenou et al., 1994).\n\nThe complex theoretical model created using this method is generally associated with the data collected for validation purposes. This association is known as model-data fit. Any theoretical model can be evaluated using available empirical data for this type of fit. SEM is recognized as an extensive sample method, usually necessitating a minimum sample size of 200 (Dash & Paul, 2021; Hayes et al., 2017). There are two primary models: the path analysis and the measurement model. While some advanced models, such as multilevel and growth models, are also considered, this study will focus on i) the measurement model and ii) path analysis.\n\nBefore examining the path analysis among latent variables (also called factors or constructs), we first assess the measurement of these unobserved variables. Since these variables are not directly observable, they are represented through a set of measured variables from which the latent constructs are derived. Each latent variable is quantified using observed indicators tested for reliability and validity. SEM uses Confirmatory Factor Analysis (CFA) to evaluate the measurement model. In this case, the model fit is assessed to validate the measurement model. Once the model fit is confirmed, path models among the latent variables are evaluated (Hair et al., 2019; Hayes et al., 2017). In our research, before employing SEM, we followed the recommendations of Doanh et al. (2024) and Huy et al. (2024) by conducting exploratory factor analysis (EFA) to identify latent variables. EFA aims to uncover the latent constructs underlying a set of observed variables. EFA is used when the research goal is to determine the nature and number of common factors among these variables (Omura et al., 2022). Subsequently, we performed confirmatory factor analysis (CFA) by examining factor loadings, composite reliability (CR) indexes (Joreskog et al., 1971), and average variance extracted (AVE). While not a parameter estimate, AVE helps evaluate how much of the variance in indicators is explained by the latent factor. Calculated using factor loadings and residual error variances for a latent factor, AVE values of 0.50 or higher are generally acceptable. Composite Reliability (CR), like AVE, is not a parameter estimate but is valuable for interpreting the CFA model. Generally, CR values of 0.70 or higher are considered acceptable; however, values between 0.60 and 0.70 may indicate questionable reliability but are not necessarily unacceptable (Fornell & Larcker, 1981; Joreskog et al., 1971). This methodology, commonly referenced in the literature, rigorously assesses our research constructs and ensures the validity and reliability of our findings.\n\nThe path model is a form of multiple regression model estimated simultaneously, illustrating mediation, moderation, and interaction effects among variables. It defines the structural relationships between latent variables based on their associations with observed indicators (measured variables). Once the measurement models of latent constructs are validated through CFA, these paths can be interpreted as causal or covariance-based. It can assess the unidimensionality, validity, and reliability of an unobserved latent construct (factor) (Dash & Paul, 2021; Hair et al., 2019).\n\nSome of the fit indices in the SEM model are used to test and compare models, such as Chi-square, Comparative fit index (CFI), Tucker–Lewis Index (TLI), and Root mean squared error of approximation (RMSEA). Overall model fit is evaluated using the chi-square statistic, which reflects the discrepancy between the sample data and the model’s specified covariance matrices. This statistic is widely regarded as an indicator of model fit quality, with a non-significant value at the 0.05 level being preferable. Additionally, the chi-square to degrees of freedom ratio (CMIN/df ) provides a more straightforward assessment, with a value of 3 or less (sometimes up to 5) typically indicating a good fit. The Comparative Fit Index (CFI) is an incremental fit index that compares the focal model to a baseline model, often called the null or independent model. CFI tends to be less affected by sample size than the chi-square test. A CFI value of 0.95 or above typically signifies a good fit to the data, although some may consider a threshold of 0.90 acceptable. The Tucker-Lewis Index (TLI) is a comparative or incremental fit index. Generally, a TLI value of 0.95 or higher indicates a good model fit to the data, though some guidelines permit a lower cutoff of 0.90. The Root Mean Square Error of Approximation (RMSEA) is an absolute fit index that penalizes model complexity, favoring more parsimonious models. Generally, an RMSEA value of 0.06 or lower indicates a good fit to the data, although some guidelines may relax this threshold to 0.08 or even 0.10 (Bagozzi & Yi, 1988; Dash & Paul, 2021).\n\nWe selected SEM as the analysis method for this study due to its robustness in testing theories, as highlighted by Steenkamp & Baumgartner (2000). This makes SEM particularly suited to our research focus. Our research model encompasses multidimensional constructs that are not directly observable but are measured through observable indicators. Thus, SEM, which emphasizes construct operationalization (Bagozzi, 1994), is an appropriate and practical approach for our investigation. Furthermore, our application of SEM is consistent with prior research (Thongsri et al., 2019).\n\nFollowed Fan et al. (2016); Kline (2018), we deploy SEM, which consists of five main steps: model specification, identification, parameter estimation, model evaluation, and model modification. The model specification defines hypothesized relationships among variables based on prior knowledge, while model identification checks if the model is over-identified, just-identified, or under-identified, as coefficients can only be estimated in just-identified or over-identified models. Parameter estimation then calculates these coefficients. The model evaluation assesses how well the model fits using quantitative indices to measure the overall goodness of fit. If necessary, model modification adjusts the model to improve fit, often in a post hoc fashion. Finally, validation enhances the model’s reliability and stability. In our study, SEM analysis was conducted using JASP (https://jasp-stats.org/).\n\nTable 1 presents the demographic features of the respondents to the survey. According to the study’s gender review, 42.6% are male, and 57.4% are female. Most respondents are between the ages of 31 and 40 (229 individuals, accounting for 45%), followed by the age range of 41 to 50 years (143 individuals, accounting for 28.1%). In terms of culture, the majority are ethnic minorities such as Tay and Nung, accounting for 78.2%, while the remaining belong to the Kinh and other groups. Regarding educational level, most interviewers had completed college or university degrees, accounting for 56.7%, followed by those who graduated high school (24.6%). Those with education levels below secondary school and secondary school constituted a small proportion (10.4%). Most families have 4 to 5 members, accounting for 61.1%. The average monthly income of people is meager; the number with income equal to or greater than 5 million VND/month accounts for only 29.1%, and the rest all have income below 5 million. One of the reasons is that their primary income comes from their profession, in which data shows that 44.6% are purely farmers, the remaining 55.4% are workers working away from home, and commune-level civil servants.\n\n\n4. Results\n\nBefore proceeding with SEM model testing to evaluate the hypotheses, we conducted EFA and CFA to assess the variables’ construct and confirm the reliability and validity of the measurement model. Table 2 shows that the total Cronbach’s alpha is 0.938 greater than 0.6, and all observed variables have Cronbach’s alpha coefficients ≥ 0.935. The results also indicate that seven variables were extracted from 30 observed factors; the eigenvalue value is 1.053 (>1) with a variance of 71.62%. The results of the EFA in Table 2 show that the factor loadings of the items ranged from 0.661 to 0.853, and the construct of items is consistent with the literature. The test coefficient KMO = 0.916 satisfies the 0.5 < KMO< 1, showing that the exploratory factor analysis is appropriate for our data. The Chi-square statistic of the Bartlett test reached 9630.515, with the p-value = 0.000, showing that the data is suitable and reliable for performing the EFA method.\n\nCFA allows for testing the validity and accuracy of specific models constructed based on data and theoretical foundations. We assess the goodness-of-fit of the measurement model using various tests, including the Chi-square test (χ2), Comparative fit index (CFI), Tucker–Lewis Index (TLI), and Root mean squared error of approximation (RMSEA), composite reliability (CR) and the average variance extracted (AVE). As shown in Table 3, the composite reliability (CR) of latent variables exceeds 0.836, and the AVE values range from 0.560 to 0.687. In addition, the results indicate that the measurement model exhibits favorable fit index values (χ2/df = 2.486, CFI = 0.943, TLI = 0.931, RMSEA = 0.05, SRMR = 0.03). These findings support our proposed model’s suitability, reliability, and validity; the data exhibit a good model fit.\n\nTable 4 and Figure 2 present the model’s estimation results using the SEM method. The assessment revealed favorable fit index values: χ2/df = 3.014, CFI = 0.909; TLI = 0.895, RMSEA = 0.06, SRMR= 0.05. These results indicate that the empirical findings are reliable and valid.\n\nAs a result, all hypotheses are positive and statistically significant at the 1% level. It means that all hypotheses are supported.\n\nIt is crucial to emphasize the importance of addressing the Skewness-Kurtosis test. To tackle this issue, we consulted the studies by Barnes et al. (2001) and Vieira (2011). Additionally, following the recommendation of Diamantopoulos & Siguaw (2000) we conducted a model cross-validation analysis.\n\nOur analysis used multivariate normality tests, such as the Mardia mSkewness and Mardia mKurtosis tests, to evaluate our model’s performance. The findings reveal that our model satisfied the criteria set by both the mKurtosis and mKurtosis tests. This means that our research model is appropriate for maximum likelihood (ML) estimation and demonstrates a good fit.\n\n\n5. Discussion\n\nThis study aims to utilize an extended version of the Trust and TAM model, incorporating the TPB, to better understand the acceptance behavior toward adopting digital payments in the Northern mountainous area of Vietnam. The empirical results from the SEM model reveal that the standardized path coefficients are all positively significant except for the path from PU to ATT.\n\n5.1.1 TAM model\n\nPerceived usefulness (PU) negatively influences attitudes (ATT) towards adopting digital payments at the 5% level, as supported by the standard regression coefficient value of -0.131. Therefore, the hypothesis H1 has been rejected. This result contrasts previous studies (Ariffin et al., 2021; Chawla & Joshi, 2019; Mabkhot et al., 2023; Ranpariya & Joshi, 2024; Wu & Chen, 2005). This indicates that users do not feel digital payments are useful. This may come from their daily habits of using cash instead of digital payment methods. Therefore, it is essential to keep expanding the spread of information and communication regarding the practical advantages of digital and cashless payments. Additionally, implementing safeguards and strict measures to prevent fraud and property theft on online platforms is equally important.\n\nOur results also show the positive influence of perceived usefulness (PU) at the 1% significance level on DPA, thereby supporting H9. Conclusively, the results obtained are supported by the results of previous studies (Aji et al., 2020; Chawla & Joshi, 2019; Nguyen & Ao, 2022; Ranpariya & Joshi, 2024; Siagian et al., 2022). This means that when consumers achieve significant benefits from digital payment systems, they will trust DP more and continue to use it. Therefore, service providers should focus on further developing and improving the quality of DP to increase customers’ perception of its usefulness. This will help increase the number of users adopting DPs.\n\nThe findings of H2 align with previous studies, showing that perceived usefulness positively and significantly influences users’ attitudes toward using digital payment (Ariffin et al., 2021; Mabkhot et al., 2023); however, in contrary to Chawla & Joshi (2019). This study’s findings indicate that consumers found it easy to conduct payment transactions using a digital payment system. The system not only streamlined their payment processing but also enhanced their transaction efficiency, leading to a positive attitude toward adopting digital payments.\n\nFurthermore, the finding of H3 is consistent with previous research, which demonstrated that perceived ease of use positively and significantly influences perceived usefulness at the 1% level (Aji et al., 2020; Chawla & Joshi, 2019; Ranpariya & Joshi, 2024; Siagian et al., 2022; Wu & Chen, 2005). It proved that perceived ease of use increases the perceived usefulness of adopting digital payments. Therefore, service providers should focus on further developing and improving their payment system to be simpler to understand, quick to learn, and straightforward to operate digital payment services.\n\n5.1.2 TPB model\n\nAttitude (ATT) was also determined to impact DPA at the 1% significance level positively; hence, hypothesis H10 is supported. It means that customers have a positive opinion about adopting digital payment methods. This study is also in accordance with the results of research by Ariffin & Lim (2020); Ayudya & Wibowo (2018); Chawla & Joshi (2019); Ranpariya & Joshi (2024).\n\nPerceived behavioral control (PBC) is supposed to positively affect the use of DP at the 1% level. This hypothesis is supported by the value of the standard regression coefficient (0.178). Therefore, the acceptance of hypothesis H11 has been verified. This finding reveals that consumers nowadays have enough resources, knowledge, and opportunities to adopt a digital payment method. This result was consistent with the results of Ariffin et al. (2021); Ariffin & Lim (2020); Ayudya & Wibowo (2018); Mabkhot et al. (2023).\n\nSimilarly, subjective norm (SN) also positively impacts users’ adoption of digital payments at the 1% significance level. Hence, hypothesis H12 is supported. The result aligns with the viewpoints of Aji et al. (2020); Ariffin et al. (2021); Jusoh & Jing (2019) but not consistent with Ayudya & Wibowo (2018). This insight demonstrates that people’s willingness to adopt digital payments as a new mode of transaction is significantly influenced by their peers’ opinions and behaviors. Reliable information from trusted sources like relatives, neighbors, or friends boosts consumers’ trust in digital payment methods, leading to a stronger intention to adopt them.\n\n5.1.3 Trust and TAM relationship\n\nPerceived ease of use (PEU) is found to positively and significantly influence trust (TR) towards adopting digital payments, and hypothesis H4 is supported. The result in light of the previous studies, which also showed the importance of PEU in enhancing user trust (Chawla & Joshi, 2019; Gefen et al., 2003; Wu & Chen, 2005). It reveals that consumers had a favorable impression of e-vendors and trust when using digital payment transactions.\n\nMoreover, trust (TR) positively impacts perceived usefulness (PU). This relationship was proved by the value of the standard regression coefficient of 0.478 at the 1% significant level. Hence, the hypothesis H5 is supported. It confirmed that consumers feel comfortable being vulnerable with digital payment service providers and can receive the expected value from their actions and services. Then, they will adopt more and more digital payment methods for their daily buy and sell activities. Previous studies support this result (Gefen et al., 2003; Wu & Chen, 2005).\n\n5.1.4 Trust and TPB relationship\n\nOur research findings corroborate those of (Ariffin & Lim, 2020; Wu & Chen, 2005), who similarly suggested that trust (TR) positively influences attitude (ATT) towards adopting digital payments, with a coefficient of 0.751 and a p-value of 0.000. Based on these findings, the hypothesis H6 is confirmed. This supports the previous findings on trust and attitude, showing that when consumers believe in the services and information of e-vendors, they will increase the likelihood of adopting digital payment methods.\n\nThe positive significance of H7 proves that trust (TR) boosts perceived behavioral control (PBC) in online transactions by making interactions between customers and e-vendors more stable and predictable. This result is consistent with the studies of Ariffin & Lim (2020); Wu & Chen (2005). It confirms that when customers trust a digital payment provider that fulfills their expectations, this trust will likely increase their perceived control over digital payment transactions.\n\nNotably, the results have highlighted the significant role of trust (TR) in influencing subjective norm (SN) toward adopting digital payments. This trust has a positive impact on subjective norm, with a coefficient of 0.821 and a p-value of 0.000. This result is not in line with research conducted by Ariffin & Lim (2020) but consistent with Wu & Chen (2005). It shows that customers in this region had trust in e-vendors, particularly in terms of their reputation, brand recognition, and service quality, which may positively affect subjective norm related to digital payment transaction behavior.\n\nAmong the control variables, the results show that age is not statistically significant, suggesting that there is no difference in the adoption of DPs based on the respondents’ age. Education is found to have a positive significance with DPA at a 10% level and in light with Cao et al. (2018). It proves that users with higher education levels are more likely to use DP systems to transfer money, shop, and pay for utility services.\n\nThe previous body of literature concerning intentions to adopt digital payments has primarily relied on established theories such as TRA, TAM, TPB, UTAUT, and UTATU2 (Kabir et al., 2017; Susanto et al., 2022). In line with this existing research, the analysis in this study makes a noteworthy contribution to the existing literature by extending the version of the Trust and TAM model, incorporating the TPB, to better understand the acceptance behavior toward adopting digital payments. Our empirical findings indicate that only the standardized path coefficient from PU to ATT is negative, while others are all positively significant. These findings improve our capacity to analyze the issue more effectively and provide valuable recommendations to increase the adoption of digital payments in the Northern mountainous regions of Vietnam.\n\nWhile digital payments are primarily enabled by Internet and communication technologies, this study highlights the importance of addressing both technological and trust-related issues to enhance citizens’ decision to use these services. The Technology Acceptance Model (TAM) identifies perceived usefulness (PU) and perceived ease of use (PEU) alongside trust as critical factors influencing behavioral intention. Each factor significantly affects adoption through mediators such as attitude, perceived behavioral control, and subjective norms.\n\nCareful attention must be given to both technological design and trust components to encourage citizens to adopt digital payments. Additionally, as noted earlier, novice users tend to prioritize trust in non-technological aspects over PEU and usefulness when forming their attitudes. This suggests that trust is more critical in shaping a user’s attitude toward digital payments than the technology’s perceived ease of use or usefulness. Major trust concerns include privacy protection, accuracy of information, and unauthorized access, among others.\n\nFundamentally, trust has been empirically identified as a precursor to perceived usefulness (PU), which in turn influences attitude. This has important practical implications for improving attitudes toward digital payments. Providers of digital payment services should focus on developing trust-building mechanisms to attract novice users. Examples of such mechanisms include guarantees, increased familiarity through advertising, reliable customer service, and incentives for usage.\n\nOnce trust is established, enhancing the perceived usefulness of digital payments becomes crucial for attracting new users. This requires careful design aligning with users’ needs to communicate the service’s benefits effectively. Without initially addressing trust, even a well-designed digital payment system with high perceived usefulness may struggle to engage novice users.\n\nWhile this study enhances the existing literature by integrating multiple models to examine users’ adoption of digital payments, it is essential to acknowledge its limitations. First, we used perceived usefulness to capture the overall benefits of digital payments for users. However, these benefits should be distinguished between economic and non-economic aspects, such as user satisfaction and service quality. Second, the number of farmers with low levels of education is less than that of others working away from home and commune-level civil servants. Farmers with low levels of education may be less likely to have adequate information to trust and adopt digital payment methods than cash. Therefore, future research should explore the impact of adopting digital payments on farmer income.\n\n\n6. Conclusion\n\nThe aim of this research is to propose an extended model that integrates Trust and the Technology Acceptance Model (TAM) with the Theory of Planned Behavior (TPB) to predict user adoption of digital payment methods more comprehensively. An extensive survey of digital payment users was conducted to test this research model empirically. As previously discussed, several new findings emerged regarding the roles of Trust, TAM, and TPB in digital payment adoption. The empirical results from the SEM indicate that all standardized path coefficients are positively significant, with the exception of the path from perceived usefulness to attitude. These findings carry significant implications for both practitioners and researchers.\n\n\nEthics and consent\n\nThere was no ethics or institutional committee at Phenikaa University when this study was conducted. Our university published Decision No. 498/QĐ-ĐHP-KHCN of the Rector on promulgating the Regulations on ethical standards and integrity in scientific and technological activities of Phenikaa University on 30th October 2020. It is a rule for all researchers and lecturers to create a healthy and professional research environment, ensuring standards and integrity in scientific research and in accordance with international practices. Our university has a medical ethics committee for the health sciences, but this committee has not yet been established for the social sciences and humanities. We have also recommended the establishment of a research ethics committee for our leaders.\n\nIn our research, we follow the best ethical practices. All respondents were asked for their permission, and the details of the questionnaires were explained before answering. The survey form was designed based on previous studies and checked carefully by colleagues and experts. The questions focus on two main parts: personal information and respondents’ perceptions of digital payments. The collected data is only used for the authors’ research purposes. Therefore, this study is low-risk in nature.\n\nInformed consent for participation was obtained through written forms. Respondents were asked to provide personal information, including their name, address, age, education level, income, and occupation, which the interviewers recorded on the survey forms. Finally, participants reviewed their answers for accuracy and signed both the survey form and a receipt for the gift. We collected and stored written consent from all the participants.\n\n\nAuthor contributions\n\nTruong Tuan Linh suggested ideas and wrote the “Introduction,” “Theoretical background”, “Methods” and “Conclusion” sections. Nguyen Thi Thanh Huyen wrote the “Empirical results” and “Discussion” sections.", "appendix": "Data availability\n\nReshare: Analysis of Factors Influencing the Use of Electronic Payment Methods in Consumer Behavior Among Households in the Northern Mountainous Region, Vietnam. https://reshare.ukdataservice.ac.uk/857466/.\n\nDOI: 10.5255/UKDA-SN-857466\n\nThe project contains the following underlying data:\n\n- An Extension of Trust and TAM Model with TPB in the Adoption of Digital Payment.xlsx\n\n- Readme_An Extension of Trust and TAM Model with TPB in the Adoption of Digital Paymen.docx\n\nAn Extension of Trust and Technology Acceptance Model with Theory of Planned Behavior in the Adoption of Digital Payment: An Empirical Study in Vietnam, 2023-2024\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nReshare: Analysis of Factors Influencing the Use of Electronic Payment Methods in Consumer Behavior Among Households in the Northern Mountainous Region, Vietnam. https://reshare.ukdataservice.ac.uk/857466/\n\nDOI: 10.5255/UKDA-SN-857466\n\nThe project contains the following extended data:\n\n- Consent form_An Extension of Trust and TAM Model with TPB in the Adoption of Digital Payment_English.docx\n\n- Data dictionary_An Extension of Trust and TAM Model with TPB in the Adoption of Digital Payment.xlsx\n\n- Survey Guidelines.docx\n\n- Summary table of survey information.docx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgment\n\nThe authors are grateful to the journal’s anonymous referees for their extremely useful suggestions to improve the quality of the article.\n\n\nReferences\n\nAgag G, El-Masry AA: Understanding consumer intention to participate in online travel community and effects on consumer intention to purchase travel online and WOM: An integration of innovation diffusion theory and TAM with trust. 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Reference Source\n\nRachmawati I, Rahardi RAM: Analysis of Electric Vehicle Purchase Intentions in Indonesia Using the Extension C-TAM-TPB Model. Int. J. Curr. Sci. Res. Rev. 2023; 06(12): 8065–8078. Publisher Full Text\n\nRamayanti R, Rachmawati NA, Azhar Z, et al.: Exploring intention and actual use in digital payments: A systematic review and roadmap for future research. Comput. Hum. Behav. Rep. 2024; 13: 100348. Publisher Full Text\n\nRanpariya T, Joshi A: Factors influencing cumsumer attitude and intentions towards using mobile wallet in India-An emperical study. Annals of the Bhandarkar Oriental Research Institute. 2024; CI(1).\n\nSiagian H, Tarigan ZJH, Basana SR, et al.: The effect of perceived security, perceived ease of use, and perceived usefulness on consumer behavioral intention through trust in digital payment platform. Int. J. Data Netw. Sci. 2022; 6(3): 861–874. Publisher Full Text\n\nSon TH, Liem NT, Khuong NV: Mobile money, financial inclusion and digital payment: The case of Vietnam. Int. J. Financ. Res. 2020; 11(1): 417–424. Publisher Full Text\n\nSteenkamp JBEM, Baumgartner H: On the use of structural equation models for marketing modeling. Int. J. Res. Mark. 2000; 17(2–3): 195–202. Publisher Full Text\n\nSusanto E, Solikin I, Purnomo BS: A Review of Digital Payment Adoption in Asia. Advanced International Journal of Business, Entrepreneurship and SMEs. 2022; 4(11): 01–15. Publisher Full Text\n\nTavera-Mesías JF, van Klyton A , Collazos AZ: Technology readiness, mobile payments and gender- a reflective-formative second order approach. Behav. Inform. Technol. 2023; 42(7): 1005–1023. Publisher Full Text\n\nTaylor S, Todd PA: Assessing IT usage: the role of prior experience. Manag. Inf. Syst. Q. 1995a; 19: 561–570. Publisher Full Text Reference Source\n\nTaylor S, Todd PA: Assessing IT usage: the role of prior experience. Manag. Inf. Syst. Q. 1995b; 19: 561–570. Publisher Full Text\n\nTeng S, Khong KW: Examining actual consumer usage of E-wallet: A case study of big data analytics. Comput. Hum. Behav. 2021; 121: 106778. Publisher Full Text\n\nThao HTP, Ngoc NK: Vietnamese customers’ intention to continue using e-wallets and the important role of trust. J. Asian Bus. Econ. Stud. 2022; 3: 79–97.\n\nTharenou P, Latimer S, Conroy D: How Do You Make It to the Top? An Examination of Influences on Women’s and Men’s Managerial Advancement. Acad. Manag. J. 1994; 37(4): 899–931. Publisher Full Text\n\nThongsri N, Shen L, Bao Y: Investigating factors affecting learner’s perception toward online learning: evidence from ClassStart application in Thailand. Behav. Inform. Technol. 2019; 38(12): 1243–1258. Publisher Full Text\n\nVenkatesh V, Thong JYL, Xu X: Consumer acceptance and use of information technology: Extending the unified theory of acceptance and use of technology. MIS Q.: Manag. Inf. Syst. 2012; 36(1): 157–178. Publisher Full Text\n\nVieira AL: Interactive LISREL in Practice. Heidelberg: Springer Berlin; 2011. Publisher Full Text\n\nWu IL, Chen JL: An extension of Trust and TAM model with TPB in the initial adoption of on-line tax: An empirical study. Int. J. Hum.-Comput. Stud. 2005; 62(6): 784–808. Publisher Full Text\n\nZhang Q, Ariffin SK, Richardson C, et al.: Influencing factors of customer loyalty in mobile payment: A consumption value perspective and the role of alternative attractiveness. J. Retail. Consum. Serv. 2023; 73: 103302. Publisher Full Text" }	[ { "id": "363010", "date": "04 Feb 2025", "name": "Mohammad Rakibul Islam Bhuiyan", "expertise": [ "Reviewer Expertise Cashless Society", "Digital Transformation", "Industry 4.0", "Emerging Technologies" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n1. Overall Evaluation:\nThe paper titled \"An extension of Trust and TAM model with TPB in the adoption of digital payment: An empirical study in Vietnam\" presents a timely and relevant study on digital payment adoption, with a particular focus on Vietnam. The study contributes to the body of knowledge by integrating the Trust Model, the Technology Acceptance Model (TAM), and the Theory of Planned Behavior (TPB) in a comprehensive framework. However, there are several areas where revisions are needed to improve the clarity, depth, and completeness of the research.\n2. Clarity and Precision of the Presentation:\nThe paper is generally well-written but could benefit from further refinement in some sections, particularly in the literature review and the interpretation of results. The connection between the theoretical models (Trust, TAM, TPB) could be more clearly articulated, specifically how they complement each other in the context of digital payment adoption. The introduction could also be expanded to better emphasize the research gap and the study’s contribution to the field.\n3. Literature Review and Citations:\nWhile the paper cites some foundational studies, it is noticeably lacking in recent references (2022-2025). The literature review should be updated to include more recent research on digital payment adoption, especially considering the rapidly evolving nature of the digital payment landscape. Relevant studies on the impact of trust, technology acceptance, and behavioral intentions in digital finance should be integrated to strengthen the paper’s theoretical foundation.\n4. Methodology and Analysis:\nThe methodology is generally sound, but more detail is needed to clarify certain aspects of the research design. For example, the sampling process and sample size justification should be provided more thoroughly. Additionally, the survey instrument used to collect data could benefit from a more detailed explanation of its validation process. The use of structural equation modeling (SEM) is appropriate, but the model could be more thoroughly explained, particularly with regard to the measurement model and the path coefficients.\n5. Statistical Analysis:\nThe statistical analysis is partly addressed, but there are areas for improvement. It would be helpful to provide more detailed explanations of how the validity and reliability of the constructs were assessed. Additionally, further discussion of the model fit indices and how they support the hypotheses would strengthen the analysis. A clearer discussion of the limitations of the model would also be beneficial.\n6. Contribution to the Field:\nThe paper makes a solid contribution to understanding digital payment adoption in Vietnam, but the proposed model’s novelty and value would be more apparent with some improvements in the literature review, methodology, and analysis sections. Once these issues are addressed, this paper could provide important insights into how trust, technology acceptance, and behavioral intentions influence digital payment adoption in emerging economies like Vietnam.\n7. Recommendations for Revision:\nLiterature Update: Add more recent citations (2022-2025) to reflect the latest developments in the digital payment domain. Methodology: Provide more details on the sampling procedure, sample size justification, and survey instrument validation. Statistical Analysis: Clarify the SEM approach, provide more details on model fit indices, and discuss how the statistical findings relate to the hypotheses. Theoretical Framework: Strengthen the explanation of how the integrated model (Trust, TAM, and TPB) contributes to the field of digital payment adoption, and clarify the relationships between the constructs.\nOnce the above points are addressed, this paper has the potential to contribute significantly to the literature on digital payment adoption, particularly in the context of developing countries like Vietnam.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] } ]	1	https://f1000research.com/articles/14-127
https://f1000research.com/articles/13-150/v1	01 Mar 24	{ "type": "Research Article", "title": "Waveform characteristics in thoracic paravertebral space: a prospective observational study", "authors": [ "Amorn Vijitpavan", "Sivaporn Termpornlert", "Pattika Subsoontorn", "Lalinthip Vareesunthorn", "Amorn Vijitpavan", "Pattika Subsoontorn", "Lalinthip Vareesunthorn" ], "abstract": "Background With increased use of thoracic paravertebral block (TPVB) in thoracic surgery, many faced the challenge of locating the thoracic paravertebral space (TPVS) ultrasonographically. This observational study aimed to investigate the waveform characteristics and pressure value within the TPVS in anaesthetized patients with controlled ventilation.\n\nMethods 50 patients scheduled for elective lung surgery were enrolled. After conduction of anesthesia, all patients underwent TPVB at T4/5 and T6/7 using transverse, in-plane ultrasound guidance. A pressure transducer system with a desktop monitor was connected to the needle hub to measure pressure values and waveform characteristics in three locations: the paraspinal muscles, immediately behind the superior costotransverse ligament, and within the TPVS. Next, 15 mL of 0.33% bupivacaine was injected into each desired TPVS. After completion of the surgery, the extent of dermatomal blockade and the pain score was assessed in all patients.\n\nResults 98 typical regular respiratory waveforms with a mean pressure of ≤ 25 mmHg were detected in the TPVS of 50 patients. The sensitivity of the combined ultrasound and pressure waveform measurement technique to identify the TPVS was 95.45% (95% confidence interval, 84.527–99.445). Nontypical respiratory waveforms were present in two patients. Factors interfering with the TPVS waveform characteristics were previous thoracic surgery and chronic pleural inflammation.\n\nConclusion The TPVS had low pressure and showed a smooth, regular waveform pattern corresponding to respiration.", "keywords": [ "Thoracic paravertebral block", "Respiratory waveform", "Pressure value", "Thoracic paravertebral space", "Observational study", "Ultrasound-guided" ], "content": "Introduction\n\nThoracic paravertebral block (TPVB) has become an increasingly popular technique for pain control after thoracic surgery through various approaches such as the anatomical-based technique.1 However, this technique has a failure rate of up to 10% and is associated with several potential adverse events: hypotension (4.6%), vascular puncture (3.8%), pleural puncture (1.1%), pneumothorax (0.5%), hematoma (1.9%), and epidural or spinal spread (1.1%)2 Identifying the thoracic paravertebral space (TPVS) is crucial in achieving success and preventing adverse events. Numerous methods have been proposed to locate the TPVS, such as the loss-of resistance technique,3 nerve stimulation,4–7 pressure measurement,8–10 and an acoustic signal.11 Ultrasound guidance is another approach for TPVB and was first introduced by Hara et al.12 for breast surgery. The evidence to date demonstrates that ultrasound-guided TPVB (UG-TPVB) is safe to perform in sedated and ventilated patients.13 Most anesthesiologists currently use ultrasound to locate the TPVS and needle path. Patnaik et al.14 reported that UG-TPVB resulted in a more successful block than the anatomical landmark technique (94% and 72%, respectively), although the complication rates were comparable (13.8% and 22.2%, respectively). Several approaches can be used for UG-TPVB, such as a parasagittal or transverse probe orientation and an in-plane or out-of-plane technique for needle visualization.15,16 However, the optimal UG-TPVB method remains unclear.15\n\nPractically, observation of the needle tip by ultrasound while simultaneously advancing the needle to the target area surrounded by the bone is challenging. The TPVS is a narrow channel adjacent to the lung and spinal canal, and the needle tip may be misplaced into a non-target area, causing block failure and complications.17 As the TPVS lies adjacent to the pleural space, we speculated that the characteristics of the respiratory waveform could be detected from the needle tip once it was located within the TPVS. Thus, this study aimed to observe waveform patterns and pressure values in the TPVS when performing UG-TPVB after the induction of general anesthesia with controlled ventilation.\n\n\nMethods\n\nThis prospective observational study was provided by the Ethics Committee of the Ramathibodi Hospital, Mahidol University, Bangkok, Thailand on 19th May 2020 (reference no. MURA2020/860). The protocol for this study was registered in the protocols.io repository (https://www.protocols.io/view/waveform-characteristics-in-thoracic-paravertebral-14egn3mxpl5d/v1).\n\nA total of 50 patients scheduled for elective lung surgery (open thoracotomy and video-assisted thoracoscopic surgery) were recruited during 9th February 2021 to 17th May 2021. Anesthesiology residents or fellows at Ramathibodi Hospital obtained preoperative information and provided informed consent. The inclusion criteria were an age of 18 to 80 years and an American Society of Anesthesiologists (ASA) physical status of I to III. The ASA physical status was defined as the following: ASA I is a normal healthy patient, ASA II is a patient with mild systemic disease, ASA III is a patient with severe systemic disease, ASA IV is a patient with severe systemic disease that is a constant threat to life, ASA V is a moribund patient who is not expected to survive without the operation.18\n\nThe exclusion criteria were no provision of informed consent, refusal to receive UG-TPVB, a body mass index of >35 kg/m2, significant thoracic kyphoscoliosis, coagulopathy (platelet count of <100,000 per mL or international normalized ratio of >1.4), allergies or contraindications to medications used in the study protocol, and refusal to participate or withdrawal of consent at any stage of the study.\n\nAll enrolled patients received standard protocol for elective lung surgery. They were fasted for at least eight hours before surgery. Standard ASA monitoring was performed throughout the surgery. Anesthesia was induced using propofol (2.0–2.5 mg/kg), fentanyl (1–2 mcg/kg), and cisatracurium (0.15–0.2 mg/kg) intravenously. Patients were intubated with left-sided double-lumen tubes. The anesthetized patient was placed in the lateral decubitus position with the operative site up for UG-TPVB. During UG-TPVB, both lungs were ventilated with continuous positive pressure ventilation (pressure-controlled mode with inspiratory pressure of 20 cmH2O, inspiratory time of 1 second, respiratory rate of 12 breaths per minute, and positive end-expiratory pressure of 5 cmH2O). Under sterile conditions, UG-TPVB was performed with a high-frequency linear transducer (12-MHz 9L-RS probe, GE Vivid IQ ultrasound machine; GE Healthcare, Chicago, IL, USA) by experienced operators using the transverse in-plane technique at the fourth and the fifth thoracic vertebrae (T4/5) and the sixth and the seventh thoracic vertebrae (T6/7) of the TPVS. The ultrasound probe was covered with a sterile plastic sleeve and placed on the back of the shoulder area. The operator identified the first rib and then counted downward until the fourth rib was reached. The probe was then moved inward to locate the fourth transverse process. The ultrasound probe was then dragged downward to locate the fifth transverse process and identify the location of the TPVS between T4 and T5, labelling the site with an indelible pen. The ultrasound probe was moved further downward to locate the sixth and seventh transverse processes and the TPVS was marked between T6 and T7.\n\nAn echogenic needle (SonoTAP; Pajunk GmbH Medizintechnologie, Geisingen, Germany) was connected to a pressure transducer system (TruWave PX260; Edwards Lifesciences, Irvine, CA, USA) via a three-way stopcock (Discofix 3SC; B. Braun, Melsungen, Germany) and a 36-inch noncompliant pressure tubing (Edwards Lifesciences). The pressure transducer was connected to a desktop monitor (IntelliVue MP70; Philips, Amsterdam, Netherlands) and levelled at the spinous process. The needle was then inserted at the skin approximately 3 cm from the midline and advanced laterally to medially under in-plane ultrasound visualization. We observed the mean pressure and waveform characteristics when the needle tip was in three locations (Figure 1).\n\n(A) Paraspinal muscle. (B) Immediately posterior to SCTL. (C) In TPVS.\n\nAbbreviation: SCTL, superior costotransverse ligament; TPVS, thoracic paravertebral space; dotted arrow represents the needle path.\n\nFirst, the tip of the needle was identified in the paraspinal muscles. Second, the needle tip was advanced immediately posterior to the superior costotransverse ligament (SCTL) and confirmed by a 1.0-mL normal saline injection. Third, the needle tip was located in the TPVS and confirmed by a 0.5- to 3.0-mL saline injection, which widened the TPVS and caused anterior displacement of the pleura.\n\nThe operator then slowly injected 15 mL 0.33% bupivacaine into each desired TPVS. The collected waveforms were classified into three patterns (A, B, and C) according to our pilot study and based on previous trials.8–11 The “A” waveform or typical waveform was defined as a smooth and regular sine wave resembling the respiratory pattern with a mean value of ≤ 25 mmHg; the “B” waveform was defined as an irregular coarse, wavy line; and the “C” waveform was defined as a tense, straight line. B and C waveforms were referred to as atypical waveform.\n\nThe attending anesthesiologists maintained anesthesia to achieve adequate anesthetic depth using 1:1 of air: oxygen, 2% sevoflurane, fentanyl, and cisatracurium. After completion of surgery, all patients were extubated and transferred to the postanesthetic care unit.\n\nThe objectives of this study encompassed the observation of thoracic paravertebral waveforms and pressure values in TPVS, as well as an assessment of the efficacy of UG-TPVB. This evaluation was accomplished by gauging the subjects’ Numeric Rating Scale (NRS) scores and the extent of dermatomal blockade, determined by pinprick sensation, once they regained full consciousness. An unsuccessful block was characterized as the inability to confirm more than three levels of dermatomal blockade, as per Eason and Wyatt’s criteria, or an NRS score at rest ≥3.3\n\nContinuous variables were presented as mean ± standard deviation or median ± range as appropriate after Shapiro-Wilk and Shapiro-Francia tests for normality. Categorical variables were presented as numbers and percentages. The quantile regression was applied to test the median difference between injection site, multiple comparison, thoracotomy group, and the difference between the median pressure values of T4/5 and T6/7 to estimate the sensitivity and positive predictive values. All statistical analysis was calculated by STATA 17 (StataCorp. 2021. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC; RRID: SCR_012763). The significance was set at p-value of < 0.05.\n\n\nResults\n\n50 patients were recruited between February 2021 and May 2021. Their demographic and perioperative data are summarized in Table 1.\n\nAll patients were extubated and assessed for dermatomal sensory blockade and NRS scores before discharge from the post-anaesthetic care unit. Compared with the pressure values at each position of the needle at both levels, the pressures in the TPVS were significantly different from the pressures from the paraspinal muscle and SCTL as shown in Table 2. The median pressure value in the TPVS of T4/5 was 17.0 (3.0, 47.0) mmHg, and that of T6/7 was 15.5 (8.0, 26.0) mmHg. There was significant difference in the pressure value between T4/5 and T6/7 (p < 0.001). The waveform characteristics were presented in Table 3 and Figure 2. The number B and C waveform were counted as an atypical waveform group; the intra-muscle and SCTL layers were combined together as non TPVS. When compared with the UG- TPVB, the sensitivity, specificity, positive and negative predictive value (PPV, NPV) and receiver operating characteristic (ROC) area of typical waveform to locate the TPVS were 98.0 (93.0, 99.8), 99.5 (97.2, 100.0), 99.0 (94.5, 100.0), 99.0 (96.5, 99.9), 99.8 (97.3, 100.0), respectively (Table 4).\n\n* P<0.05 (statistically significant).\n\n50 patients had 98 typical respiratory waveforms within the TPVS. The pressure values of the TPVS at T4/5 and T6/7 of 5 patients with redo-thoracotomy were 20.5 (18.0, 37.0) mmHg and 18.0 (4.0, 26.0) mmHg respectively with no significant differences between both levels. Two successful UG-TPVB showed an atypical waveform with a mean pressure of >25 mmHg. The sensitivity of the pressure value and waveform characteristics to identify TPVS was 95.45% (95% confidence interval, 84.527–99.445) when successful dermatomal blockade was used as reference (Table 4).\n\nNevertheless, six patients who underwent unsuccessful block exhibited typical respiratory waveforms in the TPVS. The specificity of the study was limited because none of the patients who underwent unsuccessful block showed an absent TPVS waveform.\n\nThe overall mean NRS scores for patients at rest was 2.52±2.32 (0–8) and on movement was 4.06±2.40 (0–10). Additionally, patients with redo thoracotomy and without redo thoracotomy at rest and on movement scored similarly with no significant difference (at rest: 4.6±2.97 (0-8) vs 2.29±2.16 (0-7) respectively, p = 0.164) (on movement: 6.4±2.61 vs 3.8±2.26 respectively, p = 0.164).\n\n\nDiscussion\n\nThere was a significant difference in the waveform characteristics and pressure values in the TPVS and the surrounding outer structures. As the needle passed through TPVS, the pressure monitoring showed that pressure values of T4/5 and T6/7 dropped to the lowest level which parallel to a sudden transition from a tense straight line (C -waveform) or irregular wave (B-waveform) to an “A” waveform that resembled to the respiratory waveforms corresponding to the ventilator’s setting. The apparent differences in the pressure values and waveform patterns in each position reflected the dynamic effect of the pressure transmitted from the thoracic cavity to the adjacent area such as the TVPS. The study showed that 96% of the subjects had similar respiratory-like waveform pattern in the TPVS. Thus, these differences in each position can be utilized to locate the TPVS during TPVB. The sensitivity, specificity and PPV of waveform to identify TPVS were 98% and 99.5%, 99%, respectively, when ultrasound was used as reference, Similarly, the sensitivity and PPV were 95.5%, 83.4%, respectively when successful dermatomal blockade was used as reference. Therefore, both pressure values and waveform characteristics can be applied as an adjunct to locate the TPVS.\n\nOn the contrary, Richardson et al. used a sudden pressure drop to identify the TPVS.8 The average pressure in the TPVS was 7.6 mmHg for mean expiratory pressure and 3.3 mmHg for inspiratory pressure, which were lower than the mean pressure derived from our study. As in our study, Okitsu et al. reported the pressure value (<30 mmHg) in the TPVS after induction of general anesthesia with the patients in the decubitus position which was close to our study (25 mmHg).9 The lower pressure value reported by Richardson et al. could be due to their subjects were spontaneously breathing, whereas in our study and Okitsu et al. performed in subjects who underwent positive pressure ventilation.8,9\n\nPrior insults to the pleura might influence the pressure and wave configuration in the TPVS. In this study, there were four patients with a history of ipsilateral thoracotomy, and two were diagnosed with empyema thoracis. However, these patients had a fairly high pressure in TPVS. They also had a relatively high NRS score with borderline statistical significance [at rest: 4.6±2.96 (p=0.07), during movement: 6.4±2.61 (p=0.05)] when compared with patients who had an innocent pleural lining. Although there were some discrepancies between the statistical significances for the pressure value at different locations of the two vertebral levels, the sample size of only four patients with redo-thoracotomy was insufficient to represent the pressure values at each location and its effect on pain control.\n\nInevitable adhesion formation and inflammation post-thoracotomy tends to alter or obliterate the TPVS.19 Cheema et al. reported that extrapleural adhesions and scar tissue after the previous thoracotomy may be technically more challenging.20 The disrupted pleura cannot contain the infused local anaesthetic agent, diminishing the analgesic efficacy of TPVB. A comparative study on the importance of pleural integrity for safe TPVB by Komatsu et al. showed that patients with a previous pleural tear required significantly more rescue medications on the first postoperative day.21\n\nThe waveform characteristics in patients who underwent redo-thoracotomy or empyema were almost identical to those in patients with normal pleura. Eleventh of the twelve waves from six patients had a typical respiratory waveform (“A” waveform) in the TPVS. The rest of the patients in redo-thoracotomy group had a regular respiratory-like waveform, but the mean pressure was >25 mmHg. Therefore, this study confirmed that the characteristics of the respiratory waveform can be used to identify TPVS, even, in patients with pleural disorder.\n\nOne patient with a history of redo-thoracotomy showed a pulsatile waveform synchronized with arterial pulsations. This event occurred when the needle tip was obscurely located immediately deep to the SCTL during ultrasound scanning. Similar to a patient with empyema thoracis, a pulsatile waveform also appeared as the needle tip moved into the TPVS. None of the patients showed signs of widening or anterior displacement of the pleura after testing with saline injection and arterial puncture was ruled out by blood aspiration. Compared with the specific pulsatile waveforms in the epidural space produced by previous analysis studies, we deduced that the needle tip may have been in the epidural space and the respiratory waveform was displayed after repositioning of the needle path.22,23 Therefore, patients with a distorted pleural lining from previous surgery may have TPVS waveform alterations, and TPVB should be performed with caution.\n\nNontypical respiratory waveforms within the TPVS were found in two patients with a successful block. The first patient showed a tense, straight waveform with a mean pressure of 47 mmHg, which might be explained by the needle tip contacting a bony part (e.g., transverse process or vertebral body) or the pleura during pressure measurement, resulting in falsely high pressure without a typical sine wave. Costache et al. postulated that blockade of the thoracic nerve roots in the TPVS can be achieved through several injection points outside the TPVS as paravertebral block variants.24 The second patient with a history of thoracic surgery demonstrated a respiratory waveform with a mean pressure of 37 mmHg, which was defined as an atypical waveform. This pattern might be explained by the scar of redo-thoracic surgery on the same side, which could have affected pleural integrity and compliance in the TPVS.\n\nSix patients underwent unsuccessful blocks despite the needle tip being ultrasonographically visible in the TPVS along with widening of the TPVS and anterior displacement of the pleura being observed after confirmation by saline injection. Furthermore, a typical respiratory waveform was observed in all these patients. This unfavourable result might be explained by the uncontrollable variations in the spread of local anaesthetic. Previous cadaveric studies demonstrated direct communication between the TPVS and the intercostal space. Cowie et al. performed UG-TPVB with contrast injection and found a greater spread of contrast in the intercostal space than in the TPVS.25 Naja et al. used nerve stimulator and roentgenogram data to show four main types of injectate spreading patterns in TPVB: pure longitudinal (TPVS), longitudinal with intercostal (TPVS with intercostal), intercostal, and cloud-like spread around the injection sites. In addition, isolated paravertebral contrast was found in only 30% of patients.26 Termpornlert et al. also found that the spreading of dye through a paravertebral catheter showed considerable differences in patterns.27 Several factors can impact the distribution of local anaesthetic agents in the TPVS, such as the compliance in the space, pressure and injection speed, injection volume, viscosity of the local anaesthetic agent, and size of the patient.28\n\nTo improve block quality, Choi et al. and Li et al. studied combined UG-TPVB and pressure measurement for TPVB and found a shorter procedure time, higher success rate, and superior analgesia compared with UG-TPVB alone.10,29 The results of our study can also be applied to TPVB. A regular respiratory waveform pattern can be used as an adjunct to identify the TPVS and could be more effective than the pressure value alone.\n\nThe pressure and waveform pattern in the TPVS obtained in this study were derived from observing patients undergoing positive pressure ventilation, which may differ from those in individuals breathing spontaneously.\n\nDermatomal sensory block and NRS score assessment were performed postoperatively; analgesia might have passed its peak effect, resulting in dermatomal regression.\n\nEach patient received UG-TPVB at two levels with a high volume of local anesthetic agent, as a routine practiced by our team; the spread might have overlapped, leading to potential misinterpretation of the blockade’s effectiveness at each level. This study was prospective observational; therefore, a randomized controlled trial is necessary to elucidate the benefits of analysing the waveform in the TPVS.\n\n\nConclusions\n\nThe wave in the TPVS was low pressure and showed a smooth, regular pattern corresponding to respiration. This waveform was reliable for verifying the needle tip in the TPVS. Hence, these findings can be applied as an adjunct technique to perform TPVB combined with an anatomical-based method or an UG-TPVB, especially when the needle cannot be seen clearly.", "appendix": "Data availability\n\nFigshare: data analysis figshare new.xls, https://doi.org/10.6084/m9.figshare.24189234.v2. 30\n\nThis project contains the following underlying data:\n\n- Data analysis figshare.xls\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nCadavid-Puentes AM, Casas- Arroyave FD, Palacio-Montoya LM, et al.: Efficacy of paravertebral block techniques in thoracic surgery: systemic literature review. Colomb.J.Anesthesiol. 2020; 48: 20–29. Publisher Full Text\n\nLönnqvist PA, MacKenzie J, Soni AK, et al.: Paravertebral blockade. Anaesthesia. 1995; 50: 813–815. Publisher Full Text\n\nEason MJ, Wyatt R: Paravertebral thoracic block-a reappraisal. Anaesthesia. 1979; 34: 638–642. Publisher Full Text\n\nWheeler LJ: Peripheral nerve stimulation end-point for thoracic paravertebral block. Br. J. Anaesth. 2001; 86: 598–599. PubMed Abstract\n\nLang SA, Saito T, Naja MZ, et al.: Thoracic paravertebral nerve block, nerve stimulator guidance and the endothoracic fascia. Anaesthesia. 2005; 60: 930–931. PubMed Abstract \| Publisher Full Text\n\nNaja MZ, Ziade MF, Lönnqvist PA: Nerve-stimulator guided paravertebral blockade vs. general anaesthesia for breast surgery: a prospective randomized trial. Eur. J. Anaesthesiol. 2003; 20: 897–903. PubMed Abstract \| Publisher Full Text\n\nJadon A: Nerve stimulator-guided thoracic paravertebral block for gynecomastia surgery. Indian J. Anaesth. 2012; 56: 298–300. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nRichardson J, Cheema SP, Hawkins J, et al.: Thoracic paravertebral space location. Anaesthesia. 1996; 51: 137–139. Publisher Full Text\n\nOkitsu K, Maeda A, Iritakenishi T, et al.: The feasibility of pressure measurement during an ultrasound-guided thoracic paravertebral block. Eur. J. Anaesthesiol. 2018; 35: 806–807. Publisher Full Text\n\nLi H, Wei H, Ma D, et al.: Ultrasound and pressure-guided thoracic paravertebral block. Eur. J. Anaesthesiol. 2020; 37: 824–826. PubMed Abstract \| Publisher Full Text\n\nAbdellatif AA, Ali MA: Acoustic puncture assist device™ versus conventional loss of resistance technique for thoracic paravertebral space identification: clinical and ultrasound evaluation. Saudi J. Anaesth. 2017; 11: 32–36. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHara K, Sakura S, Nomura T, et al.: Ultrasound guided thoracic paravertebral block in breast surgery. Anaesthesia. 2009; 64: 223–225. Publisher Full Text\n\nDaly DJ, Myles PS: Update on the role of paravertebral blocks for thoracic surgery: are they worth it? Curr. Opin. Anaesthesiol. 2009; 22: 38–43. PubMed Abstract \| Publisher Full Text\n\nPatnaik R, Chhabra A, Subramaniam R, et al.: Comparison of paravertebral block by anatomic landmark technique to ultrasound-guided paravertebral block for breast surgery anesthesia. Reg. Anesth. Pain Med. 2018; 43: 385–390. PubMed Abstract \| Publisher Full Text\n\nKrediet AC, Moayeri N, van Geffen G-J , et al.: Different approaches to ultrasoundguided thoracic paravertebral block. Anesthesiology. 2015; 123: 459–474. Publisher Full Text\n\nNair S, Gallagher H, Conlon N: Paravertebral blocks and novel alternatives. BJA Educ. 2020; 20: 158–165. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nNaja Z, Lönnqvist PA: Somatic paravertebral nerve blockade incidence of failed block and complications. Anaesthesia. 2001; 56: 1181–1201.\n\nAbouleish AE, Leib ML, Cohen NH: ASA provides examples to each ASA physical status class. ASA Monitor. 2015; 79: 38–39.\n\nThomas PW, Sanders DJ, Berrisford RG: Pulmonary haemorrhage after percutaneous paravertebral block. Br. J. Anaesth. 1999; 83: 668–669. PubMed Abstract \| Publisher Full Text\n\nCheema S, Richardson J, McGurgan P: Factors affecting the spread of bupivacaine in the adult thoracic paravertebral space. Anaesthesia. 2003; 58: 684–687. PubMed Abstract \| Publisher Full Text\n\nKomatsu T, Sowa T, Kino A, et al.: The importance of pleural integrity for effective and safe thoracic paravertebral block: a retrospective comparative study on postoperative pain control by paravertebral block. Interact. Cardiovasc. Thorac. Surg. 2014; 20: 296–299.\n\nLeurcharusmee P, Arnuntasupakul V, Chora De La Garza D, et al.: Reliability of waveform analysis as an adjunct to loss of resistance for thoracic epidural blocks. Reg. Anesth. Pain Med. 2015; 40: 694–697. PubMed Abstract \| Publisher Full Text\n\nArnuntasupakul V, Van Zundert TCRV, Vijitpavan A, et al.: A randomized comparison between conventional and waveform-confirmed loss of resistance for thoracic epidural blocks. Reg. Anesth. Pain Med. 2016; 41: 368–373. PubMed Abstract \| Publisher Full Text\n\nCostache I, Pawa A, Abdallah FW: Paravertebral by proxy – time to redefine the paravertebral block. Anaesthesia. 2018; 73: 1185–1188. PubMed Abstract \| Publisher Full Text\n\nCowie B, McGlade D, Ivanusic J, et al.: Ultrasound-guided thoracic paravertebral blockade. Anesth. Analg. 2010; 110: 1735–1739. Publisher Full Text\n\nNaja MZ, Ziade MF, Rajab ME, et al.: Varying anatomical injection points within the thoracic paravertebral space: effect on spread of solution and nerve blockade. Anaesthesia. 2004; 59: 459–463. Publisher Full Text\n\nTermpornlert S, Sakura S, Aoyama Y, et al.: Distribution of injectate administered through a catheter inserted by three different approaches to ultrasound-guided thoracic paravertebral block: a prospective observational study. Reg. Anesth. Pain Med. 2020; 45: 866–871. PubMed Abstract \| Publisher Full Text\n\nYokoyama M, Hanazaki M, Fujii H, et al.: Correlation between the distribution of contrast medium and the extent of blockade during epidural anesthesia. Anesthesiology. 2004; 100: 1504–1510. PubMed Abstract \| Publisher Full Text\n\nChoi EK, J-il K, Park S-J: A randomized controlled trial comparing analgesic efficacies of an ultrasound-guided approach with and without a combined pressure measurement technique for thoracic paravertebral blocks after open thoracotomy. Ther. Clin. Risk Manag. 2020; 16: 727–734. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nVijitpavan A: data analysis figshare new.xls. figshare. Dataset. 2023. Publisher Full Text" }	[ { "id": "319560", "date": "13 Sep 2024", "name": "Sasikaan Nimmaanrat", "expertise": [ "Reviewer Expertise Pain management", "Anesthesia", "Quality Assurance" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript is well written.\nThe research question was to answer the knowledge gap of TPVS waveform patterns in patients with \"controlled ventilation\" under general anesthesia.\nThe methodology was well designed. The results were clearly presented.\n\nThe discussion was adequate on similarities and dissimilarities with other publications with logic explanations.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] }, { "id": "345406", "date": "12 Dec 2024", "name": "Sirirat Tribuddharat", "expertise": [ "Reviewer Expertise Anesthesia", "Cardiac anesthesia", "regional anesthesia", "hemodynamics monitoring" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study presents a novel method for identifying the thoracic paravertebral space, offering an alternative to ultrasound guidance. While well-designed, some areas require further clarification:\nNumerals: Avoid beginning sentences with numerals. \"50\" and \"98\" in the Abstract should be written as \"Fifty\" and \"Ninety-eight,\" respectively, and similar changes should be made throughout the manuscript. Abstract Results: \"Chronic pleural inflammation\" should be removed from the Abstract Results, as it's not addressed in the manuscript's Results section. Introduction P-values: Include p-values for the percentages \"(94% and 72%, respectively)\" and \"(13.8% and 22.2%, respectively)\" presented in the Introduction. Complication Order: Reorder the listed complications—hypotension (4.6%), vascular puncture (3.8%), pleural puncture (1.1%), pneumothorax (0.5%), hematoma (1.9%), and epidural/spinal spread (1.1%)—according to their incidence. Methods Wording: In the Methods section, change \"provided by the Ethics Committee\" to \"approved by the Ethics Committee\" and \"obtained preoperative information and provided informed consent\" to \"provided preoperative information and obtained informed consent.\" Sample Size Rationale: Justify the sample size of 50 patients, potentially with a power analysis or reference to similar studies. ASA Definition Removal: Remove the detailed ASA physical status definitions, as referencing #16 is sufficient. Ventilation Clarification: Address the discrepancy between the stated inspiratory pressure (20 mmHg) and the mean inspiratory pressure reported in Table 1 (14 ± 1.54 mmHg). Include details on tidal volume and EtCO2 adjustments. \"A\" Waveform Definition: Remove \"a mean value of ≤25 mmHg\" from the \"A\" waveform definition, as it has mean values with a range between 3.0-47.0 or 8.0-26.0 (Table 2). Please clarify. Unsuccessful Block Definition: Delete \"or an NRS score at rest ≥3\" and all other mentions of NRS scores, as they are not relevant per reference #3. I suggest deleting ‘Numeric Rating Scale (NRS) scores’ because they were not presented in Table 1. Table 1 Formatting: Remove \", mean±SD\" and \", n (%)\" from Table 1 contents and \"(range)\" from its caption. Change the caption to \"Data are presented as mean ± SD or n (%)\". Figure 2 Label: Correct the \"ICP\" label in Figure 2. Provide the correct term (e.g., \"Intrathoracic Pressure\"). Redo-Thoracotomy Count: Reconcile the inconsistent reporting of redo-thoracotomy patients (5 in Results, 6 in Discussion, 4 in Table 2). Table 2 P-values: Add p-values for intramuscular pressure, SCTL pressure, TPVS pressure, and respiratory waveform presence for redo and non-redo thoracotomy groups at T4/5 and T6/7. Table 2 Formatting: Change the Table 2 caption to \"Data are presented as median (range) or n (%)\". Remove \", %\" from the first column. Present \"Respiratory waveform present\" values as n (%) and change all other percentage values (e.g., 94.0, 100.0, 93.5) accordingly. Table 3 Discrepancy: Resolve the discrepancy between the 98 (98%) regular sine waveforms in Table 3 and the 94.0% respiratory waveform presence in Table 2. Table 3 Captions: Remove \"Sensitivity, Specificity, ROC area, Positive predictive value, and Negative predictive value\" captions from Table 3; these belong in Table 4. NRS Score Paragraph Removal: Delete the paragraph discussing NRS scores, as it's not relevant to the study's objective. In the Discussion, the authors stated that ‘The study showed that 96% of the subjects had similar respiratory-like pattern in the TPVS’, where did 96% come from? According to Table 3, this number should be 98%. Please clarify. To assess the efficacy of sine waveform visualization for identifying the thoracic paravertebral space (TPVS), comparison with a reference standard is essential. While not a true gold standard, ultrasound-guided TPVB (UG-TPVB) is the de facto standard for TPVS identification in clinical practice. Therefore, the sine waveform's visibility should be compared directly with UG-TPVB confirmation of needle tip location within the TPVS (e.g., % sine waveform visibility vs. US-TPVB confirmation). Comparing sine wave visibility with block success (Table 4) is inappropriate. The current criterion for unsuccessful block—inability to confirm more than three levels of dermatomal blockade—introduces numerous confounding factors unrelated to TPVS identification. Block success itself is not a valid reference standard for accurate needle placement within the TPVS as confirmed by US-TPVB. Table 4 Revision: Recalculate and revise Table 4 to compare sine waveform visibility directly with US-TPVB confirmation, using a total of 100 tests. Discussion Wording: Change \"Eleventh\" to \"Eleven\" in the Discussion.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13138", "date": "27 Jan 2025", "name": "Amorn Vijitpavan", "role": "Author Response", "response": "Respond to the reviewer questions Question 1: Numerals: Avoid beginning sentences with numerals. \"50\" and \"98\" in the Abstract should be written as \"Fifty\" and \"Ninety-eight,\" respectively, and similar changes should be made throughout the manuscript. Answer 1: This issue has been revised as per the editor's suggestions, in accordance with the journal format, as shown in the attached document. The journal editor suggests using numbers rather than letters. Question 2: Abstract Results: \"Chronic pleural inflammation\" should be removed from the Abstract Results, as it's not addressed in the manuscript's Results section. Answer 2: We have removed the term “chronic pleural inflammation” from the abstract results. Question 3: Introduction P-values: Include p-values for the percentages \"(94% and 72%, respectively)\" and \"(13.8% and 22.2%, respectively)\" presented in the Introduction. Answer 3: We added the p-values to (94% and 72%, p = 0.024, respectively) and (13.8% and 22.2%, p = 0.54, respectively), as suggested. Question 4: Complication Order: Reorder the listed complications—hypotension (4.6%), vascular puncture (3.8%), pleural puncture (1.1%), pneumothorax (0.5%), hematoma (1.9%), and epidural/spinal spread (1.1%)—according to their incidence. Answer 4: We have reordered the words by occurrence, from most to least, as suggested, as follows: hypotension (4.6%), vascular puncture (3.8%), hematoma (1.9%), pleural puncture(1.1%), epidural or spinal spread (1.1%), and pneumothorax (0.5%). Question 5: Methods Wording: In the Methods section, change \"provided by the Ethics Committee\" to \"approved by the Ethics Committee\" and \"obtained preoperative information and provided informed consent\" to \"provided preoperative information and obtained informed consent.\" Answer 5: I have rearranged the sentence as suggested, as follows: “approved by the Ethics Committee” and “provided preoperative information and obtained informed consent”, as suggested. Question 6: Sample Size Rationale: Justify the sample size of 50 patients, potentially with a power analysis or reference to similar studies. Answer 6: This is an observational study of pressure levels and waveform characteristics in the paravertebral space, which has never been studied before. The sample size for this study was derived from the study period, during which participants were observed from February 9, 2021, to May 17, 2021—approximately 3 months. A total of 50 cases were included. Question 7: ASA Definition Removal: Remove the detailed ASA physical status definitions, as referencing #16 is sufficient. Answer 7: Thank you for your helpful suggestion. Since the editor of the journal recommended adding a definition of ASA physical status in the previous review, we will retain the definition in the manuscript. Question 8: Ventilation Clarification: Address the discrepancy between the stated inspiratory pressure (20 mmHg) and the mean inspiratory pressure reported in Table 1 (14 ± 1.54 mmHg). Include details on tidal volume and EtCO2 adjustments. Answer 8: Because the thoracic paravertebral space is adjacent to the thoracic cavity, the researchers concerned that the pressure generated by positive pressure ventilation might influence the pressure and waveform characteristics being studied. Therefore, the same PCV ventilation settings (20 mmHg) were applied to all cases during the brief study period. The values reported in Table 1 represent the actual mean airway pressures (14 ± 1.54 mmHg), which typically do not match the set pressure (20 mmHg) in the PCV mode. We aim to demonstrate that both the set pressure level and the mean airway pressure were not significantly different across participants. Adjustments to tidal volume and EtCO2 could affect the ventilated pressure; however, since the study duration was brief, the varation of EtCO2 should not harm the participants. Question 9: \"A\" Waveform Definition: Remove \"a mean value of ≤25 mmHg\" from the \"A\" waveform definition, as it has mean values with a range between 3.0-47.0 or 8.0-26.0 (Table 2). Please clarify. Answer 9: This study examines the pressure in the paravertebral space and the respiratory-like pattern of waveforms that may be observed in this space. The definitions of waveforms A, B, and C combine both pressure and waveform characteristics, as follows: Waveform A is a smooth, regular sine wave resembling the respiratory pattern, with mean pressure in the space ≤ 25 mmHg; Waveform B is an irregular, coarse, wavy line with pressure < 40 mmHg; and Waveform C is a tense, straight line with pressure > 40 mmHg. Table 2 shows the pressure and waveform data, with the numbers (3, 47.0) or (8.0, 26.0) representing the median values measured in the paravertebral space. As noted by the reviewer, pressures over 25 mmHg, such as those corresponding to (3, 47.0) or (8.0, 26.0), were classified as either waveform C or B, not waveform A. Only two patients were found to have pressure greater than 25 mmHg in the thoracic paravertebral space. To clarify, we have provided additional information about the waveform characteristics in the Methods section, as shown in Table 3. The “A” waveform, or typical waveform, was defined as a smooth and regular sine wave resembling the respiratory pattern, with a mean pressure ≤ 25 mmHg. The “B” waveform was defined as an irregular, coarse, wavy line with a mean pressure ≤ 40 mmHg. The “C” waveform was defined by a tense, straight line with a mean pressure > 40 mmHg. Question 10: Unsuccessful Block Definition: Delete \"or an NRS score at rest ≥3\" and all other mentions of NRS scores, as they are not relevant per reference #3. I suggest deleting ‘Numeric Rating Scale (NRS) scores’ because they were not presented in Table 1. Answer 10: We agree to remove the NRS (Numeric Rating Scale) scores from the section on the definition of unsuccessful blockade and from all other parts of the manuscript where NRS is mentioned. Question 11: Table 1 Formatting: Remove \", mean±SD\" and \", n (%)\" from Table 1 contents and \"(range)\" from its caption. Change the caption to \"Data are presented as mean ± SD or n (%)\". Answer 11: We removed the words “mean±SD” and “n” from Table 1 and the word “range” from the caption, and changed the caption to “Data are presented as mean±SD or n(%)” as recommended. Question 12: Figure 2 Label: Correct the \"ICP\" label in Figure 2. Provide the correct term (e.g., \"Intrathoracic Pressure\"). Answer 12: We agreed to omit parts of the ICP text from Figure 2 to prevent confusion among readers who might mistake it for intracranial pressure, as this study focuses on the paravertebral space. Question 13: Redo-Thoracotomy Count: Reconcile the inconsistent reporting of redo-thoracotomy patients (5 in Results, 6 in Discussion, 4 in Table 2). Answer 13: Thank you for your help in checking. We would like to change the number of participants who underwent redo-thoracotomy from 5 patients to 4 patients in the results section. The number of 6 patients in the discussion section is correct because it includes 4 redo-thoracotomy cases and 2 empyema cases. Both the redo-thoracotomy and empyema cases involve issues with pleural integrity, which is why we reported them together. Question 14: Table 2 P-values: Add p-values for intramuscular pressure, SCTL pressure, TPVS pressure, and respiratory waveform presence for redo and non-redo thoracotomy groups at T4/5 and T6/7. Answer 14: I have added the p-values to Table 2 for intramuscular pressure, SCTL, TPVS pressure, and the presence of respiratory waveforms for the Redo and non-redo thoracotomy groups at the T4/5 and T6/7 levels. Question 15: Table 2 Formatting: Change the Table 2 caption to \"Data are presented as median (range) or n (%)\". Remove \", %\" from the first column. Present \"Respiratory waveform present\" values as n (%) and change all other percentage values (e.g., 94.0, 100.0, 93.5) accordingly. Answer 15: As per your recommendation. We have adjusted Table 2 as follows: 1. In the table header, we removed the word “Mean” in the “Mean pressure values” and added “(n=100)” for clarity. 2. In columns 2 and 3, specifying T4/5 and T5/6, we removed the word “median (range)” replaced it with “(n=50)”. 3. We removed the “%” at the end of “Respiratory waveform present, %” and presented it as n(%) instead. 4. We recalculated the data, correcting the value from 93.5 to 95.6. 5. The caption of Table 2 was edited to “Data are presented as median (range) or n(%)”. Question 16: Table 3 Discrepancy: Resolve the discrepancy between the 98 (98%) regular sine waveforms in Table 3 and the 94.0% respiratory waveform presence in Table 2. Answer 16: The number 94 in Table 2 represents the number of times the respiratory waveform occurred in the observational study, presented as percentages. It is not specified whether this occurred in the thoracic paravertebral space. In this study, only one case was found to have a respiratory waveform in the SCTL (superior costotransverse ligament) position, which was also observed in the thoracic paravertebral space. Additionally, two cases did not exhibit the respiratory-like waveform in the paravertebral space. Therefore, in Table 2, the number 94 has been revised to 96 (48/50 at T4/5 for all participants), and the number 93.5 has been revised to 95.6 (44/46 in the not-redo-thoracotomy group), with these numbers presented as percentages. The number 98 in Table 3 represents the total number of events in which the respiratory waveform occurred in the paravertebral space (two levels of paravertebral block for one patient). Question 17: Table 3 Captions: Remove \"Sensitivity, Specificity, ROC area, Positive predictive value, and Negative predictive value\" captions from Table 3; these belong in Table 4. Answer 17: In Table 3, we reported the use of ultrasound as the gold standard for identifying the paravertebral space before measuring the pressure and waveform characteristics. Therefore, we would like to retain these data. Additionally, we used the success of the blockade to reconfirm the paravertebral space after the blockade, as shown in Table 4. Question 18: NRS Score Paragraph Removal: Delete the paragraph discussing NRS scores, as it's not relevant to the study's objective. Answer 18: We have removed the paragraph discussing the NRS, as suggested. Question 19: In the Discussion, the authors stated that ‘The study showed that 96% of the subjects had similar respiratory-like pattern in the TPVS’, where did 96% come from? According to Table 3, this number should be 98%. Please clarify. Answer 19: As answered in question 16, the number 96% comes from the events showing the respiratory-like waveform, which includes 48 cases out of 50. However, the number 98 represents the total events showing the respiratory-like waveform from 100 events involving fifty patients. Question 20: To assess the efficacy of sine waveform visualization for identifying the thoracic paravertebral space (TPVS), comparison with a reference standard is essential. While not a true gold standard, ultrasound-guided TPVB (UG-TPVB) is the de facto standard for TPVS identification in clinical practice. Therefore, the sine waveform's visibility should be compared directly with UG-TPVB confirmation of needle tip location within the TPVS (e.g., % sine waveform visibility vs. US-TPVB confirmation). Comparing sine wave visibility with block success (Table 4) is inappropriate. The current criterion for unsuccessful block—inability to confirm more than three levels of dermatomal blockade—introduces numerous confounding factors unrelated to TPVS identification. Block success itself is not a valid reference standard for accurate needle placement within the TPVS as confirmed by US-TPVB. Answer 20: This is because the researcher needed to understand the pressure and waveform characteristics in the paravertebral space, as these have never been studied before. The researcher had previously studied the characteristics of waves found in the epidural space and discovered that they resembled arterial waves, which were used to determine the location of the epidural space. In the paravertebral space, which is connected to the epidural space and adjacent to the thoracic cavity, there may be arterial waves or possibly waves similar to respiratory waves following breathing. Therefore, the researcher aimed to study the nature of the waves in the paravertebral space, their form, and whether they could be used to determine the location of the paravertebral space. In this study, ultrasound was used to identify the location of the paravertebral space. However, even with ultrasound, the tip of the needle could sometimes not be clearly visualized, and it was necessary to confirm that the location identified with ultrasound was indeed the paravertebral space. Therefore, the researcher also tested the level of analgesia after the blockade. In future studies, the use of respiratory waveforms may be compared with ultrasound for determining the location of the paravertebral space. Question 21: Table 4 Revision: Recalculate and revise Table 4 to compare sine waveform visibility directly with US-TPVB confirmation, using a total of 100 tests. Answer 21: Table 4 presents the relationship between the visibility of the respiratory waveform and the success of the block, as determined by testing the level of analgesia. The study involved 50 patients, and the level of analgesia was tested after they had recovered from anesthesia. Therefore, the calculations were based on 50 patients, not 100. We acknowledge that this is a limitation of the study, as the analgesic level should have been tested before the patient fell asleep for each blockade. We addressed this point in the limitation section. Question 22: Discussion Wording: Change \"Eleventh\" to \"Eleven\" in the Discussion. Answer 22: An error occurred. We have changed the word “eleventh” to “eleven”." } ] } ]	1	https://f1000research.com/articles/13-150
https://f1000research.com/articles/11-344/v1	21 Mar 22	{ "type": "Research Article", "title": "Accounting for the expansion of the universe using an energy/momentum model to construct the space-time metric", "authors": [ "Hugh James" ], "abstract": "Background: The success of the theories of special and general relativity in describing localised phenomena, such as objects undergoing high speed motion or located in gravitational fields, needs no further elaboration. However, when applied to the evolution of the universe several problems arise which can require an additional model, e.g., inflation during the early expansion, and adjustments to parameters to account for phenomena such as the late-time acceleration of the universe. Methods: Focusing on the difference between the ways in which space and time are measured, this paper shows that there are two paths which allow the equations of special relativity to be produced from the same basic postulates. Results: While the standard theory assumes a fundamental existence of a coordinate framework which incorporates both space and time, an alternate path is possible which uses an energy/momentum, or dynamic model to derive a new metric equivalent to the standard space-time framework. When utilising the dynamic metric, the relativistic equations are unchanged for local phenomena such as the Lorentz coordinate transformation and the energy/momentum equation for high-velocity objects. Conclusions: However, the derived metric alters the perceived overall structure of the universe in a manner that, for the simplest model under this system, allows the reproduction of observed cosmological features, such as the intrinsic flatness of the universe and the apparent late-time acceleration of its expansion, without the need of additional models or changes in parameter values.", "keywords": [ "Cosmology", "large-scale structure of universe", "relativistic processes." ], "content": "Introduction\n\nThe success of the current theories of special (SR) and general relativity (GR) in describing localised phenomena, such as objects undergoing high speed motion, located in local gravitational fields or generating gravitational waves, needs no further elaboration. However, when applied to the evolution of the universe several problems arise which require either an additional model, e.g., inflation to account for the flatness or the horizon problems, or adjustments to coefficients and/or parameters to account for phenomena such as the universe’s late-time acceleration and the lack of observable mass to match the universe’s expansion1.\n\nIn exploring an approach which attempts to answer at least some of these problems, while still satisfying the basic postulates of relativity, it will be shown that it is possible to construct a space-time metric that satisfies the Lorentz coordinate transformation while producing an alternative overall structure of the universe. Any modification of the current theory must still conform to both the observation that the speed of light (c) is a constant in all inertial frames, and to the principle that the laws of nature are the same in all inertial frames. It also must conform to the principle of consistency, i.e., any new theory has to account for the successful predictions of the Newtonian and relativistic theories that it attempts to modify.\n\nThe alternative approach taken by this paper is based on the argument that in space-time it is only the spatial dimensions that are directly observable, while a time dimension must be constructed from indirect observations such as the reliance on memory or artificial aids such as film. Current theories rely on such a construction to complete a four-dimensional space-time, which has been very successful but has some problems on a universal scale such as those outlined above. An alternative approach is discussed which assumes, for reasons explained below, that it is the energy and momentum of objects that are fundamental to their behaviour, and from which the time element of a four-dimensional space-time coordinate system can be inferred, rather than starting from a four-dimensional coordinate system against which the energy and momentum of objects can be measured. The possible reason for this change in emphasis will be discussed, and the consequences of such a change are explored.\n\nThe simplest model of the universe that can be constructed using this dynamic metric consists of a surface, which is locally observed to consist of three spatial dimensions and a changing present, but has a non-local view in which this surface is expanding along four spatial dimensions. All observers are located on this surface and consequently have no local view of this fourth spatial dimension into which this expansion occurs, but instead interpret it as time (i.e. the changing present, see subsequent sections on the basis of the dynamic theory and also its relevance to cosmology). All gravitational effects that we can see and measure take place along this surface. Consequently when this model also approximates the mass distribution along this surface, and at any given time during the surface’s expansion, as being uniform, the gravitational potential along the surface (which is normal to its expansion) is zero. This approximation allows the surface expansion to be calculated using only special relativity and without recourse to general relativity - as will be shown in the cosmology sections. Obviously more detailed analyses using realistic mass distributions would require GR to take a role, but the current approach shows that even in its most basic form this model provides very good predictions of the universe’s expansion (Cosmology Section).\n\n\nThe basis of the dynamic theory in special relativity (SR)\n\nAs already stated, a possible area that could lead to more than one approach arises with the inclusion of time as the equivalent of a spatial dimension. Leaving aside any philosophical questions about what space and time are, and just concentrating on how they are measured when considering relativistic effects illustrates the problem of mixing time and space to form the space-time of coordinate relativity.\n\nBasically, relativistic effects are measured with a clock and a ruler. To state the obvious a ruler is composed of a distribution of matter which is taken to define a spatial dimension. For the purposes of relativistic measurements, the ruler is unchanging for an observer in the same inertial frame, i.e. the coordinates it provides along a spatial dimension are static within an inertial frame and any position on this ruler can be revisited at will (albeit at different times). In contrast a clock gives a continuous (and regular) conversion of potential into kinetic energy which is able to do work on its surroundings, e.g. the release in energy from a clock spring to continuously move the clock’s hands, or the decay of radioactive material to activate a counter. This is intended to model what an observer experiences as time, i.e. he is always trapped in the current moment in the sense that he can only influence or be influenced by events which happen in the present (memories of past events may be said to influence him, but can only do so in his present), but this moment is always changing. Since the observer is always in the present, past events can only be accessed by memory or aids such as film. This access is of a different order to the interactions granted to events in the present. An observer can visit a spatial location many times and interact with what is happening at that location. The ability to physically interact with an event in time is restricted by the fact that a temporal location can only be visited once. Since the observer only exists in the present, temporal coordinates can only be constructed by integrating experiences in the present using memories or other recording devices. The ever-changing present has no real coordinate that can be directly experienced (in the sense of spatial coordinates that can be both seen to be separated and individually revisited at will) since from within an inertial frame no dimension can be seen in what can be assumed as the time direction. The experience of time is analogous to a piece of cardboard with a vertical slit cut in it being placed over a train window. There is an ever-changing view of a segment of the landscape seen through the slit, but you cannot see what is coming and you need either a good memory or some recording apparatus to build a complete picture of where you have been. The whole directly observable view of the world is the ever-changing view through the slit.\n\nTime in this view appears to facilitate the change of the energy state - objects appear, grow, change or vanish as they pass the slit - while space provides a framework which can facilitate a distribution of objects. Consequently, there are two routes that can be taken when attempting to mix space and time. The coordinate route of the standard theory keeps the spatial dimension unchanged while integrating the changing temporal view to give a fourth dimension which is analogous to space. The dynamic view keeps time as an ever-changing entity but requires this to be linked to objects (including other observers) which have an ever-changing spatial position. Hence the dynamic view is based on energy and momentum while the coordinate view is based on trajectories.\n\nSince the integral of the dynamic view will give coordinates (albeit artificially constructed), and since it has already been stated that, at least locally, the two theories must match for the dynamic view to have any validity, the next two sections show where the two theories coincide and where they diverge.\n\nTo clarify which theory is being referred to in the following, the derivatives in the standard theory result from infinitesimal changes in the dimensional coordinates and relate to trajectories. In this paper such changes are denoted by d(). In the dynamic theory D() are infinitesimal changes in coordinates which are derived from the magnitude of the change in energy experienced in the present (located in what can be constructed as the time direction - i.e., orthogonal to the spatial directions), and the momentum of objects in the spatial dimensions. Subscripts N and M denote any inertial frame, in contrast to A and B which usually have specified conditions such as which frame contains the observer and which the observed. In the standard theory a single subscript is used to denote the frame in which the coordinates are located, e.g. see Equation (1) below. In the dynamic theory two subscripts are used for time, e.g. DtAB where the first subscript is the frame containing the observer and the second the frame containing the object being observed. For space there are three subscripts, e.g. DxACB where the first and third subscripts are as in the description for time, while the middle subscript is the frame in which the ruler is located against which the spatial motion is measured. In this example A is the observer, B is the object being observed and C is the frame containing the ruler against which A measures B’s motion.\n\nBoth theories must satisfy the condition that the speed of light is the same in all inertial frames.\n\nFor the standard dimensional coordinate theory, this leads to the Minkowski metric which provides the following relationship between space and time\n\nwhere A and B are inertial frames of reference, velocities are along the x axis and so changes in y and z are zero, and dτ is defined as the proper time interval, i.e. it is time recorded by a clock which moves with the object of interest and is an invariant quantity. In this paper, for brevity - but without any loss of generality - only spatial motions along the x axis are considered. For photons dτ = 0.\n\nIn the dynamic theory several points must be considered.\n\nThe view of all inertial frames is always done from the present of an observer, and since both theories agree that there is no such thing as a universal present, the continuous changes are seen from a single viewpoint.\n\nThe dynamic theory deals with energy and momentum, i.e. the constant change in time (where coordinates must be inferred) and space (real coordinates). For brevity, these phenomena will sometimes be referred to as “motion”. As already outlined, this motion will be denoted by DtNM for time – where M is the frame in which the clock resides, and N is the frame containing the observer – while DxNNM refers to spatial motion where M is the frame in motion relative to both a ruler (middle subscript) and observer (first subscript) located in N.\n\nThe key point in dynamic SR is that the theory assumes that the fundamental parameters are the energy/momentum (motions) of objects (which includes observers) which are used to construct a 4-vector coordinate system, and not a 4-vector coordinate system that the motion is measured against. Consequently, for the dynamic theory the above equation has to be written as\n\nto preserve both the existence and equivalence of two unique viewpoints - A sees B as B sees A - as well as the constant value of the speed of light from both viewpoints, i.e. if B is a photon then DtAB2=0, and vice versa. However, as will now be shown, the grouping of the parameters and the general invariance of the time term will be different.\n\nConcentrating on A as the observer with the single viewpoint, then in an inertial frame the only motion that he can directly experience is that of his clock (DtAA). He does not experience any spatial motion (DxAAA = 0), and any such motion that could be seen from outside the frame will, from A’s view, be added to the spatial motion of B. This motion A sees as being relative to A’s own ruler (DxAAB). However, A is able to see (for this illustration) B’s clock (DtAB). Consequently, grouping the motion that A can see of himself, and the motion that A sees of B on separate sides of the above equation gives the dynamic metric (which should be compared to the Minkowski metric in Equation (1)) as\n\nThe same view can be seen from B with the appropriate change in subscripts, i.e.\n\nThe first thing to note is that the invariant is now DtNN as this is the only parameter that N can experience of itself, and one of the main principles of SR is that nature’s laws must be the same when seen from inside an inertial frame. Since a lot of these laws are time-dependent, then if DtAA ≠ DtBB there should be an effect seen from outside the frame which cannot be ascribed to either relative velocity or gravity. No such effect has ever been reported so it is a safe postulate that DtAA ≡ DtBB.\n\nThe second thing is that the only coordinates that A can directly observe are spatial. Hence the three subscripts for Dx – where the middle one relates to a ruler - compared to the two subscripts for Dt. However, as already mentioned, a time coordinate can be inferred by simply integrating Dt. If there is to be any overlap between the dynamic and coordinate theories, we need to find the relationship between the inferred and standard coordinates and, consequently, the relationship between their differentials.\n\nIn Figure 1 the axes labelled cdtN are the infinitesimal changes in temporal coordinate in inertial frame N in the standard theory, and additionally the continuously changing temporal coordinates constructed by N in the dynamic theory (i.e., DtNN) when comparing events from both his frame, and other inertial frames, to changes in his clock, i.e. OA = cDtAA, OB = cDtBB and OE = cDtAB. Equally dxN is on the axis where position O corresponds to DxAAA = DxBBB = 0, and OF = EB = DxAAB when A measures B’s spatial motion relative to A’s ruler.\n\nIn the standard coordinate theory, it is dτ that is the invariant between inertial frames, i.e. when we look for where the two theories overlap, we are looking for specific conditions where dτ = DtNN. This will be shown to be along the time-like hyperbola in Figure 1 where dτ is an invariant for all possible inertial frames that have their origin at O.\n\nIn Figure 1, A is the observer, dxA = DxAAB and dtA = DtAA, while DtAB is the time of a moving clock (B’s) as seen in what an observer considers as stationary axes (A). However, the condition dτ = DtNN can then only occur where the observer and the event or object being observed lie on their respective time axes, e.g. at A, B and G in Figure 1. This condition corresponds to dxN = 0 in Equation (1), and DxNNM = DxNNN = 0 in Equation (3) and Equation (4). The three sets of inertial axes (A, B and G) in this figure are shown from A’s viewpoint. All frames have a common initial location at O. The divisions shown on the axes in the figure are arbitrary.\n\nThe hyperbola in Figure 1 is given by Equation (1), i.e. c2dτ2=c2dtA2−dxA2=c2dtN2−dxN2. Then position A is where dτ = dtA = DtAA, and DxAAN = DxAAA = 0.\n\nAlso positions B and G are where dτ = dtN = DtNN (and DxNNN = 0, while DxAAN ≠ 0). However, when examining position B, it also corresponds from A’s viewpoint to\n\nHence for the dynamic theory, in Equation (5) OB = cDtBB(= cDtAA, see previous arguments), and OF = DxAAB. Equally OE is A’s view of B’s clock and so OE = cDtAB. Consequently at position B we have\n\nNote that in attempting to find where the two theories match, we are looking for the intersection of a Euclidean metric with a non-Euclidean surface, for example at B in Figure 1. This results in the distortion of some of the distances between points in what is basically a Euclidean representation of what is happening. OA and OB have different lengths in this Figure even though they represent a constant parameter (cDtNN). Hence, it is the case that at B, dτ = DtBB, which in turn must equal DtAA (see previous arguments) and so at B\n\ni.e. the intersection of the dynamic and Minkowski metrics in the Figure is consistent with Equation (1) and Equation (3). This can be extended to any inertial frame originating at O, e.g. G, where G is simply substituted for B in Equation (7).\n\nIn the Figure it can be seen that all inertial time axes must intersect the hyperbola, and so this hyperbola can be considered as the locus of intersections of all the time axes of objects undergoing different inertial spatial motions as seen from A. So DtAA (= DtNN) is also constant along this hyperbola. What changes is that DtAN, which corresponds to OE for frame B, changes its value when it corresponds to OE’ for frame G due to the difference in relative velocities between B and G.\n\nConsequently, for these conditions to be met, the dynamic equivalence of the coordinate viewpoint requires that every object (and hence every observer) must be located on its own time axis, even if such an axis can only be inferred by such an observer. This corresponds to the initial definitions that were given about the dynamic condition. Every point on the above hyperbola coincides with a time axis of an object which has a given relative velocity to A, and whose velocity is different to every other point on the curve. As has already been discussed the location of an object on its own time axis means that DtAA = DtNN. However, since this occurs at every point along this curve, in general terms, DtNN and dτ are both invariant along this hyperbola.\n\nHence, from the above along the time-like hyperbola\n\nand\n\nThe equivalent dynamic diagram to Figure 1 is, from A’s viewpoint, given in Figure 2. However, from this Figure when B moves relative to A in the dynamic theory, it appears to A that B’s time is partly at a reduced time rate and partly as a motion against A’s spatial dimensions. In the limit a photon would appear to A as only having a spatial motion and with no time element present. Although to an imaginary observer within the photon’s frame of reference, according to the requirement of nature’s laws having to be constant, the photon’s time would appear to proceed at DtNN while A would only have a motion along the photon’s spatial dimension during which A’s clock would appear frozen. Hence in this limit of possible frame rotations, what appears to be time from within the frame is seen from the outside as a motion through space against the background of the outside observer’s spatial dimensions. To an observer within a frame there is no observation (as distinct from inference) of any dimension of any sort - temporal or spatial - in the time direction and so it appears that the space against which this motion takes place does not exist, i.e. it has collapsed to a point on the time axis where it corresponds to the ever-changing, dimensionless present. However, the summation of all the views from every possible frame indicates the overall framework within which any individual observation is made is of four orthogonal spatial dimensions. It is just that the individual observer can only see three of them plus a changing present (see Cosmology Section).\n\nTime dilation. In Equation (3) it should be noted that all the observations can be made by A, so the dynamics are A’s clock as seen by A (cDtAA), equated to B’s spatial motion (DxAAB) and clock (cDtAB). Dividing through by c2DtAA2 and noting v = DxAAB/DtAA, gives DtAB = γ–1 DtAA, where γ = (1 − v2/c2)−1/2.\n\nHence for the standard theory where dtA ≠ dτ\n\ni.e. the dynamic is the same as the standard coordinate time dilation relationship.\n\nLength contraction The key element when dealing with spatial dimensions in the dynamic theory is that no spatial dimension can be seen to exist by an observer in his own time direction. However, there will be items that have unchanging spatial coordinates within an inertial frame, and which can be seen outside of that frame. Take frames A and B as being stationary relative to each other at some point in time. Both are equipped with a rods of equal length along the x axis. The frames are then given a relative velocity of v, and A then compares B’s rod with his own. The dynamic equations given above can be represented by a simple axis rotation equal to ζ = sin−1(v/c), and by the acknowledgement that the spatial x coordinates lie in the same direction as Dx.\n\nFor the dynamic theory let any coordinate terms be represented (e.g. the rod length) by δx, δy etc. Being a coordinate within an inertial frame, this is unchanging in time, in contrast to Dx which we have defined as constantly changing to match the ever-changing present. The subscript convention is the same as for Dx, e.g. δxABC where A is the observer, B the frame containing the ruler and C is the frame containing an object that A wishes to measure and which lies in A’s x direction. For Euclidean-type coordinate transforms, A would see δxBBB as having a component δxBBB cos ζ in A’s spatial direction and δxBBB sin ζ along A’s time axis. However, since there is no spatial dimension that can be seen by A along his own time axis, the length of B’s rod which is present in A’s inertial frame is seen by A to only be\n\nThis is the same length contraction result as for the standard theory, and this length contraction is independent of time since we are using δx. The apparent contraction in coordinate space for B (seen from A), is also seen (by A) to occur in the spatial motion of frames relative to B, since the motion takes place in a space that appears to have contracted by a factor of γ−1. Since only space is involved when considering just δ, and A’s clock is unaffected, then in turn the motion arising from this contraction can be assumed to occur for all times between inertial frames. This includes observations by both A and B due to the postulation of the equivalence of viewpoints in inertial frames in SR.\n\nBoth the time and space effects in special relativity are apparent effects. The word \"apparent\" is used as the changes in the parameters are brought about by changes in perspective rather than any fundamental change of the value of the parameter, e.g. in the length contraction discussed above, the same contraction is seen by B in A’s rod. Fundamental changes may be assumed to only occur once gravitation (or acceleration according to Einstein’s equivalence principle) is considered, but this is beyond the scope of the present paper.\n\nIt should also be noted that in the dynamic theory while DxNNN and DxNMM are always zero (the frame cannot move relative to its own ruler), δxNNN and δxNMM can have non-zero values.\n\nLorentz transformation. An additional spatial motion must be used by the dynamic theory to obtain the Lorentz transformation, as DxNNN is zero. For all spatial motions taking place along A’s x direction, the transformation can be derived as follows.\n\nTake frame G moving relative to both A and B, where the spatial motion of G relative to the ruler in B is observed by B to be DxBBG, and the spatial motion relative to a ruler in A (observed by A) is DxAAG. The velocity of B (observed by A) is given by v = DxAAB/DtAA ; the velocity of G relative to B (observed by B) is w = DxBBG/DtBB and the velocity of G relative to A (observed by A) is u = DxAAG/DtAA. Then for velocities very much smaller than c, we have w = u − v, or\n\nFor A to be the sole observer in Equation (12) we note that A could (for this illustration) see G moving along a ruler carried by B. For low velocities there is negligible space contraction and so DxBBG = DxABG, i.e. B’s ruler (and G’s motion along it) appears the same to both A and B.\n\nFor relativistic velocities, and dealing with spatial transformations first, the time element is kept constant by noting that DtNN is an invariant in the dynamic theory.\n\nIn this velocity regime B’s space, when seen by A, contracts by a factor γ−1 (i.e. γ−1 DxBBG = DxABG, see previous section), but A sees his own space as uncontracted. Hence Equation (12), on eliminating DtNN, can be written as\n\nFrom B’s viewpoint, using the same arguments, this observation can be written as\n\nThese relationships give the spatial transformation elements.\n\nNote that while DxAAB/DtAA = v, then DxBBA/DtBB = −v. By substituting vDtAA and −vDtBB into the appropriate spatial equation and, after some manipulation, this allows the time element to be found, i.e. we can now write the complete transform as\n\nAs can be seen from the subscripts, the left side of the first two elements of Equation (15) and the right side of the last two elements are B’s observations of G’s motion relative to the clock and ruler in B’s frame. The reverse is true for A, with A’s observations of G being on the right of the first two elements and the left of the last two.\n\nDividing the first by the second element gives\n\nwhile dividing the third by the fourth element gives\n\nWhen comparing these equations with the coordinate version of the Lorentz transformation, they give the same velocity-addition relationships.\n\nEquation (15) gives the relationship between two views (A and B) of the same frame or event (G) rather than the single view which we have dealt with up until now. If we reduce these relationships to a single view by making G travel at the same velocity as B or A, it can be shown that these equations collapse back to the single velocity results.\n\nLet G move at the same velocity as B. Then the Equation (15) becomes\n\nThe first element in Equation (18) has A’s view as v = DxAAB/DtAA. Also the second and fourth temporal elements, are identical (DtBB = γ−1DtAA).\n\nDividing the third element by the fourth element, gives\n\nγ−1DxAAB/γ−1DtAA = (−DxBBA)/DtBB = v.\n\nHence A’s viewpoint in the last two elements gives\n\n(γ–1DxAAB)/γ–1DtAA = v,\n\nwhile B’s viewpoint for these elements is v = −(DxBBA/DtBB), i.e. both views agree that the single velocity in this case is v.\n\nSince we now have γ−1DxAAB/γ−1DtAA = (−DxBBA)/DtBB, then by rearranging we obtain DtBB/γ−1DtAA = γ(−DxBBA)/DxAAB.\n\nNow (−DxBBA) = DxAAB, since they are equivalent views of the same relative motion (see previous discussions on inertial frame equivalence), and so, once the single velocity between the two frames has been established, the above relationships also reduce to\n\nDtBB = DtAA,\n\ni.e. the invariant time relationship which has previously been discussed.\n\nBy making G move at the same velocity as A and applying the same analysis gives the same answers.\n\nThe 4-vector, energy and momentum. The dynamic theory gives the same energy/momentum relationship as the coordinate theory, but results in a change of interpretation of the role of rest mass energy (E0). This result can be obtained geometrically for the dynamic theory by taking the top right-hand quadrant of Figure 2, but omitting the G axis. In the following, the terms OA, OB, OE and EB are those used in Figure 2.\n\nLet each of the sides of the triangle OBE in this figure be divided by cDtAB and denote them by a dashed superscript, which then gives OB/ =OB/cDtAB; OE/ = OE/cDtAB. Hence triangles OBE and OB/E/ are similar which gives\n\nOB/ = OA/ = cDtBB/cDtAB = cDtAA/cDtAB = γ;\n\nE/B/ = DxAAB/cDtAB = γDxAAB/cDtAA = γv/c;\n\nOE/ = 1.\n\nThe energy/momentum vectors can then be obtained by multiplying each of the sides by B’s rest mass energy (E0 = mc2) where m is B’s mass. In turn this gives\n\nOE/ = E0.\n\nOB/ = γE0 = E.\n\nE/B/ = γmc2v/c = pc,\n\nwhere p is momentum, i.e. p = γmv.\n\nFrom Figure 2, OB2 = OE2 + EB2. Hence (OB/)2 = (OE/)2 + (E/B/)2, and so\n\nas in the coordinate theory.\n\nIt should be noted that the rest mass energy lies in A’s time direction and so appears to be linked to the continually changing time, i.e. it is a kinetic rather than a static phenomenon.\n\nLet κ = E/cDtAA = E/cDtBB where the mass term m in E = γmc2 is still B’s mass. From this, κ is also equal to E0/cDtAB. Substituting κ into Equation (19) leads to the general conclusions that DtNN is proportional to E; DtNM is proportional to E0 and hence\n\nThis is consistent with the basic hypothesis made in the dynamic theory that the measurement of time, which underpins SR, is based on the observed expenditure of the energy of objects.\n\nThe 4-vector, acceleration and force. Strictly acceleration does not belong in SR, but since we are dealing with 4-vectors, and this is an area of significant difference in terms of interpretation between the theories, it is included here.\n\nIn the standard coordinate theory the 4-force (F) is\n\nFµ = dpµ/dτ\n\nwhere µ = 0, 1, 2, 3 denoting the dimension the force is acting in, i.e. Fµ is equivalent to force components acting in time(t), x, y, z.\n\nBy removing the mass we get the 4-acceleration (Aµ) which is equal to dUµ/dτ (U equals velocity). The acceleration in the time direction is\n\nA0 = dU0/dτ = dγ/dτ.\n\nAlong the x axis the acceleration is A1 = dU1/dτ = d(γv)/dτ.\n\nIn the dynamic theory sinζ = BE/OB (≡ BE/OA) in Figure 2,\n\ni.e. ζ = sin−1(DxAAB/cDtAA) = sin−1(v/c).\n\nNow γ = (1 − v2/c2)−1/2 or γ = cos−1ζ. From this, and after some manipulation\n\nand\n\nAs v → 0, sinζ → ζ, A0 → 0, but A1 → cDζ/DtAA, i.e. while spatial acceleration in the Newtonian limit for the coordinate theory is a = dv/dtA, in dynamic terms this is\n\nHence for the dynamic theory in the Newtonian regime, it is the change in angle per change in time which produces the acceleration rather than the change in velocity per unit time. The total (albeit largely unseen) velocity of the object (c) remains the same before and after the acceleration, only the direction has changed to produce a spatial velocity relative to the observer’s axes, and an apparent time dilation shown by the object’s clock.\n\n\nCosmology\n\nIn describing the universe, the standard theory has evidence of an expanding space-time which started at a singularity and was impelled outwards by the Big Bang some 13.7 billion years ago. In the simplest model the mass of the universe is assumed to be uniformly distributed and the expanding 4D space-time is taken as analogous to the surface of an expanding balloon in which all views and expansions are along the surface. Nothing is assumed to exist outside of this surface so what can be taken in an ordinary balloon as an expansion which is normal to its surface, is only seen in the standard model as a stretching surface. There are a number of problems with this model1 which can be summarised as\n\nThe need for an inflation model. This postulates that at very early times the universe underwent a very rapid expansion which was abruptly switched on and then off, and has never been seen since. There currently appears no solid physical explanation for this model1,3 and the reason for adopting it is that it provides an explanation of some of the following observational conundrums.\n\nThe flatness problem. From observation the universe is very close to its critical mass density which means the curvature of space-time is near zero4. Since the universe is thought to start from a point, the inflation model is needed to suddenly expand to a surface whose curvature is locally insignificant.\n\nThe isotropic or horizon problem. The microwave background radiation is very uniform in all directions. Either we are somehow at a unique place in the cosmos, or all parts of the universe were in contact at the earliest times after the Big Bang. However, the areas that needed to be in contact exist along a line of sight that precludes even the speed of light to be fast enough to provide a connection. Again, the inflation theory can be used to provide an initial expansion that was far faster than the speed of light and so allowed such connections to exist at early times.\n\nThe existence of quantum fluctuations needed to provide the seeds of the current galaxies. The origin of such fluctuations requires the formation of virtual particles that are separated by space-time expanding too fast for them to recombine. An inflation-type model is needed for this expansion.\n\nAnd some items which cannot be explained by inflation.\n\nDark matter. There is a lack of observable mass in the universe needed to account for its expansion using the standard general relativity theory. There also appears to be too little mass to account for the rotation of galaxies. The shortfall is sometimes postulated as being due to a so-far unobserved particle and is often referred to as dark mass. To account for the dynamics of the universe’s expansion using the standard theory, this dark mass would have to consist of about 25 percent of the matter in the universe.\n\nDark energy. It has recently been found5,6 that the expansion of the universe appears to be accelerating, rather than decaying as would be expected if the expansion were only controlled by gravitational effects (or at least, effects due to the standard theory of gravitation). This energy would be equivalent to about 70 percent of the matter needed to model the universe using the standard theory.\n\nThe dynamic theory will attempt to answer all of the above points based on the different structure of the universe generated by the differences between coordinate and dynamic relativistic models. In the dynamic theory no further models, such as inflation, will be needed. The next segment will construct the simplest model of the universe that is consistent with the dynamic theory. The last segment will compare quantitative predictions from this theory with observations.\n\nIn the simplest model the dynamic theory assumes the universe started as a singularity embedded in four spatial (not space-time) dimensions at, what we consider, the time of the Big Bang. This provides a uniform radial expansion in the four dimensions if we assume that mass is uniformly distributed throughout the history of the expansion. This is assumed to be analogous to the expanding shell of a 3D sphere, where the mass can be taken as lying at the centre of the sphere, despite all the material being located in the shell, and there is no gravitational potential along the shell normal to the radial expansion vector.\n\nTime comes into being as soon as the expansion starts. This is the radial expansion vector which is related to the speed of light (see above). In effect the model is the opposite of the standard theory. There nothing exists apart from a 4D surface and expansion, gravitation etc. takes place along this surface. In the dynamic theory, assuming uniform mass, the expansion only occurs radially into a 4D space. From the model outlined in the first few Sections, in our local surroundings 3D beings such as ourselves see this radial expansion as time acting on 3D space, but with no observation of a fourth spatial dimension.\n\nBecause this is a radial expansion, an observer (A) sees a non-local galaxy (such as B) as having a spatial motion away from him as the radial expansion occurs at an angle to A’s time direction. This is very similar to the behaviour of inertial frames in special relativity section. To reiterate, the motion and the curvature is assumed to be normal to a three-dimensional spatial surface. This 3D spatial surface is assumed to be flat, i.e., there is zero intrinsic curvature along this surface while there is extrinsic curvature in the fourth dimension which is locally seen as time, and non-locally seen as providing an increasing velocity of the 3D surface in relation to A, so providing a stretching surface. However, it should be emphasised that the curvature is only in the fourth dimension (see Figure 3).\n\nThere are some points which have to be attached to the simple 4D picture of the dynamic universe (see also Figure 3):-\n\nThere is no significant motion along the surface normal to the radial expansion. Otherwise matter will tend to clump and the uniform mass model will tend to be invalid. Obviously this does happen to an extent in the real universe as galaxies etc. exist. But in this model we are taking the simplest possible mass distribution where in spatial terms it is assumed that most of the universe can be treated as not having clumped matter.\n\nThere is no overall gravitational potential along the 3D surface as it is assumed analogous to a uniform shell of material which forms the surface of a 3D sphere in Newtonian space, where the potential gradient lies along the radius but is zero along the surface normal to this radius. Locally the same comment about non-uniformity applies as in the previous bullet.\n\nAs a consequence of the last point General Relativistic effects can, to a first approximation, be ignored when considering the observed overall motion of this surface, in contrast to the standard theory where they dominate due to all forces having to lie along a 4D surface*.\n\nIn the standard theory the redshift in B, as seen by A, could be generated by either a receding velocity or a gravitational redshift (or a combination of both). From the previous bullets, in the dynamic theory it is assumed that to fit the simple theory the redshift is overwhelmingly provided by a receding velocity, which in turn results from the angle the radial velocity at any location makes with an observer. Hence, to reiterate previous bullets, it is assumed that there is little matter (compared to the mass of the universe) that is trapped in intense local gravitational fields (in a black hole or around stars) or moving at high speeds along the 3D surface.\n\nThe expansion velocity of the universe would be observed to be constant (and equal to the speed of light) once the perspective effects due to curvature have been subtracted, despite the overall expansion probably decreasing. This apparently contradictory state of affairs results from there being no direct way for 3D observers to measure changes in the actual 4D radial expansion rate from within the universe. Any real change in radial motion will be equally seen in both the passage of time and the expansion of space (see Figure 3), so that a phenomenon such as velocity remains unchanged.\n\nIronically having spent most of the first part of this paper trying to emphasise that the time dimension does not exist - at least not when observed from within a given reference frame - now most of the remaining analysis requires the construction of a “time dimension” in order to situate the relative position of bodies and events, e.g. such as where and when A locates galaxy B, or where events are located relative to the Big Bang. This is carried out by integrating the radial motion to provide a dimensional construct in which events lie relative to A.\n\nThere are two types of time shown in the following diagram (Figure 4). Solid black lines are “actual” surfaces which consist of the locus of 4D trajectories from the Big Bang to the present. Each trajectory is locally constructed, e.g. OA and OB in the Figure. The present is the surface constructed from the termination of these trajectories such as at A and B. This surface is where the 4D sphere lies, but is not observable other than locally since information about B can only arrive at A in B’s past. These surfaces are defined in time by integrating cDtAA (see previously for nomenclature).\n\nThe second type (red line) is an observed surface. Observer A sees time dilation effects in B because of the galaxy’s recessional velocity, and these, plus the time delay for photons from B to reach A, only allows A to see B in B’s past (see below for a more detailed analysis). Such observations always occur in A’s present since this is the only time at which A can interact with events or phenomena such as photons. However, that the observation is of B’s past is assessed as being so by A through the methodology discussed below, and which allows A to construct B as a point in A’s own past, i.e. at the location shown on A’s time dimension. These surfaces are defined in time by integrating cDtAB.\n\nTo quantify the simple dynamic model we can draw the Figure 4 from the assumptions previously discussed, i.e. that each part of the universe’s surface is expanding radially outwards at a function of the speed of light and that the trajectories of OA and OB since the Big Bang are straight. These straight lines result from the unchanged velocity (see above) of objects seen by an observer to be moving with this surface. Note that in this simple model the only observable movement on a universal scale is due to the expansion of this surface, high velocity objects along the surface are ignored. From the viewpoint of these observers the surface resulting from the locus of the endpoints of these trajectories is located at cT0 (T0 is the integral of DtNN over the period from the Big Bang to the present - see previous Section). The principal observer is located in the present at position A, although the same figure will be obtained if we swap to B being the principal observer.\n\nAt the risk of some repetition, the details of Figure 4 are summarised in the following bullet points.\n\nA’s view of the universe originates from the “observed” surface (red line) whose derivation is explained in Appendix 1.\n\nAn imaginary superhuman, who can see in four dimensions, will see the “actual” surface moving radially out from the Big Bang. He will see all observers located on the “present” surface (although they will only have A’s view of the rest of the universe), and the past is located at previous positions of the present surface as it expanded out from the Big Bang. These are the concentric surfaces represented by C’C and DD’ on A’s time axis. Note that T = 0 is the location of the Big Bang while T = T0 is the present. Also R = 0 is the Big Bang location in what A sees as a spatial axis, while R = cT0 is the actual (but for A not observable - see above) spatial position of the present surface.\n\nAgain it should be emphasised that from A’s viewpoint his time axis is an imaginary construct where the locations of “actual” past surfaces are obtained by integrating cDtAA in the dynamic theory. The observation of past events - such as the most recent view of galaxy B - will occur in A’s present because this involves the integration of cDtAB, and as explained above, this will be observed by A in his present despite this view being from B’s past. A’s construction of a time axis helps visualise the order of these events, so that A sees B as existing at D’ (T/T0 = 0.55) in the figure (the detailed construction of this is explained below and the next section), while B sees herself at T/T0 = 1. For brevity A’s time axis will be referred to as if it were a real axis in the rest of this paper.\n\nA will see the time of events, such as his view of B, given by clocks located at the event, i.e. in this example the clock is moving with B, hence the time is a function of cDtAB. The exact form of this function is derived below. Photons have DtAP = 0 and so always travel along vertical trajectories in this figure (e.g. CD’ is a photon path). A will see actual surfaces only along his time axis (e.g. at D’ and C’).\n\nNote that each surface links cT to R, so that for A in the present, T0 is the time from the Big Bang while R0(= cT0) is the spatial radius of the present surface.\n\nHow does A observe B?\n\nLet us assume that A and B had clocks travelling with them that were set to zero at the Big Bang and have been accumulating time ever since. Because of the fourth-dimension curvature, A sees B moving at velocity v/c along A’s spatial axis. Because B has a straight radial trajectory, this velocity has not changed over time.\n\nWe are only dealing with special relativity so that A’s observation of B is from C where OC/OB = OC′/OA = (1 − v2/c2)1/2, i.e. to A the galaxy at B has not travelled as far along OB as it should due to the time dilation factor of the apparent velocity.\n\nNote the actual surface CC’, the observed surface (red line) and B’s trajectory all coincide at C (shown in Figure 4 within the limits of the drawing package). The photon from C travels vertically (CD’) to reach A to show B appearing at D in A’s past. In geometric terms the actual surfaces are constructed as OA = OB; OC′ = OC; OD′ = OD.\n\nHow does the dynamic theory answer the problems laid out at the start of this Section which are faced by the coordinate theory?\n\nThe evolution of the universe. The scale factor s of the universe at time T after the Big Bang can be expressed as\n\nHence it can measure the amount of stretch in the surface between then (T) and now (T0), and is often used when comparing experiment and theory. Let s be the scale factor resulting from the ratio, shown in Figure 4, of B’s apparent position on A’s time axis (OD’) and A’s present (OA), i.e. s = OD′/OA. (Equally B locates A along her time axis (OB) as being on the same surface, DD’, but with s = OD/OB). However, when concentrating on A, A’s estimation of the real position of B (OB), and the ratio of the apparent to real positions (OD’/OB), are not entirely along A’s time axis (OA). Hence his view of the apparent value of s for B on surface DD’ is affected by three phenomena discussed below\n\nThe relativistic Doppler redshift.\n\nThe redshift z is related to the frequency of light emitted at B from surface DD’ (fe) and the frequency observed at A (f0) by 1 + z = fe/ f0. The coordinate relativistic Doppler redshift is then related to the recessional velocity by 1+z = ((1+v/c)/(1−v/c))1/2. The redshift has the same function as if the object being measured is embedded in a surface which is stretching between it and the observer.\n\nThen 1 + z = fe/f0 = λ0/λe = OA/OD′ = OB/OD = 1/s.\n\nBy combining the two versions of 1+z and rearranging we get\n\n\n\nThis only applies along B’s trajectory (OB) from A’s viewpoint as A cannot see himself in motion, only B appears to have motion - see the Special Relativity (SR) Section.\n\nThe trajectory reduction.\n\nAs already mentioned, A will see B’s trajectory foreshortened due to the space-time dilation effects of B’s relative velocity. B will have only apparently travelled to OC rather than OB where OC/OB = (1 − v2/c2)1/2. However, we already have v/c as a function of s from the Doppler redshift, and so to make the two phenomena consistent, A’s ultimate view of OD′/OB has to incorporate OC/OB (= OC′/OB), i.e.\n\n\n\nThe photon travel.\n\nFrom A’s viewpoint B is on surface CC’, from which a photon has to be emitted to reach A. This is along CD’ which is a time OC′ − OD′ in the past from the surface CC’ on which (from A’s viewpoint) B should be located. We note that OC′−OD′ lies entirely along A’s time axis and so is purely a geometric term when looking at Figure 4. Let angle DOD′ = ζ.\n\nThen in geometric terms, cosζ = OD′/OC = OD′/OC′ = OC′/OA.\n\nHence OD′/OA = (OC′/OA)2 = s, and so along A’s time axis\n\nWe have already defined the scale factor s to be OD′/OA along A’s time axis. However, A sees the scale factor for B between the same two actual surfaces as\n\nOD′/OB = (OD′/OC′)(OC′/OB) = s1/2(1 − [(1 − s2)/(1 + s2)]2)1/2.\n\nLet OD′ = cT and OB = cT0 and after some simplification A’s view of B is\n\nLet H(T) be the Hubble parameter at time T after the Big Bang and H0 is the present value of the parameter. H0 = 1/T0 and H(T) = s−1ds/dT. From A’s viewpoint H(T) varies along the time axis (OA) and along this axis R/T = dR/dT = c, the velocity of light (each actual surface is at R = cT). Since s = R/R0 then ds/dT = R0−1dR/dT and so\n\nLet H(T) be designated as just H. Now H =1/T and so H/H0 = T0/T. Note that in the dynamic theory H is different to the coordinate theory where H = 2/(3T). This difference occurs because in the coordinate theory the variation in H is based on the density of the universe, in contrast to the dynamic theory which is based on geometric effects, i.e. in the coordinate theory\n\nwhere ΩM is the current normalised density of matter (the Standard Cosmology Model (SCM) value quoted in 9 is 0.32); ΩR is the normalised density of radiation (5×10−5 and so is ignored for what follows); and the SCM value for ΩΛ (the normalised dark energy coefficient) is 0.68.\n\nIn the dynamic theory the variation in H is based on the geometry of the universe and, since this is based on special rather than general relativity, this is due to perspective effects (as discussed further below) and so is more apparent than real.\n\nIn the dynamic theory, from the above relationships A’s view of B is\n\nRemembering that s = 1/(1 + z), Figure 5 shows a comparison of the two theories (Equation (30) and Equation (31)).\n\nConsidering the simplicity of the model used in the dynamic theory, it is remarkably close overall to the SCM coordinate theory’s values for the coefficients (red dashed line, in the Figure). A rather better fit to the higher z values is given by the blue line (coefficients given in the Figure) as will be explored below and in Figure 6 when the relationships are differentiated. The dynamic theory (solid black line) comes just from the geometry of the universe’s structure that was obtained by changing from coordinate to dynamic representations of space and time as outlined previously.\n\nThe important points to take away from the dynamic theory are: -\n\nThe change in Hubble parameter shown in Figure 5 is obtained from A’s observation of B. However, these are not the actual surfaces. For that H0/H = T/T0 = s. Very much like in special relativity A’s view of B, i.e. T/T0 = 2s3/2/(1+s2), is due to perspective rather than any real relationship. B’s view of A will be identical.\n\nThe match between the dynamic and coordinate theories in describing the universe’s evolution means that if there is any merit in the dynamic solution, there is no need to consider that the overwhelming proportion of dark mass (represented by ΩM in the coordinate theory) exists. However, some must be present (or some currently unknown physical phenomenon must apply) as the rotation of galaxies requires more mass than is observable.\n\nThe match can also mean that dark energy (the accelerating universe represented by ΩΛ) is also just a feature of perspective. This follows from the differential of the observable surface that shows the universe slowing down at large redshifts - as would be expected in the coordinate theory from the effects of gravity - and then in the relatively recent past beginning to accelerate. This is shown below (Figure 6), along with the position, in terms of redshift, where the dynamic theory predicts the acceleration to start. Comparisons of this start (za) with results from various models based on both the coordinate theory and observational astronomy are given in Table 1 below.\n\nThe differential ds/dT of A’s observation of B in the dynamic theory is given by H0/H = T0−1s(ds/dT)−1. Hence\n\n\n\nThis should be compared to the coordinate acceleration of\n\n\n\nThese equations are shown in terms of redshift (z) in Figure 6 and (za) in Table 1 below.\n\nIt should be noted from Figure 6 that when the dynamic curve is divided by T0 - the current age of the universe for an observer - the shape of the curve (i.e. the late time acceleration) is independent of the epoch in which the observation is made.\n\nThe flatness problem. In the dynamic theory the curvature is always caused by the radial velocity. In turn this is always in the time direction for human observers - a direction in which locally they cannot see any sort of dimension. This is illustrated in qualitative terms by Figure 3 in which it is assumed that A can see the current (according to both A’s and B’s clocks) position of B with no account taken of time dilations or delays. See previous Section for a more quantitatively precise description of A’s view of B in the dynamic theory. In Figure 3, A is again the main observer and B a distant galaxy. The real (i.e., total) motion of B lies along B’s time axis, which is orthogonal to the 4D surface. A sees only the spatial component of B’s real motion as a velocity lying parallel to A’s spatial dimension, and hence, from A’s viewpoint, projected onto it. In the Figure, a photon would have its time direction aligned with A’s spatial axis and its space direction along A’s time axis.\n\nThe dynamic universe has an extrinsic curvature, the curvature being confined to the fourth dimension. However, to any observer on this 4D surface one of these dimensions is missing (it is in the time direction) and the three remaining spatial dimensions having no intrinsic curvature appear flat.\n\nConsequently, it is possible for this 3D space to appear flat from the viewpoint of any observer located on the 4D surface (B and A can be interchanged in terms of what each sees of the other). The only view an observer such as A has of this curvature is the projection of the radial velocity onto his 3D space by distant objects.\n\nThe horizon problem. This is simply solved in the dynamic theory because all elements of the universe are in contact in the 4D space at the location of the Big Bang. While the coordinate theory has to deal with connections between various parts of the universe within an expanding surface when trying to explain the isotropic nature of the microwave radiation, the dynamic theory postulates that all parts were initially in contact and expanded radially outwards.\n\nDark mass and dark energy. The dark energy needed to explain the late-time acceleration of the universe in the coordinate theory, appears in the dynamic theory to be due to the perspective created by the presence of observed rather than actual surfaces (see above), i.e. in the dynamic theory there is no requirement for it to exist.\n\nA lot of the dark mass also appears to be due to problems with the perspective and can be explained away as not required in the dynamic theory. However, this may not be true for all of it as there remains some unanswered questions about the rotation of galaxies for instance.\n\nInflation-type behaviour. Working through the various relationships obtained previously shows that Equation (32) can be written as\n\n\n\nwhere R = R/R0, i.e. the radius of the universe at time T from the Big Bang, normalised by the current radius. As can be seen dR/dT = c at the present time, and tends to infinity for values of R close to zero at T = 0. Hence the inflation-type behaviour is implicit in the model without resorting to a separate phenomenon.\n\n\nDiscussion and conclusions\n\nThe basis of this paper results from a paradox. The way we measure space and time show that they are two very different entities. And yet it has been shown beyond doubt that they need to be fused into space-time in order to accurately describe our universe. One may argue that “real” space and time are far removed from the way we measure them, and this could well be the case. However, at its most basic construction these two entities have been defined by the ruler and the clock, and on this has been erected one of the most successful theories in science. However, it is a theory which on a cosmic scale has produced conundrums. It has been argued in this paper that such conundrums have arisen because there is more than one way that this fusion of space and time can be achieved.\n\nThe use of a dynamic theory to create such a fusion allows for the same local dynamic descriptions as the standard coordinate theory for special relativity (SR), but has them occurring against the background of a different universal structure. This theory arises from the following summary of the chain of arguments:-\n\nThere is no directly observable dimension in time when seen from within an inertial frame, and changes in time are the only dynamic property of the frame that can be experienced by an observer from within this frame. However, both spatial and temporal changes relating to that frame can be seen from other frames.\n\nOnly spatial coordinates are present in all the observed frames. A spatial position can physically be visited many times, a temporal event can only be physically visited once.\n\nSpatial coordinates can be observed but temporal coordinates have to be constructed from second-hand experiences, such as memory or films, coupled with the calculation of the integral of the change in time displayed by clocks.\n\nIt is argued that the changes in the present are measured by changes in energy, and so it is possible to choose energy and momentum to construct a space-time coordinate system rather than assume a coordinate system exists against which energy and momentum can be measured.\n\nHow does such a system tie up with a coordinate description to give the same predictions for SR phenomena such as high-speed objects?\n\nChanges in coordinates can be grouped together by the Minkowski metric, i.e. c2dτ2 = c2dtN2−dxN2 (see previously for nomenclature), where dτ is an invariant for inertial frames. Grouping together the dynamic properties gives the dynamic metric c2DtNN2=c2DtNM2+DxNNM2,\n\nwhere DtNN is the invariant. Both Minkowski and dynamic metrics apply along the time-like hyperbola in Figure 1 (Equation (9)).\n\nBoth theories give the same Lorentz transformation (Equation (15)–Equation (17)).\n\nBoth theories give the same relativistic energy/momentum equation (Equation (19)).\n\nWhere does the dynamic theory part company with the standard coordinate theory?\n\nIt is shown that time from a viewpoint within a frame is a constant motion along a space dimension from a viewpoint outside that frame.\n\nIn the limit this spatial motion is equivalent to the speed of light, while the space along which this motion takes place is rolled up into a point for an observer inside the frame who experiences this phenomenon as time (i.e. there is no observable dimension in one’s own time).\n\nThis indicates a universe of four spatial dimensions, which are always seen as three spatial dimensions and a continuously changing present.\n\nIn this theory, relative velocity is obtained from differences in the spatial direction of the motion in the fourth dimension, and not by changing its real magnitude.\n\nSR phenomena such as time dilation result from a change of perspective, not a change in magnitude. Consequently, while frame A sees frame B as having a slower clock than his own, frame B has exactly the same view of A.\n\nCounter-intuitively GR does not play a role in the simplest dynamic cosmology model outlined in the next segment. The reason is that GR is important in local phenomena such as the space-time surrounding massive objects, but on the cosmological scale in the dynamic theory, observations such as the Hubble redshift can be treated as geometric-based phenomena. These arise from the presence of a fourth spatial dimension, as discussed above.\n\nThe extra spatial dimension along which objects are in motion, that is derived from the SR model in the dynamic theory, allows a simple description of the universe:-\n\nIn the simplest model that can be constructed, the dynamic theory assumes the universe started as a singularity embedded in four spatial (not space-time) dimensions at - what we consider to be- the time of the Big Bang.\n\nThis provides a uniform radial expansion in the four dimensions if it is assumed that mass is uniformly distributed throughout the expansion.\n\nTime comes into being as soon as the expansion starts. This is the radial expansion vector which is related to the speed of light. In the simple dynamic model, assuming uniform mass and negligible motion along the universe’s surface, the expansion only occurs radially into a 4D space. See Figure 3 and the accompanying section for how the radial expansion is experienced locally as time, and from a distance as a spatial velocity.\n\nEqually, for such a model, there is assumed to be no overall gravitational potential along the 3D surface. It is assumed to be analogous to a uniform shell of material which forms the surface of a 3D sphere in Newtonian space, where the potential gradient lies along the radius but is zero along the surface.\n\nIn the standard theory the redshift in a distant galaxy, as seen from Earth, could be generated by either a receding velocity or a gravitational redshift (or a combination of both). From the previous two bullets, in the dynamic theory it is assumed that to fit the simple theory the redshift is overwhelmingly provided by a receding velocity, which in turn results from the angle the radial velocity at any location makes with an observer (Figure 3). Hence, it is also assumed that there is little matter (compared to the mass of the universe) that is trapped in intense local gravitational fields (in a black hole or around stars) or moving at high speeds along the 3D surface.\n\nIn effect the model is the opposite of the standard theory. There nothing exists apart from a 4D surface, and expansion, gravitation etc. takes place along this surface. From the model outlined above, in our local surroundings 3D beings such as ourselves see this radial expansion as time acting on 3D space, but with no observation of a fourth spatial dimension. The universe, from some outside perspective, is a 3D surface located in a 4D space into which it is expanding.\n\nThe quantitative version of the model is derived in the cosmology sections. The detailed mathematics is left for the main text but the results can be summarised as follows:-\n\nThere is excellent agreement between the dynamic theory and the best observations of the evolving universe (Figure 5, Figure 6 and Table 1). Consequently, if there is any merit in the dynamic theory the implications can be summarised by the following bullets.\n\nVery much like in special relativity Earth’s view of a distant galaxy’s motion (i.e. the redshift) is due to perspective. The galaxy’s view of Earth will be identical.\n\nThe match between the dynamic and coordinate theories in describing the universe’s evolution means that there is no need to consider that the overwhelming proportion of dark mass exists. However, some must be present (or some currently unknown physical phenomenon must apply) as the rotation of galaxies requires more mass than is observable.\n\nThe match means that dark energy is just a feature of perspective and not real, or at least cannot be determined by current observations. (One drawback of the dynamic theory is that there is no direct way for 3D observers to measure changes in the actual 4D radial expansion rate from within the universe. Any real change in radial motion will be equally seen in both the passage of time and the expansion of space, so that a phenomenon such as velocity remains unchanged.)\n\nComparisons of the theory’s start of the universe’s late time acceleration (za) with results from various models based on both the coordinate theory and observational astronomy show good agreement.\n\nIt should be noted from Figure 6 that when the universe’s acceleration curve is normalised to the current age of the universe, the shape of the curve (i.e., the late time acceleration) is independent of the epoch in which the observation is made.\n\nThe inflation model is not needed to account for the flatness and horizon problems, although it is implicit in the dynamic model. Near the time of the Big Bang the expansion tends to infinite velocity to an observer at any point (except in a black hole) on the current 3D surface of the universe. Consequently, it can be deduced to have the right conditions to supply the quantum fluctuations needed to provide the seeds of the current galaxies. The origin of such fluctuations requires the formation of virtual particles that are separated by space-time expanding too fast for them to recombine.\n\nTo sum up, this paper attempts to show that it is possible to have an alternative view of space-time which agrees with the standard theory for local phenomena but provides a different view of the overall structure of the universe. This in turn provides some possible answers to some of the current problems faced in cosmology. It is far from the complete answer to every conundrum, but it is hoped that it may provide some alternative pathways to explore in the future (or from the dynamic viewpoint, in a present which is not currently being accessed!).\n\nAppendix 1: equation for the observable surface\n\nIn Figure 4, the observable surface is OCA (red line). In this figure angle DOD′ = ζ gives the relationships sinζ = v/c = BC′/OB = CD′/OC. As already defined in this figure cT = OD′ and cT0 = OB. Let cT1 = OC′ and remember that with the actual surfaces OB = OA; OC = OC′; and OD = OD′.\n\nHence sinζ = BC′/cT0 = CD′/cT1 . As previously found cosζ = T/T1 = T1/T0, and so cos2ζ = T/T0.\n\nThen T/T1 = cosζ = (1 − sin2ζ)1/2 = (1 − CD′2/(cT1)2)1/2.\n\nRearranging\n\nT2 = T12 − CD′2/c2.\n\nThen combining this with T/T0 gives\n\nT/T0 = cos2ζ = 1 − CD′2/(cT1)2 = 1 − CD′2/[(cT)2 +CD′2].\n\nFrom this\n\nT/T0 = (cT)2/[(cT)2 +CD′2]\n\nand after some manipulation\n\nCD′/cT0 = CD′/R0 = [T/T0 − (T/T0)2]1/2\n\nLet CD′ = X and BC′ = X0. Then we can write for the observed surface\n\n\n\nFor the actual surface, AB is given by\n\n\n\n\nData\n\nNo data are associated with this article.\n\n\nAuthor endorsement\n\nProfessor John Curtis confirms that the author has an appropriate level of expertise to conduct this research, and confirms that the submission is of an acceptable scientific standard. Professor John Curtis declares they have no competing interests. Affiliation: Atomic Weapons Establishment; Visiting Professor UCL Mathematics Department.", "appendix": "Footnotes\n\nThis view has a long history, e.g. Heraclitus of Ephesus (c.535-c.475BC) has an ever-present change being a fundamental essence of the universe2\n\nThere are theories which postulate non-standard gravitational behaviours and a large number of alternative theories exist to explain the apparent effect of dark energy. See a summary and references in 7\n\n**See, however8, for example where an eleven dimensional space is discussed.\n\n\nAcknowledgements\n\nThe author wished to thank those who initiated invaluable discussions and gave advice during the early stages of the production of this paper.\n\n\nReferences\n\nPeebles PJE, Ratra B: The Cosmological Constant and Dark Energy. Rev Mod Phys. 2003; 75: 559–606. Publisher Full Text\n\nBeris AN, Giacomin AJ: Everything flows. Appl Rheol. 2014; 24(5): 1–13. Publisher Full Text\n\nEarman J, Mosterin J: A Critical Look at Inflationary Cosmology. Philosophy of Science. 1999; 66(1): 1–49. Publisher Full Text\n\nSuzuki N, Rubin D, Lidman C, et al.: The Hubble Space Telescope Cluster Supernova Survey. V. Improving the Dark Energy Constraints Above z > 1 and Building an Early-Type-Hosted Supernova Sample. Astron J. 2012; 746(1): 85. Publisher Full Text\n\nPerlmutter S, Aldering G, Goldhaber G, et al.: Measurements of Ω and Λ from 42 High-Redshift Supernovae. Astron J. 1999; 517(2): 565–586. Publisher Full Text\n\nRiess AG, Filippenko AV, Challis P, et al.: Observational Evidence from Supernovae for an Accelerating Universe and a Cosmological Constant. Astron J. 1998; 116(3): 1009–1038. Publisher Full Text\n\nRashki M, Fathi M, Mostaghel B, et al.: Interacting dark side of universe through generalized uncertainty principle. arXiv: 1901.05766v2. 2019. Publisher Full Text\n\nRostami T, Jalalzadeh S: Why the measured cosmological constant is small. arXiv: 1510.02068v1. 2015. Publisher Full Text\n\nPlanck Collaboration: Ade PAR, Aghanim N, et al.: Planck 2013 results. I. Overview of products and scientific results. Astron Astrophys. 2014; 571: 48. Publisher Full Text\n\nFarooq O, Madiyar FR, Crandall S, et al.: Hubble parameter measurement constraints on the redshift of the deceleration-acceleration transition, dynamical dark energy, and space curvature. arXiv: 1607.03537v2. 2016. Publisher Full Text" }	[ { "id": "139580", "date": "18 Jul 2022", "name": "Boudewijn F. Roukema", "expertise": [ "Reviewer Expertise Observational cosmology", "galaxy formation", "large-scale structure", "cosmic topology", "inhomogeneous cosmology." ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe aim of this paper is, apparently, to propose a differential pseudo-Riemannian manifold (a topological manifold M' endowed with a pseudo-Riemannian metric g', i.e. (M', g') that is an alternative to Minkowski spacetime (M, g) as a model for special relativity. However, the language and equations make it very difficult to guess what (M', g') is being proposed. It is unclear if the author is trying to express the relation between different coordinate systems for a single spacetime, or describe a relation between two or three spacetimes. Physically, the introductory section includes the experimentally absurd assertion that bradyons do not exist; and the so-far experimentally unestablished claim that tachyons exist (\"... an observer...can only influence or be influenced by events which happen in the present\").\nThe lack of a clear proposal for the paper's main aim - an alternative to Minkowski spacetime - makes it impossible to judge the proposal's implications for cosmological spacetimes. The author also appears to suggest that the proposed spacetime is identical to Minkowski spacetime (abstract: \"the relativistic equations are unchanged for local phenomena such as the Lorentz coordinate transformation and the energy/momentum equation for high-velocity objects\"), in which case there is no new proposal.\nI would suggest that the author first work through Taylor & Wheeler's \"Spacetime physics\"1 - a geometrical approach to special relativity, as opposed to the historical approach, before attempting to propose an alternative to Minkowski spacetime. The alternative model should be clearly defined using standard mathematical terminology of differential geometry, or of another field of mathematics if the model is not differentiable pseudo-Riemannian 4-manifold.\nSome specific examples of problems follow:\nThe abstract states that the \"equations\" of special relativity following from (M', g') are identical to those for (M, g). It incorrectly states that a coordinate framework is a fundamental requirement of the theory. Special relativity assumes that bradyonic particles exist as timelike world lines in (M, g) independent of any coordinate system.\nThe paragraph \"Basically, relativistic effects...\" is an extremely confusing way of presenting the worldline of an observer in Minkowski spacetime. It asserts the existence of tachyons and rejects the existence of bradyons: \"...what an observer experiences as time, i.e. he is always trapped in the current moment in the sense that he can only influence or be influenced by events which happen in the present.\" Influencing or being influenced by events at a constant time in a chosen reference frame (x, t) requires the use of tachyons, where these tachyons have world lines that exist along a constant t and cover an interval in x from the observer to the event being influenced or that influences the observer.\nThe paragraph \"Time in this view appears...\" fails to explain what (M', g') is being proposed. The sentence \"The dynamic view keeps time as an ever-changing entity...\" fails to say what time changes with respect to. If the change is with respect to time, then the simplest interpretation is that time t changes with respect to time t, yielding dt/dt = 1. This gives no difference from Minkowski spacetime, and would imply that the phrase \"time... as an ever-changing entity\" is an obfuscatory way of saying in words that dt/dt = 1.\nThe section \"The intersection of the coordinate and dynamic theories\" appears intended to present (M', g'), but fails to define energy and momentum. In Minkowski spacetime, these are defined in terms of the 4-momentum, and for a bradyon as the mass times the 4-velocity. We cannot know what the author's definition is prior to the definition of the spacetime itself.\nMore fundamentally, while the line element of metric can be expressed in terms of small changes in the values of coordinates, the author's proposal appears to combine two coordinate systems for time, and three coordinate systems for space. This leaves the reader with no help in understanding what (M', g') is being proposed. If three different metric spaces are being proposed using three different line elements written with a single coordinate system, then that should be done. The relation between the three metrics would also have to be defined.\nThe uses of the verbs \"see\" and \"exist\" in the text are generally confusing for the presentation of an alternative spacetime geometry to Minkowski spacetime.\nOne example of confusing phrases in the section \"The simple dynamical model\" is \"This provides a uniform radial expansion in the four dimensions...\" There is no radial expansion in any standard (Friedmann-Lemaitre-Robertson-Walker, FLRW) model, since an FLRW universe has no centre. In some cases, the embedding of the spatial section of an FLRW universe in a higher dimensional space X is useful for intuition and for calculations, but this does not imply any physical significance for the space X. The author's apparent inclusion of a \"fourth dimension\", which appears to be either spacelike or timelike at different points in the text, with an unclear relation to (M', g'), does not help to clarify what \"radial expansion\" might be intended to mean. (The observer's past time cone is radial by construction, with the observer at the centre, but constructing a spacetime by starting with the observer still requires unambiguously defining the general characteristics of the class of spacetimes that are under consideration).\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? No", "responses": [ { "c_id": "8594", "date": "04 Aug 2022", "name": "Hugh James", "role": "Author Response", "response": "The paper defines a possible alternative space time (Dynamic space time, or DS) to that of Minkowski. It does not assert the non- existence of bradyons and the existence of tachyons, this is based on a misconception of how DS is constructed (see below). A Cartesian coordinate system is used throughout, and only inertial frames (IFs) are considered. The alternative spacetime is based on the differences of how space and time are measured, and leaves aside any consideration of what they might “really” be. Space coordinates are based on a ruler - a distribution of mass to which coordinates can be assigned. A clock output is an energy release which can be equated to a continuously changing time, and from which temporal coordinates can be constructed. Minkowski converts clock outputs to temporal coordinates to obtain a non-Euclidean spacetime (Eqn.1). DS partners momentum to the clock energy release. An observer in an IF (e.g. labelled A) can only see a clock changing and not the IFs momentum. He also cannot see a dimension in what can be hypothesised as the time direction (orthogonal to his x,y,z space). He exists in an ever-changing present - not at a constant time (and hence nothing to do with tachyons). From this changing present can be constructed an imaginary time dimension by using memories or recording devices. A temporal coordinate in this dimension can only be physically visited once, unlike the physically real spatial coordinates which can be visited many times. As A cannot use his own momentum, he uses his observations of a different IF (B). The combination of A’s time and A’s observation of B’s energy and momentum gives A’s Euclidean DS spacetime (Eqn.3). The observation of these phenomena indicates that both (energy release and momentum) are relative, i.e. A’s clock is relative to (A’s observations of B’s) clock and spatial motion, which means that for a single observer dt is not just a change in time. The verbs “see” and “exist” refer to physically-based phenomena such as spatial coordinates or a changing time, and not to an imaginary time dimension. The derivation of A’s spacetime leads to the hypothesis that in DS it is the clock co-located with the observer that provides the invariant, in contrast to Minkowski where it is the moving clock that is invariant. DS confines any bradyon to its own time direction (OA, OB, OG in Fig.1) and actually located at A, B, G in that Figure, which is on the time-like hyperbola provided by Minkowski. Hence only along this hyperbola can the two spacetimes (Euclidean and non-Euclidean) intersect to agree on Lorentz transformations, the 4-momentum etc. Away from this they are different and Fig.2 shows how each IF is seen from within as 3 spatial dimensions and a changing time in which any dimension has rolled up to a point. From outside this IF the changing time is seen as a motion along a spatial dimension. This leads to the hypothesis that the universe consists of 4 spatial dimensions which, in the simplest case, has bradyons travel radially outwards from a common centre. These bradyons form a surface which is orthogonal to the radial motion, and although this radial motion is at the speed of light, this is the rate of expansion of the universe. The observed bradyon motion is the component of this expansion along the surface when seen from a different IF (Figs 3 & 4), and so does not contravene the requirement that bradyons should travel slower than the speed of light. From within the IF this radial motion is experienced as the changing time. This is not an FLRW model, but results from an FLRW model can be compared to those from DS (Figs 5 & 6, Table 1). The use of only IFs and not general relativity in constructing this model is discussed in the Conclusions and Discussion of the paper." } ] } ]	1	https://f1000research.com/articles/11-344
https://f1000research.com/articles/13-792/v1	11 Jul 24	{ "type": "Data Note", "title": "A guide to selecting high-performing antibodies for S1PR1 (UniProt ID: P21453) for use in western blot, immunoprecipitation, and immunofluorescence", "authors": [ "Riham Ayoubi", "Maryam Fotouhi", "Charles Alende", "Sara González Bolívar", "Kathleen Southern", "Carl Laflamme", "NeuroSGC/YCharOS/EDDU collaborative group", "ABIF consortium", "Riham Ayoubi", "Maryam Fotouhi", "Charles Alende", "Sara González Bolívar", "Kathleen Southern" ], "abstract": "Sphingosine 1-phosphate receptor 1 (S1PR1) is a G-coupled protein receptor that induces crucial biological processes when bound by sphingosine 1-phosphate. Here, we have characterized nine S1PR1 commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.", "keywords": [ "UniProt ID P21453", "S1PR1", "sphingosine 1-phosphate receptor 1", "EDG1", "antibody characterization", "antibody validation", "western blot", "immunoprecipitation", "immunofluorescence" ], "content": "Introduction\n\nSphingosine 1-phosphate receptor 1 (S1PR1), is a G-protein coupled receptor which binds to its abundant ligand, sphingosine 1-phosphate, inducing intracellular signalling pathways in cell growth, differentiation, migration and trafficking.1–4 S1PR1 activation by sphingosine 1-phosphate is essential for neuronal events, and its dysregulation may contribute to the pathogenesis of Alzheimer’s disease.5,6 High-performing S1PR1 antibodies would facilitate S1PR1 research and uncover therapeutic strategies.\n\nThis research is part of a broader collaborative initiative in which academics, funders and commercial antibody manufacturers are working together to address antibody reproducibility issues by characterizing commercial antibodies for human proteins using standardized protocols, and openly sharing the data.7–9 Here we evaluated the performance of nine commercial antibodies for S1PR1 for use in western blot, immunoprecipitation, and immunofluorescence, enabling biochemical and cellular assessment of S1PR1 properties and function. The platform for antibody characterization used to carry out this study was endorsed by a committee of industry and academic representatives. It involves identifying appropriate cell lines with adequate target protein expression, developing or contributing equivalent knockout (KO) cell lines and finally, characterizing most commercially available antibodies against the corresponding target protein. The standardized antibody characterization protocols are openly available on Protocol Exchange (DOI: 10.21203/rs.3.pex-2607/v1).10\n\nThe authors do not engage in result analysis or offer explicit antibody recommendations. A limitation of this study is the use of universal protocols - any conclusions remain relevant within the confines of the experimental setup and cell line used in this study. Our primary aim is to deliver top-tier data to the scientific community, grounded in Open Science principles. This empowers experts to interpret the characterization data independently, enabling them to make informed choices regarding the most suitable antibodies for their specific experimental needs. Guidelines on how to interpret antibody characterization data found in this study are featured on the YCharOS gateway.11\n\n\nResults and discussion\n\nOur standard protocol involves comparing readouts from WT (wild type) and KO cells.12,13 The first step is to identify a cell line(s) that expresses sufficient levels of S1PR1 to generate a measurable signal using antibodies. To this end, we examined the DepMap transcriptomics database to identify all cell lines that express the target at levels greater than 2.5 log2 (transcripts per million “TPM” + 1), which we have found to be a suitable cut-off (Cancer Dependency Map Portal, RRID:SCR_017655). The SK-HEP-1 cells expresses the S1PR1 transcript at 6.5 log2 (TPM+1) RNA levels, which is above the average range of cancer cells analyzed. Parental and S1PR1 KO SK-HEP-1 cells were obtained from Abcam (Table 1).\n\nFor western blot experiments, WT and S1PR1 KO protein lysates were rain on SDS-PAGE, transferred onto nitrocellulose membranes, and then probed with nine S1PR1 antibodies in parallel (Table 2, Figure 1).\n\n* Monoclonal antibody.\n\n Recombinant antibody.\n\nLysates of SK-HEP-1 (WT and S1PR1 KO) were prepared and 30 μg of protein were processed for western blot with the indicated S1PR1 antibodies. The Ponceau stained transfers of each blot are presented to show equal loading of WT and KO lysates and protein transfer efficiency from precast midi 4-20% Tris-Glycine polyacrylamide gel (Thermo Fisher Scientific, cat number WXP42012BOX) to the nitrocellulose membrane. Antibody dilutions were chosen according to the recommendations of the antibody supplier. Antibody dilution used: ab233386 at 1/1000, A12935 at 1/1000, ARP80838 at 1/500., NBP2-67129 at 1/1000, 63335 at 1/1000, 55133-1-AP at 1/1000, MA5-32587 at 1/1000, MA5-35431 at 1/1000, MA5-38484* at 1/500. Predicted band size: 42.8 kDa. Monoclonal antibody, Recombinant antibody.\n\nWe then assessed the capability of all nine antibodies to capture S1PR1 from SK-HEP-1 protein extracts using immunoprecipitation techniques, followed by western blot analysis. For the immunoblot step, a specific S1PR1 antibody identified previously (refer to Figure 1) was selected. Equal amounts of the starting material (SM), the unbound fraction (UB), as well as the whole immunoprecipitate (IP) eluates were separated by SDS-PAGE (Figure 2).\n\nSK-HEP-1 lysates were prepared, and immunoprecipitation was performed using 2.0 μg of the indicated S1PR1 antibodies pre-coupled to Dynabeads protein A or protein G. Samples were washed and processed for western blot on a precast midi 4-20% Tris-Glycine polyacrylamide gel with the indicated S1PR1 antibodies. For western blot, ab233386* was used at 1/1000. The Ponceau stained transfers of each blot are shown. SM = 4% starting material; UB = 4% unbound fraction; IP = immunoprecipitate, HC = antibody heavy chain, LC = antibody light chain. Monoclonal antibody, Recombinant antibody.\n\nFor immunofluorescence, nine antibodies were screened using a mosaic strategy. First, SK-HEP-1 WT and S1PR1 KO cells were labelled with different fluorescent dyes in order to distinguish the two cell lines, and the S1PR1 antibodies were evaluated. Both WT and KO cells were imaged in the same field of view to reduce staining, imaging and image analysis bias (Figure 3). Quantification of immunofluorescence intensity in hundreds of WT and KO cells was performed for each antibody tested,10 and the images presented in Figure 3 are representative of this analysis.\n\nSK-HEP-1 WT and S1PR1 KO cells were labelled with a green or a far-red fluorescent dye, respectively. WT and KO cells were mixed and plated to a 1:1 ratio in a 96-well plate with optically clear flat-bottom. Cells were stained with the indicated S1PR1 antibodies and with the corresponding Alexa-fluor 555 coupled secondary antibody including DAPI. Acquisition of the blue (nucleus-DAPI), green (identification of WT wells), red (antibody staining) and far-red (identification of KO cells) channels was performed. Representative images of the merged blue and red (grayscale) channels are shown. WT and KO cells are outlined with green and magenta dashed line, respectively. When an antibody was recommended for immunofluorescence by the supplier, we tested it at the recommended dilution. The rest of the antibodies were tested at 1 and 2 μg/ml and the final concentration was selected based on the detection range of the microscope used and a quantitative analysis not shown here. Antibody dilution used: ab233386* at 1/400, A12935 at 1/1000, ARP80838 at 1/250., NBP2-67129 at 1/1000, 63335 at 1/2000, 55133-1-AP at 1/500, MA5-32587 at 1/1000, MA5-35431 at 1/300, MA5-38484* at 1/200. Bars = 10 μm. Monoclonal antibody, *Recombinant antibody.\n\nIn conclusion, we have screened nine S1PR1 commercial antibodies by western blot, immunoprecipitation, and immunofluorescence by comparing the signal produced by the antibodies in human SK-HEP-1 WT and S1PR1 KO cells. Several high-quality antibodies that successfully detect S1PR1 under our standardized experimental protocol can be identified. Researchers who wish to study S1PR1 in a different species are encouraged to select high-quality antibodies, based on the results of this study, and investigate the predicted species reactivity of the manufacturer before extending their research.\n\nThe underlying data for this study can be found on Zenodo, an open-access repository for which YCharOS has its own collection of antibody characterization reports.14,15\n\n\nMethods\n\nThe standardized protocols used to carry out this KO cell line-based antibody characterization platform was established and approved by a collaborative group of academics, industry researchers and antibody manufacturers. The detailed materials and step-by-step protocols used to characterize antibodies in western blot, immunoprecipitation and immunofluorescence are openly available on Protocol Exchange, a preprint server (DOI: 10.21203/rs.3.pex-2607/v1).10\n\nCell lines used and primary antibodies tested in this study are listed in Tables 1 and 2, respectively. To ensure that the cell lines and antibodies are cited properly and can be easily identified, we have included their corresponding Research Resource Identifiers, or RRID.16,17", "appendix": "Data availability\n\nZenodo: Antibody Characterization Report for S1PR1, doi.org/10.5281/zenodo.10819189. 14\n\nZenodo: Dataset for the S1PR1 antibody screening study, doi.org/10.5281/zenodo.10839647. 15\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgment\n\nWe would like to thank the NeuroSGC/YCharOS/EDDU collaborative group for their important contribution to the creation of an open scientific ecosystem of antibody manufacturers and KO cell line suppliers, for the development of community-agreed protocols, and for their shared ideas, resources, and collaboration. Members of the group can be found below. We would also like to thank the Advanced BioImaging Facility (ABIF) consortium for their image analysis pipeline development and conduction (RRID:SCR_017697). Members of each group can be found below.\n\nNeuroSGC/YCharOS/EDDU collaborative group: Thomas M. Durcan, Aled M. Edwards, Peter S. McPherson, Chetan Raina and Wolfgang Reintsch.\n\nABIF consortium: Claire M. Brown and Joel Ryan.\n\nThank you to the Structural Genomics Consortium, a registered charity (no. 1097737), for your support on this project. The Structural Genomics Consortium receives funding from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Genome Canada through Ontario Genomics Institute (grant no. OGI-196), the EU and EFPIA through the Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN grant no. 875510), Janssen, Merck KGaA (also known as EMD in Canada and the United States), Pfizer and Takeda.\n\nAn earlier version of this of this article can be found on Zenodo (doi: 10.5281/zenodo.10819189).\n\n\nReferences\n\nHla T, Maciag T: An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors. J. Biol. Chem. 1990; 265(16): 9308–9313. PubMed Abstract \| Publisher Full Text\n\nLee MJ, Van Brocklyn JR, Thangada S, et al.: Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science. 1998; 279(5356): 1552–1555. PubMed Abstract \| Publisher Full Text\n\nBryan AM, Del Poeta M: Sphingosine-1-phosphate receptors and innate immunity. Cell. Microbiol. 2018; 20(5): e12836. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPyne S, Pyne NJ: Translational aspects of sphingosine 1-phosphate biology. Trends Mol. Med. 2011; 17(8): 463–472. PubMed Abstract \| Publisher Full Text\n\nJung Y, Lopez-Benitez J, Tognoni CM, et al.: Dysregulation of sphingosine-1-phosphate (S1P) and S1P receptor 1 signaling in the 5xFAD mouse model of Alzheimer’s disease. Brain Res. 2023; 1799: 148171. PubMed Abstract \| Publisher Full Text\n\nBlaho VA, Hla T: An update on the biology of sphingosine 1-phosphate receptors. J. Lipid Res. 2014; 55(8): 1596–1608. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAyoubi R, Ryan J, Biddle MS, et al.: Scaling of an antibody validation procedure enables quantification of antibody performance in major research applications. elife. 2023; 12: 12. Publisher Full Text\n\nCarter AJ, Kraemer O, Zwick M, et al.: Target 2035: probing the human proteome. Drug Discov. Today. 2019; 24(11): 2111–2115.\n\nLicciardello MP, Workman P: The era of high-quality chemical probes. RSC Med. Chem. 2022; 13(12): 1446–1459. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAyoubi R, Ryan J, Bolivar SG, et al.: A consensus platform for antibody characterization (Version 1). Protocol. Exchange. 2024.\n\nBiddle MS, Virk HS: YCharOS open antibody characterisation data: Lessons learned and progress made. F1000Res. 2023; 12: 1344. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLaflamme C, McKeever PM, Kumar R, et al.: Implementation of an antibody characterization procedure and application to the major ALS/FTD disease gene C9ORF72. elife. 2019; 8: 8. Publisher Full Text\n\nAlshafie W, Fotouhi M, Shlaifer I, et al.: Identification of highly specific antibodies for Serine/threonine-protein kinase TBK1 for use in immunoblot, immunoprecipitation and immunofluorescence. F1000Res. 2022; 11: 977. Publisher Full Text\n\nAyoubi R, Fotouhi M, Alende C, et al.: Antibody Characterization Report for Sphingosine 1-phosphate receptor.2024; 1(S1PR1).\n\nAyoubi R, Laflamme C: Dataset for the Sphingosine 1-phosphate receptor 1 (S1PR1) antibody screening study. [Data set]. Zenodo. 2024.\n\nBandrowski A, Pairish M, Eckmann P, et al.: The Antibody Registry: ten years of registering antibodies. Nucleic Acids Res. 2023; 51(D1): D358–D367. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBairoch A: The Cellosaurus, a Cell-Line Knowledge Resource. J. Biomol. Tech. 2018; 29(2): 25–38. PubMed Abstract \| Publisher Full Text \| Free Full Text" }	[ { "id": "302715", "date": "05 Aug 2024", "name": "Melissa Pitman", "expertise": [ "Reviewer Expertise I work cross cancer cell biology", "biochemistry and molecular biology and have experience with western blotting", "immunoprecipitation and immunofluorescence techniques." ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper used the WT and S1PR1 knockout SK-HEP-1 cells to evaluate the quality of the anti-S1PR1 antibodies obtained from different companies in three different applications, i.e. WB, IP, and IF. The results could be a useful guide for other scientists to help identify antibodies that are validated for their experimental application.\nGeneral comments: -REQUIRED CHANGE: In the introduction there is one single line that indicates a role for S1PR1 only in neuronal events. S1PR1 has many roles throughout the body and this background needs to reflect that. -REQUIRED CHANGE: It is unclear from the methods (in the paper or the linked protocols) and figure legends how many times these experiments were conducted. Please include the number of experiments (n=?) in the figure legends. Three independent experiments is the standard for most scientific studies. -There are a number of published papers from the ABIF consortium with the same format. While understandable for such a multi-pronged study, some of the wording is identical between each paper and some of the same issues are present in those other studies. -Although the reason is explicitly stated in the manuscript, it is highly unusual for a study to not explain any interpretations of their data or make any conclusions. -REQUIRED CHANGE: The catalog number for the Abcam S1PR1 KO cells is not included - were these made custom? Please include details on how these were made e.g. CRISPR/Cas9.\nREQUIRED CHANGEs: Specific comments: -Results: \"nine antibodies were screened using a mosaic strategy.\" Please add further detail to this sentence as not all readers will know what this strategy means. -Figure 1: far right gel. Please check the molecular weight markers are correct on the gel. The numbers appear to be shifted down compared to the other gel images. -Figure 2: The immunoprecipitation experiments appear to use an anti-rabbit (ab233386) antibody to detect the S1PR1 in the western blots (after immunoprecipitation). Unfortunately, using anti-rabbit antibodies in both the blots and IPs means that the heavy and light chain will be detected by the secondary antibodies. For S1PR1 that runs around the same size as the heavy chain this means that conclusive information cannot be gained. As stated in your protocol (section 2E), if you do not have an appropriate secondary antibody from a different species then other methods may need to be considered. The authors should consider using an appropriate TrueBlot (Rockland) secondary antibody to avoid detection of heavy chain or test whether running their gels under non-denaturing conditions will move the antibody band out of the same size range as the S1PR1 target. -Figure 2 - please include the protein quantity of lysates (ug) for the IP.\n\nIs the rationale for creating the dataset(s) clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and materials provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? Partly", "responses": [ { "c_id": "12222", "date": "05 Sep 2024", "name": "Kathleen Southern", "role": "Author Response", "response": "Thank you to Melissa Pitman for your comprehensive review of this manuscript. The authors have taken great consideration from all suggested changes and made the necessary changes to ensure future reproducibility of the antibody characterization procedure. That being said, we have replied to all of your comments (italicized) below and created a new version of the manuscript to address all concerns, when appropriate. We hope that the adjustments made meet your expectations and clarify any concerns you previously had. Please see below. General comments: -REQUIRED CHANGE: In the introduction there is one single line that indicates a role for S1PR1 only in neuronal events. S1PR1 has many roles throughout the body and this background needs to reflect that. To address this concern, the authors have revisited the introduction to provide further background on the function of S1PR1 throughout the body. Please refer to version 2. -REQUIRED CHANGE: It is unclear from the (1)methods (in the paper or the linked protocols) and figure legends how many times these experiments were conducted. Please include the number of experiments (n=?) in the figure legends. Three independent experiments is the standard for most scientific studies. We understand the perceived concern of the lack of replicates in our study. To address this concern, as well as other concerns commonly reported from reviewers, the authors have included a limitation section that will proceed the methods section. To reiterate the rationale behind this selected approach, the validation of the KO cell lines involves the use of multiple antibodies targeting various epitopes. Once a specific antibody is identified, it validates the protein expression of the intended target in the selected cell line at a concentration that is detectible by a suitable antibody and supports conclusions regarding the specificity of the other antibodies. Typically, we have access to the same antibody from 2-3 manufacturers (cross-licensed antibodies), which effectively serve as replicates, enabling the validation of test reproducibility. All experiments are performed using master mixes, and meticulous attention is paid to sample preparation and experimental execution. In IF, the use of two different concentrations serves to evaluate antibody specificity and can aid in assessing assay reliability. In instances where antibodies yield no signal, a repeat experiment is conducted. After careful consideration, it was determined that conducting experiments in replicates does not offer significant benefits in this context. -There are a number of published papers from the ABIF consortium with the same format. While understandable for such a multi-pronged study, some of the wording is identical between each paper and some of the same issues are present in those other studies. The YCharOS initiative is a consensus platform developed through collaboration with academic and industry leaders to deliver antibody characterization data for human proteins to the scientific community. The collection of antibody characterization results are seen as a collection for public good, grounded on open science principles, to address research reproducibility issues and help researchers select high-quality antibodies for their experimental needs. That being said, a common template is used to deliver such antibody characterization Data Notes to the community to ensure the procedure followed is consistent and reproducible. -Although the reason is explicitly stated in the manuscript, it is highly unusual for a study to not explain any interpretations of their data or make any conclusions. We understand this concern and it is why we have chosen to submit the antibody characterization data in the format of Data Notes. As explained in the F1000 article guidelines, Data Notes do not include result analyses or conclusions. Furthermore, the authors prefer to remain unbiased while being transparent with the results obtained from the experiments. To provide context for readers who do not have experience analyzing results from such characterization methods utilizing knockout or knockdown lines as controls, we have included a subsequent Table to demonstrate how one can identify successful vs unsuccessful antibodies in each application. Please refer to Table 3 in the updated submission. -REQUIRED CHANGE: The catalog number for the Abcam S1PR1 KO cells is not included - were these made custom? Please include details on how these were made e.g. CRISPR/Cas9. The information regarding the SK-HEP-1 S1PR1 KO cell line provided by Abcam has been included in the Results section. Specific guide RNA sequences can be found in the methods section under “Antibodies and cell line used”. Please refer to version 2. REQUIRED CHANGEs: Specific comments: -Results: \"nine antibodies were screened using a mosaic strategy.\" Please add further detail to this sentence as not all readers will know what this strategy means. That you for bringing up this concern. We understand that some readers may not have experience with IF or this method in particular, which is why we have elaborated on what the mosaic strategy entails in the proceeding sentences of the IF paragraph within the results section. The clarification is also provided in the IF methods section. Please refer to version 2. -Figure 1: far right gel. Please check the molecular weight markers are correct on the gel. The numbers appear to be shifted down compared to the other gel images. After checking the raw data for antibody MA5-38484* evaluation by western blot (Wb), we can confirm that the placement of the molecular weight markers is correct. This can also be detected by the distinct 75 kDa signal on the left side of the blot. We predict that the proteins did not migrate as far down as intended during the protein separation by SDS-PAGE, which is why the S1PR1 protein was picked up by the antibody at a higher molecular weight. That being said, it is evident from the results that this antibody would not be appropriate to select for Wb analysis (refer to Table 3) given that the signal is not lost in the KO cell line, indicating that the antibody is not specific. -Figure 2: The immunoprecipitation experiments appear to use an anti-rabbit (ab233386) antibody to detect the S1PR1 in the western blots (after immunoprecipitation). Unfortunately, using anti-rabbit antibodies in both the blots and IPs means that the heavy and light chain will be detected by the secondary antibodies. For S1PR1 that runs around the same size as the heavy chain this means that conclusive information cannot be gained. As stated in your protocol (section 2E), if you do not have an appropriate secondary antibody from a different species then other methods may need to be considered. The authors should consider using an appropriate TrueBlot (Rockland) secondary antibody to avoid detection of heavy chain or test whether running their gels under non-denaturing conditions will move the antibody band out of the same size range as the S1PR1 target. As stated in the troubleshooting section of the protocol 2E, to avoid cross-reactivity of the antibody with the chains, a secondary detection system that prevents these cross-reactions with unstructured immunoglobulins should be used (https://doi.org/10.21203/rs.3.pex-2607/v1). That being said, Prot A:HRP secondary detection system was used in this study. This relevant information has been included in the antibody and Wb methods sections. Please refer to version 2. -Figure 2 - please include the protein quantity of lysates (ug) for the IP. This information has been added IP methods section. Please refer to version 2." } ] } ]	1	https://f1000research.com/articles/13-792
https://f1000research.com/articles/13-1430/v1	26 Nov 24	{ "type": "Systematic Review", "title": "Assessment of heavy metal contamination in fish, fruits, and vegetables in Southwest Nigeria: A systematic review", "authors": [ "Babafemi Laoye", "Peter Olagbemide", "Tolulope Ogunnusi", "Oghenerobor Akpor", "Peter Olagbemide", "Tolulope Ogunnusi", "Oghenerobor Akpor" ], "abstract": "Background The aim of this systematic review was to investigate the prevalence of heavy metal contamination in fish, fruits, and vegetables in Southwest Nigeria. The review focused on studies published over a ten-year period, between 2014 and 2024.\n\nMethods Articles used for the study were obtained by conducting a comprehensive literature search using several databases, including ResearchGate, Scopus, Google Scholar, ScienceDirect, and PubMed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). To identify relevant studies, a plethora of keywords were utilized to search for articles in the selected databases, including. Articles reporting heavy metal contamination in specified food products within the last decade were included.\n\nResults Of the 10,212 initially identified articles, 64 met the inclusion criteria after thorough screening. The selected studies were predominantly conducted in Lagos (30), Ondo (8), and Ogun (7) states, with few studies in Oyo, Ekiti, and Osun states. The majority of the research focused on fish (40 studies), followed by vegetables (20) and fruits (4). The commonly studied fish species were observed to be Tilapia zilli, Chrysichthys nigrodigitatus, Clarias gariepinus, and Oreochromis niloticus, with heavy metal concentrations frequently exceeded WHO limits.\n\nConclusions Therefore, this review highlights the significant risks posed by the presence of heavy metals in food products and underscores the importance of stringent environmental monitoring and the adoption of appropriate regulatory mechanisms for health and environmental risk mitigation. This could help in the formulation of appropriate policy implementation strategies geared towards mitigating heavy metal contamination in the region’s food supply.", "keywords": [ "Fish", "fruits", "vegetables", "PRISMA", "Tilapia zilli", "Chrysichthys nigrodigitatus", "Clarias gariepinus", "and Oreochromis niloticus" ], "content": "1. Introduction\n\nHeavy metals cause build-ups and biological magnification in plethora food chains because they are sturdy and loiter in the ecosystem for a long period. In the Southwestern part of Nigeria, where industrialization, rapid urbanization, and agricultural activities greatly contribute to environmental pollution (Odafivwotu and Abel, 2015; Akinnifesi et al., 2021; Akinsola et al., 2022) and stringent environmental regulations are seldom implemented, this presents a long-term debilitating health risk. The population is more dependent on locally produced food. Application of fertilizers, use of pesticides possessing heavy metal compounds, and use of unadulterated irrigation water can all contribute to heavy metal contamination in the soil, thereby affecting humans via consumption of agricultural produce. Fish in aquatic systems become contaminated by heavy metals in contaminated water bodies, frequently due to mining operations or industrial effluents. Although lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), aluminum (Al), and mercury (Hg) are not necessary for normal human functioning (Boyd and Rajakaruna, 2013), food contamination by heavy metals poses a serious health risk to consumers, especially because these metals bio accumulate in the food chain (Hussain et al., 2019; Nkwunonwo et al., 2020; Bawa-Allah 2023).\n\nIn Nigeria, fish, fruits, and vegetables contain dangerously high concentrations of heavy metals, often surpassing internationally acceptable limits set by regulatory bodies such as the Food and Agriculture Organization (FAO) and the World Health Organization (WHO). These findings have also been reported in other studies. Adegbola et al. (2021) and Abidemi-Iromini et al. (2022) conducted studies on fish from rivers in Lagos and Ogun states and revealed high concentrations of heavy metals, which are extremely harmful even in small amounts. Similarly, consuming grains (such as rice) and plants (including lettuce, amaranth, water spinach, and cowpea) cultivated in soil contaminated with mercury over an extended period of time is harmful to human health. Studies conducted in Southwest Nigeria have shown that commonly consumed food items contain elevated concentrations of heavy metals, frequently surpassing the permissible limits set by the Food and Agriculture Organization (FAO) and World Health Organization (WHO) (Adekunle et al., 2009; Akinola et al., 2020). For example, fish samples from rivers near industrial zones in Lagos were found to contain large amounts of Pb and Cd by Olayinka and Adedeji (2018), whereas vegetables irrigated with contaminated water sources had high levels of arsenic (Ogundele et al., 2015).\n\nExposure to heavy metals is associated with numerous health hazards. Lead is a common heavy metal that contaminates the environment and enters the body through absorption, bioavailability, bioconcentration, and biomagnification. It causes problems in the reproductive, neurological, skeletal, hematological, renal, and cardiovascular systems (Collin et al., 2022). Mercury exposure causes neurological damage, including ataxia, muscle weakness, numb limbs, disturbance in speech, chewing, and swallowing, as well as brisk and increased tendon reflexes in patients exposed to massive amounts of Me-Hg (Balali-Mood et al., 2021). Cd exposure can result in a variety of adverse effects, including renal and hepatic dysfunction, pulmonary edema, testicular damage, osteomalacia, and damage to the adrenal and hematopoietic systems (Genchi et al., 2020). Long-term arsenic exposure can cause cancer, developmental problems, and skin damage. Additionally, long-term exposure to arsenic may suppress the immune system by causing keratinocyte apoptosis through the interaction of Fas and Fas-ligand, lowering the percentage of peripheral blood CD4+ T cells, reducing the number of Langerhans cells, and altering their migration (Tang et al., 2023). Understanding the distribution and concentrations of heavy metals in regularly consumed foods is essential for safeguarding public health in Southwest Nigeria, given their possible health consequences.\n\nFurthermore, it is impossible to ignore how heavy metal poisoning affects society economically. Agriculture and fishing in Southwest Nigeria provide a substantial portion of the population’s income. These food supplies are contaminated, which puts the public’s health in danger, as well as the local economy, food security, and consumer confidence in the safety of locally made commodities at risk. This might result in more imported food products, which would drive up food prices and worsen poverty in areas that already have serious economic difficulties.\n\nA rigorous study of the degree of heavy metal contamination is important in Southwest Nigeria because of the growing industrial and agricultural operations there, as well as possible health repercussions. The purpose of this systematic study was to evaluate the level of heavy metal contamination in Southwest Nigerian fish, fruits, and vegetables. This study reviews previous research in an effort to provide readers with a thorough understanding of contamination levels, pinpoint possible heavy metal sources, and assess the health hazards of consuming them. In addition, this study seeks to identify areas of unmet need in the field, indicate future research directions, and offer mitigation measures for heavy metal pollution in the area’s food supply. Designing policies and actions to lower public health risks, guarantee food safety, and advance environmental sustainability in Southwest Nigeria also require an understanding of the extent and effects of heavy metal contamination in food supplies.\n\n\n2. Methods\n\nFor effective methodological integrity and validity, quality, PRISMA was utilized (Haddaway et al., 2022). For this review, a digital literature search was conducted to find articles between years 2014-2024 that as reported heavy metal contamination in food products in southwestern Nigeria. In this review, the research gate, scopus-indexed papers, connected papers, Google Scholar, Science Direct, and PubMed were the predominant databases employed. Each database search was carried out independently, and the selected articles were juxtaposed together. For this review, a plethora of keywords were utilized to search for articles on the selected databases, including heavy metal contamination, pollution, toxic metals, lead, cadmium, cobalt, mercury, arsenic, chromium, manganese, nickel, cadmium, fruits, vegetables, fish, Southwest Nigeria, Nigeria, health risks, toxicity, exposure assessment, bioaccumulation, cross-sectional study, case study, environmental monitoring, and survey. Furthermore, Boolean operators (AND and OR) was combined with “heavy metals’ which is the predominant key word to search for articles more effectively.\n\nThe inclusion criteria were articles published within the last 10 years (2014-2024), that reported heavy metal contamination in fish, fruits, and vegetables in southwest Nigeria. Articles that did not report heavy metal contamination in fish, fruits, or vegetables were excluded from this study.\n\nA custom range between the years 2014-2024 was used to select articles that reported contamination of heavy metals in fish, fruits, and vegetables in the last 10 years. Thorough scrutiny of all articles by reading the titles and abstracts was performed to select the preferred articles for this study. A total of 61 articles that reported heavy metal contamination in fish, fruits, and vegetables in Southwest Nigeria were selected for this study. Overall, 10, 212 articles were obtained from different databases. Specifically, Google Scholar yielded 8,420 hits, PubMed yielded 58 hits, Research Gate yielded 1,487 hits, and Scopus yielded 247 hits. During this review, 850 articles were removed before screening leading 9,362 articles left. Critical reading was performed to select non-eligible articles with 9, 362 articles being screened. During this review, 8,538 articles were further excluded after custom screening. Furthermore, 824 articles were sought for retrieval, and 4 articles were further removed (820 articles), 756 inconsequential articles were excluded to avoid meeting the inclusion criteria. Specifically, 44 articles were deleted as the research methodology was not well defined; 210 articles were omitted because they fell outside the 10 years ago criteria; 5 articles were removed because they were not peer reviewed; 240 articles were deleted as they did not focus on heavy metal contamination in either fish, vegetables, or fruits; 8 articles were deleted as they were books and reviews; and 313 articles were excluded because the research was not domiciled in the southwestern region of Nigeria. A total of 64 articles were included in this review.\n\n\n3. Results\n\nAmong the 64 eligible articles selected for this systematic review, 30 were carried out in Lagos, eight in Ondo, and seven in Ogun State of Nigeria. Three, six, and seven studies were conducted in the Oyo, Ekiti, and Osun states, respectively. The majority (40) of the studies included in this review were carried out on fish, while 20 and 4 studies were carried out on vegetables and fruits, respectively\n\nIn the studies reviewed, a plethora of fish species, particularly Tilapia zilli, Chrysichthys nigrodigitatus, Clarias gariepinus, Oreochromis niloticus, frequently exceeded the World Health Organization (WHO) limits for heavy metals, such as lead (Pb), chromium (Cr), and Nickel (Ni.) Multiple studies have reviewed the constant pollution of water bodies where these fish species are found, which poses health risks to humans via consumption. Tilapia zilli and Chrysichthys nigrodigitatus were found to be highly prone to pollution and contamination by heavy metals, often exceeding the WHO permissible limits for zinc (Zn), Cr, and Pb. In addition, Clarias gariepinus showed significant contamination in some articles, with remarkably elevated levels of cadmium (Cd) and lead (Pb). Oreochromis niloticus (Nile tilapia) typically showed lower contamination levels, except for lead (Pb) in some studies. Heavy metal pollution in staple foods such as fish, fruits, and vegetables is of great concern and cannot be overemphasized. In this review, lead (Pb) was mostly reported to be above safe consumption levels in many fish samples, which was reflected in studies by Yahaya et al. (2022) and Olujimi et al. (2017), which showed particularly high concentrations. Chromium (Cr) and nickel (Ni) are frequently found above safe limits, particularly in studies by Yahaya et al. (2022) and Balogun et al. (2021).\n\nIn addition, Zinc (Zn) and Iron (Fe) were found in some fish samples, exceeding the WHO limits in studies by Ajibare et al. (2021). In the articles reviewed in this study, Clarias gariepinus and Sarotherodon melanotheron were low or within the WHO safe limits of contamination in articles reviewed in this study (Adetutu et al., 2023; Akinjogunla et al., 2023). Shell fish species, such as Callinectes danae and Cardisoma armatum showed copper contamination, exceeding the WHO limits, as reported by Oladunjoye et al. (2021).\n\nFrom 2014 to 2024, heavy metal contamination patterns reflect persistence, revealing continuous environmental pollution issues. Consumption of fish contaminated with heavy metals poses a significant risk to human health, which may result in kidney diseases and neurological damage. Clarias gariepinus was reflected in a plethora of articles used for this systematic review, possibly because of its commercial importance. The less frequently detected metals in fish samples in this systematic review were mercury (Hg) and arsenic (As), as they were not tested using an Atomic Absorption Spectrophotometer (AAS), their levels were below detection limits (BDL), or were generally not detected (ND), indicating either minimal contamination [Table 1 Extended data. Akpor et al. (2024)].\n\nThe results of this systematic review revealed that a plethora of vegetables contained heavy metals that exceeded the WHO permissible limits, connoting potential health risks to humans via consumption. High levels of cadmium (3.52 mg/kg) chromium (49.13 mg/kg) and lead (9.97 mg/kg) were detected in Talinum triangulare in studies conducted by Atikpo et al., 2021, indicating the vegetable accumulate multiple heavy metals which is very much dangerous to the health of humans. Green peas (Pisum sativum) have elevated levels of Pb and Al (Ojezele et al., 2021). These heavy metal levels in Pisum sativum in this study transcend the WHO safe limits, indicating that consumption of peas is potentially dangerous for consumption (Ojezele et al., 2021). Celosia argentea, commonly known as plumed cockscomb red spinach, efo shoko, and spinach, repeatedly showed high levels of heavy metals in different studies. For example, Omoboyowa et al. (2019) recorded a high zinc (Zn) concentration of 52.00 mg/kg, well above WHO limits. In another study, Agboola et al. (2023) found Cr at 3.90 mg/kg and Zn 7.30 mg/kg, both exceeding the threshold, indicating remarkable contamination. Jatropha podagrica commonly called botuje in southwest Nigeria, has heavy metals such as copper (0.210 mg/kg) and zinc (0.220 mg/kg), which are above the WHO limits, also suggesting a hazardous effect on human health (Ogunwale et al., 2021). In addition to elevated concentrations of heavy metals, this systematic review of vegetables also revealed heavy metal contamination within safety limits in a number of vegetables such as tomato, red pepper, bell pepper, chilli pepper, and red pepper. Similarly, all vegetables assayed by Farombi et al. (2020) were within the WHO safety levels (Cd, Cr, Co, Pb, Zn, and Ni) [Table 2 Extended data. Akpor et al. (2024)].\n\nMoreso, an article by Ofudje et al. (2017), revealed acceptable levels of Zn and Mn in Telfairia occidentalis, suggesting regional differences in contamination. Among all vegetables in this review, cadmium and lead were revealed to be the prominent elevated metals in terms of concentration that appeared in this study. Amaranthus hybridus, Corchorus olitorius, and Celosia argentea revealed lead contamination in this study, and a build-up of lead in the body via consumption may lead to neurological disorders. Furthermore, heavy metals, such as Zn and Cu, were often found among vegetables in this review, exceeding the WHO limits, which was reflected precisely in Celosia argentea and Jatropha podagrica. Ojezele et al. (2021) reported elevated aluminum concentrations in green peas and mushrooms. (Table 2).\n\nThe results of this systematic review revealed only four articles that reported heavy metal contamination in southwest Nigeria; cadmium levels were reported in Carica papya at a concentration of 0.077 mg/kg, while Pb levels reached 0.074 mg/kg, with both heavy metals exceeding the WHO safety limits (Ogunkunle et al., 2014). Similarly, cobalt, manganese, and copper were also detected, but within permissible limits. Prolonged consumption of papaya from this area may pose a potential health risk. For Citrullus lanatus (watermelon), lead contamination was elevated at 1.760 mg/kg, which is well above the permissible limit, making it a cause for concern. Similarly, an article by Oladele and Aladesanmi (2020) also reported heavy metal contamination, but precisely in chromium and nickel, slightly exceeding the WHO safe limits. Results from this systematic review revealed lead contamination in Mangifera indica (Mango), which was recorded at 1.620 mg/kg, significantly exceeding the safety limit. Cadmium (0.091 mg/kg) and cobalt (0.029 mg/kg) were also detected, with Cd levels advancing towards the permissible limit, which raises concern over potential long-term health impacts from consuming contaminated mangoes (Ogunkunle et al., 2014). Malus domestica (apple) also revealed heavy metal contamination exceeding safe limits: chromium (0.300 mg/kg) and nickel (0.475 mg/kg), both of which are significantly above the WHO limits. (Omoyajowo et al., 2017). Furthermore, mixed Fruits were also reported to be contaminated in heavy metals: Lead, nickel and aluminum were found at 1.40 mg/kg, 0.625 mg/kg, and 7.00 mg/kg, respectively, with all exceeding permissible limits. In addition, orange (Citrus sinensis) in an article by Omoyajowo et al. (2017) showed safe levels of heavy metal contamination, chromium (0.080 mg/kg) and lead (0.120 mg/kg), both within the WHO guidelines [Table 3 Extended data. Akpor et al. (2024)].\n\n\n4. Discussion\n\nThe results of this review revealed widespread contamination of fruits, vegetables, and fish by heavy metals across southwestern Nigeria, with no significant public health concerns. Heavy metals, such as lead (Pb), cadmium (Cd), chromium (Cr), nickel (Ni), and zinc (Zn), were found to exceed the WHO safety limits for fish, fruits, and vegetables. These findings raise global concerns regarding the persistence of heavy metals in the environment due to pollution, industrial activities, and agricultural practices. In addition, widespread heavy metal contamination across different types of fruits in this systematic review study was highly reflected in this study, posing debilitating health risks, for example, from consuming fruits (Ojezele et al., 2021). Nonetheless, some articles have revealed fruits with heavy metal contamination within the WHO safe limits. Citrullus lanatus (Watermelon) displays safe levels of heavy metals, including cadmium (0.004 mg/kg) and lead (Atikpo et al., 2021).\n\nAdditionally, fish species, distinctly Tilapia zilli, Chrysichthys nigrodigitatus, and Clarias gariepinus, frequently exceeded the WHO limits for heavy metals, particularly Pb, Cr, and Ni. Results from this study in terms fish contamination in an article by Yahaya et al. (2020) revealed lead, and chromium contamination at levels exceeding WHO linits in Tilapia zilli with 4.36 mg/kg and 5.40 mg/kg respectively. This was similar to the results from a study by Putshaka et al. (2015), who reported contamination levels in lead and chromium at 1.132 mg/kg and 1.845, respectively, exceeding. The Pb level in the study by Yahaya et al. (2020) was much higher than that reported by Putshaka et al. (2015). The results of this study by Yahaya et al. (2020) were dissimilar to results from a study by Inalegwu et al. (2019), who reported lower levels of Pb (0.347 mg/kg) and Cr (0.848 mg/kg) contamination in Tilapia zilli when compared to the study by Yahaya et al. (2020). This suggests that the aquatic environments in which these fish are harvested are heavily contaminated, most likely from industrial runoff, mining activities, and illegitimate waste disposal. This raises public health concerns, as fish are a primary source of dietary protein globally, and long-term consumption of polluted or contaminated fish may lead to bioaccumulation of toxic metals in humans, resulting in kidney damage, congenital defects, and an increased risk of cancer.\n\nYahaya et al. (2020) reported Pb, Cu, and Ni contamination in Chrysichthys nigrodigitatus exceeding the WHO limits of 3.63 mg/kg, 1.28 mg/kg and 4.16 mg/kg respectively. The results from Yahaya et al. (2020) were similar to the results from Unaeze et al. (2023). Although, the level of Pb contamination was lower (2.00 mg/kg) in the study by Unaeze et al. (2023) when compared to the study by Yahaya et al. (2020) but exceeding WHO limit, also the concentration for Zinc in Chrysichthys nigrodigitatus was extremely high (240.00 mg/kg) in the study by Unaeze et al. (2023) unlike results from Yahaya et al. (2020) having Zinc level in the same fish as 1.28 mg/kg. Also Cu levels in Unaeze et al. (2023) (2.32 mg/kg) was higher than the level reported by Yahaya et al. 2020 (1.28 mg/kg) with both exceeding WHO limits.\n\nClarias gariepinus is a commercially liked fish species, which was reflected several times in the reviewed articles selected for this study, probably because of its significance in the local markets in Nigeria. The high levels of Cd and Pb found in this species underscore the need for stringent monitoring of fish harvested from polluted water bodies. In this review article, seven articles revealed heavy metal contamination in Clarias gariepinus (Olurin, 2024; Ogungbemi et al., 2022; Utete and Fregene, 2020; Yahaya et al., 2022; Ayanda et al., 2020; Adubiaro and Animashaun, 2021, Adewunmi et al., 2017), while, four articles (Olurin, 2024; Utete and Fregene, 2020; Yahaya et al., 2022; Ayanda et al., 2020) reported heavy metal contamination exceeding WHO limits, and three articles (Ogungbemi et al., 2022; Adubiaro and Animashaun, 2021; Adewunmi et al., 2017) reported heavy metal contamination within the WHO permissible limits. In this study, heavy metal contamination in Clarias gariepinus exceeding WHO limits is similar to the study by Odey et al. (2020), with Lead (Pb) being at the forefront, frequently appearing in these articles. Articles from this review reporting Pb contamination revealed Pb levels at levels of 9.14 mg/kg, 0.20 mg/kg, 3.23 mg/kg, 9.43 mg/kg, 11.10 mg/kg, 92.08 mg/kg, and 1.10 mg/kg in studies by Yahaya et al. (2022), Ogungbemi et al. (2022), Olurin (2024), Adewunmi et al. (2017), Utete and Fregene (2020), Ayanda et al. (2020) and Adubiaro and Animashaun (2021) respectively. Pb level (92.08 mg/kg) reported in Clarias gariepinus reported by Ayanda et al. (2020) was higher than that reported by Odey et al.(2020), although they all exceeded WHO permissible limits. However the Pb level reported by Olurin (2024) was lower than what was reported by Odey et al. (2020) More so, articles by Adubiaro and Animashaun (2021), Ogungbemi et al. (2022), Adewunmi et al. (2017) reported heavy metal contamination within WHO permissible limits in all selected metals that was assayed for, results in these studies were similar to results reported by Abubakar and Adeshına (2019). The presence of Pb in the main culprits of this fish implies that ingestion of Clarias gariepinus may be poisonous to individuals in the southwest region of Nigeria, as long-term ingestion of Pb via this fish leads to the accumulation of Pb, which may result in coma, convulsions, and even death (Ray & Vashishth, 2024).\n\nFurthermore, some articles reviewed in this study found metals such as zinc and iron exceeding WHO safety limits (Ajibare et al., 2021; Oghenechuko et al., 2022; Taiwo et al., 2019; Wangboje & Miller 2018; Taiwo et al., 2017; Taiwo et al., 2019; Olowu et al., 2015) Articles that reported heavy Zn conatamination in fish were similar to results reported by Mahidi and Albashr (2023); Yalwa et al. (2024) and Balooch et al. (2021) in terms of exceeding WHO limits Furthermore, Ajibare et al. (2021) reported Znc (112.19 mg/kg) contamination in Oreochromis which was higher than Znc level reported Mahidi and Albashr (2023); Yalwa et al. (2024) and Balooch et al. (2021) in fish at a level of 37.17 mg/kg, 50.84 mg/kg and 13.36 mh/kg respectively. Bioaccumulation of Zn may cause debilitating effects in the human body, resulting in reproductive disorders and Alzheimer’s disease (Kiouri et al., 2023) Although, Fe is an essential element for humans as it participates in a wide variety of metabolic processes, including oxygen transport, deoxyribonucleic acid (DNA) synthesis, and electron transport (Abbaspour et al., 2014). For Fe contamination of fish, reports from studies by Taiwo et al. (2017); Olowu et al. (2015); Taiwo et al. (2019) and Oghenechuko et al. (2022) revealed higher level of Fe concentration in fish at level of 8.05 mg/kg/, 8.02 mg/kg, 8.68 mg/kg and 5.51 mg/kg respectively when compared to Fe levels that was reported in studies by Bobar et al. (2022) and Salam et al. (2019) having with 0.23 mg/kg and 4.30 mg/kg respectively; suggesting a great concern in the southwestern region in Nigeria, as bioaccumulation of Fe. The ingestion of fish by humans may lead to the formation of free radicals and excessive tissue damage in the body (Abbaspour et al., 2014). Shellfish species like Callinectes danae and Cardisoma armatum also revealed levels of copper contamination, indicating that both fish and crustaceans from these regions may pose a health risk if consumed in large quantities (Oladunjoye et al., 2021). Because of the continual nature of heavy metals in aquatic habitats, the continuous consumption of contaminated fish could have long-term health implications for the southwestern people of Nigeria.\n\nVegetables and fruits are very much essential components of human diets (Rodriguez-Casado, 2016) Results from this review showed substantial contamination with heavy metals, particularly lead and cadmium. Carica papaya (pawpaw) and Mangifera indica (mango), the two frequently reported fruits captured in this systematic review, were found to contain elevated levels of lead, significantly exceeding the WHO limits. Imperatively, Pb levels in mangoes reach 1.620 mg/kg, posing a serious health risk, as chronic exposure to Pb can lead to neurological disorders, developmental delays in children, and cardiovascular diseases in adults (Atikpo et al., 2021). In the same fashion, levels in pawpaw (0.077 mg/kg) approached the safety threshold, raising concerns over kidney damage and bone demineralization with long-term consumption leading to bioaccumulation. Watermelon (Citrullus lanatus) also exhibited notable heavy metal contamination, with Pb levels reaching 1.760 mg/kg, which is significantly higher than the permissible limits. This finding is concerning given the popularity of watermelon in Southwestern Nigeria, suggesting that regular consumption could lead to bioaccumulation of heavy metals in humans, who are invariably consumers. While some fruits such as apples (Malus domestica) and mixed fruit samples showed contamination with metals such as chromium and nickel, other fruits such as oranges (Citrus sinensis) revealed metal levels exceeding WHO safe limits (Omoyajowo et al., 2017).\n\nSimilarly, vegetables, a very important food in the diets of individuals in southwestern Nigeria, revealed alarming levels of contamination. Talinum triangulare, green peas (Pisum sativum), and Celosia argentea were reported to contain high concentrations of Cd, Cr, Zn, and Pb. The presence of a plethora of heavy metals in these vegetables, most importantly lead and cadmium, is also of great concern, as these metals can cause cumulative dangerous effects over time, leading to severe health issues, including neurotoxicity, reproductive issues, and carcinogenic effects (Rodriguez-Casado, 2016).\n\nThe high levels of aluminum in green peas and mushrooms in this systematic review (Ojezele et al., 2021) further suggest the potential for widespread heavy metal contamination, as aluminum has been implicated in anemia and neurological disorders (Cirovic et al., 2023). In addition to aluminum, lead was also reported in a study by Ojezele et al. (2021), which contaminates green peas and mushrooms at high levels. Precisely, for green peas Al (14.0 mg/kg), Pb (1.68 mg/kg), and for mushroom Al (11.0 mg/kg) Pb (1.38 mg/kg). The results from the study by Ojezele et al. (2021) were dissimilar to those of Pb levels reported by Oloruntoba et al. (2017), which were below detectable limits. For mushroom, the Pb level(1.15 mg/kg) reported by Orywal et al. (2021) was slightly lower than the Pb (1.38 mg/kg) level in mushroom reported by Ojezele et al. (2021), with mushrooms being of great concern in the southwest region of Nigeria. The accumulation of aluminum in vegetables may lead to anemia and neurological disorders, making it a metal of great concern. Overall, Amaranthus hybridus (Pb and Cd), Telfairia occidentalis (Cu and Pb), and Celosia argentea (Cr, Zn, and Cu) had heavy metal concentrations exceeding the WHO limits, having a robust tendency to cause debilitating effects on human health. Furthermore, some vegetables, such as red peppers, chilli peppers, and tomatoes, were found to have heavy metal levels according to the WHO safety guidelines, suggesting possible regional variations in contamination. The remarkable levels of contamination among various food groups indicate that stringent measures by the government, private organizations, and environmental management strategies must be strengthened to reduce these risks. This review highlights the persistent contamination of essential food items in Southwest Nigeria, which may have profound long-term health consequences. Chronic exposure to elevated levels of lead, cadmium, and other heavy metals is linked to a range of adverse health effects, including neurotoxicity (Mitra et al., 2022) cardiovascular diseases, and increased cancer risks (Ebrahimi, et al., 2020) Lead exposure, particularly in children, can cause irreversible cognitive impairments, whereas cadmium accumulation in the body is associated with kidney dysfunction and osteoporosis (Ma et al., 2022).\n\n\n5. Conclusion\n\nThis systematic review highlights the prevalence and persistence of heavy metal contamination in fish, fruits, and vegetables in Southwest Nigeria between 2014 and 2024. Most of the reviewed studies revealed significant contamination in fish, fruits, and vegetables. The reviewed studies revealed that the concentrations of chromium and nickel frequently exceeded the permissible limits of the World Health Organization (WHO), which could pose significant health risks to consumers. A number of fish species (Tilapia zilli, Chrysichthys nigrodigitatus, and Clarias gariepinus) in the reviewed studies, showed high levels of contamination, thus making them critical indicators of environmental pollution in the region. Although vegetables and fruits have been less frequently studied in the region, the reviewed studies showed that they still exhibited significant levels of heavy metal contamination in some instances. Therefore, this review highlights the significant risks posed by the presence of heavy metals in food products and underscores the importance of stringent environmental monitoring and the adoption of appropriate regulatory mechanisms for health and environmental risk mitigation. This could help in the formulation of appropriate policy implementation strategies geared towards mitigating heavy metal contamination in the region’s food supply.\n\n\nEthics and consent\n\nEthical approval and consent were not required.", "appendix": "Data availability\n\nNo data are associated with this article.\n\nFigshare repository - “Manuscript Tables, PRISMA flowchart and PRISMA Checklist for Systematic Review on Heavy Metal Contamination of Fish, Fruits and Vegetables in Southwest, Nigeria”. https://doi.org/10.6084/m9.figshare.27453258.v3 (Akpor et al., 2024).\n\nThis project contains following datasets:\n\n1. Table 1_Levels of Heavy Metal Contamination in Various Fish in Southwest Nigeria.docx\n\n2. Table 2_Levels of Heavy Metal Contamination in Various Vegetables in Southwest Nigeria.docx\n\n3. Table 3_Levels of Heavy Metal Contamination in Various Fruits in Southwest Nigeria.docx\n\n4. PRISMA flow chart systematic review.docx\n\n5. PRISMA abstract Checklist.docx\n\n6. PRISMA Main text checklist\n\n7. Systematic review Table references\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nFigshare repository - PRISMA checklist for ‘Assessment of Heavy Metal Contamination in Fish, Fruits and Vegetables in Southwest Nigeria: A Systematic Review’. https://doi.org/10.6084/m9.figshare.27453258.v3 (Akpor et al., 2024).\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nAbbaspour N, Hurrell R, Kelishadi R: Review on iron and its importance for human health. J. Res. Med. Sci. 2014; 19: 164–174. 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Publisher Full Text\n\nYalwa LM, Iya SGD, Abdulrazaq GI, et al.: Assessment of Some Selected Heavy Metals (Zn, Cu, Pb, and Cd) Contamination in Kafin Hausa River using Atomic Absorption Spectroscopy. Sule Lamido University Journal of Science and Technology. 2024; 9: 1–2." }	[ { "id": "354120", "date": "13 Jan 2025", "name": "Harry R. Yucra-Condori", "expertise": [ "Reviewer Expertise Environmental remediation", "environmental contamination and health risk", "food design." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReport Systematic Review of Heavy Metal Contamination in Fish, Fruits, and Vegetables in Southwestern Nigeria (2014-2024) Abstract This comprehensive systematic review meticulously examines heavy metal contamination in fish, fruits, and vegetables in southwestern Nigeria over the decade spanning 2014-2024. The researchers conducted an exhaustive search across multiple scientific databases, rigorously selecting 64 studies that met specific inclusion criteria.\nKey Findings The analysis reveals alarming levels of contamination, particularly by lead, cadmium, chromium, and zinc, in various fish species and some vegetables, frequently exceeding the limits established by the World Health Organization (WHO). Although less extensively studied, fruits also exhibited a degree of contamination. Methodology Enhancement Recommendations Research Foundation and Objectives\nFormulate specific objectives and clear research questions. Provide a detailed justification for the selection of the 2014-2024 study period.\nMethodological Approach and Data Analysis\nDelineate the complete search strategy for at least one database. Specify the study selection process, including the number of reviewers at each stage. Describe data extraction and synthesis methodologies. Incorporate a quality assessment or risk of bias evaluation for included studies.\nConclusion Formulation\nExplicitly link conclusions to the presented data. Discuss the quality and consistency of the evidence. Address limitations of both included studies and the review itself.\nAdditional Considerations\nHealth Risk Assessment: Conduct a more rigorous analysis considering exposure levels and consumption patterns, utilizing guidance from articles such as:\nRomán-Ochoa Y, et al., 2021 (Ref 1) Choquenaira-Quispe C, et al., 2022 (Ref 2)\n\nInter-Study Variability: Discuss potential reasons for observed discrepancies. Practical Implications: Address consequences for consumers and public health authorities. Sensitivity Analysis: Consider including an assessment of evidence certainty (e.g., using GRADE methodology). Keywords: Review relevance to facilitate web-based identification of the review. Figure 1: Include a brief justification for selection criteria and the number of participating reviewers. Cereal Inclusion: Justify the exclusion of cereals, considering their importance in local diets as evidenced by studies such as:\nSowunmi F, et al., 2020 (Ref 3) Ikudayisi A, 2020 (Ref 4) Otemuyiwa IO, et al., 2012 (Ref 5)\n\nResults Presentation Uniformity: Standardize the presentation of concentration data across all sections (fish, vegetables, and fruits). Table Structure: Uniformize format, including units, complete row numbering, WHO maximum values, and justify the absence of references in some rows. Legends and Abbreviations: Include explanations for BDL, ND, and clarify terms such as \"Si\" and \"exceeds limit\" in the WHO limits column. Geographic Information: Add a column in tables identifying the specific study region. Data Format: Standardize the number of decimal places and metal nomenclature (acronyms or full names). Article Accessibility: Identify the quantity of open access and subscription articles utilized. It is suggested to provide quantitative summaries of contamination levels by food type and metal (ranges, medians).\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Partly\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Partly\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable", "responses": [ { "c_id": "13163", "date": "23 Jan 2025", "name": "Babafemi Laoye", "role": "Author Response", "response": "Dear Reviewer, Thank you so much for the review comments. The authors are grateful for the comments. Below are responses to the review: Reviewer’s comment: Methodology Enhancement Recommendations Research Foundation and Objectives Formulate specific objectives and clear research questions. Provide a detailed justification for the selection of the 2014-2024 study period. Methodological Approach and Data Analysis Delineate the complete search strategy for at least one database. Specify the study selection process, including the number of reviewers at each stage. Describe data extraction and synthesis methodologies. Incorporate a quality assessment or risk of bias evaluation for included studies. Authors’ response: This has been attended to as revised according. Justification for selection of study period included Reviewer’s comment: Conclusion Formulation Explicitly link conclusions to the presented data. Discuss the quality and consistency of the evidence. Address limitations of both included studies and the review itself. Authors’ response: The conclusion has been revised and limitation included Reviewer’s comment: Additional Considerations Health Risk Assessment: Conduct a more rigorous analysis considering exposure levels and consumption patterns, utilizing guidance from articles such as: Román-Ochoa Y, et al., 2021 (Ref 1) Choquenaira-Quispe C, et al., 2022 (Ref 2) Authors’ response: Health risk assessment was not part of the study objectives. The study was a systematic review, so the authors had no access to data on exposure and consumption levels of the food items. If it was an original research article, the authors would have considered that. Reviewer’s comment: Inter-study variability: Discuss potential reasons for observed discrepancies. Authors’ response: This has been indicated in the limitation. Reviewer’s comment: Practical Implications: Address consequences for consumers and public health authorities. Authors’ response: This is reflected in the discussion Reviewer’s comment: Sensitivity Analysis: Consider including an assessment of evidence certainty (e.g., using GRADE methodology). Authors’ response: The PRIMA protocol was holistically followed during the course of the study Reviewer’s comment: Keywords: Review relevance to facilitate web-based identification of the review. Authors’ response: Keywords have been added Reviewer’s comment: Figure 1: Include a brief justification for selection criteria and the number of participating reviewers. Authors’ response: This is already reflected in the article selection section Reviewer’s comment: Cereal Inclusion: Justify the exclusion of cereals, considering their importance in local diets as evidenced by studies such as: Sowunmi F, et al., 2020 (Ref 3) Ikudayisi A, 2020 (Ref 4) Otemuyiwa IO, et al., 2012 (Ref 5) Authors’ response: The inclusion of cereal was outside the objectives of the study. The study was solely focused on fish, fruits, and vegetables. There is no way all food products can be included in a single study. The authors may consider that in subsequent studies. Reviewer’s comment: Results Presentation Uniformity: Standardize the presentation of concentration data across all sections (fish, vegetables, and fruits). Authors’ response: Although that would have been the ideal thing to do, data were extracted from the information provided by the authors of the manuscript. We have no option but to report exactly what they provided and make our interpretation based on that. Reviewer’s comment: Table Structure: Uniformize format, including units, complete row numbering, WHO maximum values, and justify the absence of references in some rows. Authors’ response: The authors are of the view that it will be clumsy to insert WHO limits for all the metals. Different articles investigated different metals; hence, the use of the word…exceeded or within the WHO limit as currently reported could suffice. On the aspect of units, the authors can confirm that units are indicated Reviewer’s comment: Legends and Abbreviations: Include explanations for BDL, ND, and clarify terms such as \"Si\" and \"exceeds limit\" in the WHO limits column. Authors’ response: That has been attended to Reviewer’s comment: Geographic Information: Add a column in tables identifying the specific study region. Authors’ response: The inclusion criteria for the study already indicated the region. The systematic review setting was the southwest region of Nigeria. Reviewer’s comment: Data Format: Standardize the number of decimal places and metal nomenclature (acronyms or full names). Authors’ response: That has been attended to Reviewer’s comment: Article Accessibility: Identify the quantity of open access and subscription articles utilized. Authors’ response: The authors had full access to all the included articles that were used. Reviewer’s comment: It is suggested to provide quantitative summaries of contamination levels by food type and metal (ranges, medians). Authors’ response: We can only report based on data provided by the authors. The different articles used different reporting formats. Since this was not an original research article, it will be difficult to harmonize and add that information consistently" } ] } ]	1	https://f1000research.com/articles/13-1430
https://f1000research.com/articles/14-122/v1	23 Jan 25	{ "type": "Research Article", "title": "Artificial Intelligence and Finance: A bibliometric review on the Trends, Influences, and Research Directions", "authors": [ "Prasenjit Roy", "Biswajit Ghose", "Premendra Kumar Singh", "Pankaj Kumar Tyagi", "Asokan Vasudevan", "Prasenjit Roy", "Biswajit Ghose", "Pankaj Kumar Tyagi", "Asokan Vasudevan" ], "abstract": "Background This bibliometric study examines the intersection of artificial intelligence (AI) and finance, providing a comprehensive analysis of its evolution, central themes, and avenues for further exploration. The study aims to uncover the theoretical foundations, methodological approaches, and practical implications of AI in financial contexts.\n\nMethods The research employs bibliometric techniques, using 607 Web of Science (WoS) indexed papers. The Theory-Context-Characteristics-Methodology (TCCM) framework guides the analysis, focusing on thematic mapping to explore key topics. Core areas such as risk management, market efficiency, and innovation are analyzed, alongside emerging themes like ethical AI, finance applications, and factors influencing AI-driven financial decision-making.\n\nResults The findings reveal critical gaps in interdisciplinary methods, ethical considerations, and methodological advancements necessary to develop robust and transparent AI systems. Thematic mapping highlights the increasing importance of ethical AI practices and the influence of AI on financial decision-making processes. Emerging research areas emphasize the need for innovative frameworks and solutions to address current challenges.\n\nConclusions This study provides valuable insights for academics, industry practitioners, and policymakers to harness transformative potential of AI in finance. This research offers a foundation for future studies and practical applications by addressing key gaps and promoting interdisciplinary and ethical approaches in a rapidly evolving field.", "keywords": [ "Artificial Intelligence", "Finance", "Bibliometric Analysis", "TCCM", "Thematic Mapping" ], "content": "1. Introduction\n\nArtificial intelligence (AI) has caused significant changes in several industries, among which the finance industry has been the most impacted. AI is defined as the imitation of human intelligence processes by machines, particularly computer systems (Russell & Norvig, 2016). AI improves decision-making, increases efficiency, and reduces human errors. The convergence of AI and finance, sometimes referred to as Fintech (financial technology), has produced novel tools and models, including automated customer service, credit scoring, and algorithmic trading (Arner et al., 2016). These advancements, powered by machine learning, deep learning, and natural language processing, have altered customer experiences and market dynamics, in addition to improving the accuracy and speed of financial decision-making (Chong et al., 2017). Identifying the development and major trends in AI has become crucial for researchers, practitioners, and policymakers alike, as the field’s significance in the financial sector has only increased.\n\nAcademic focus on AI in finance has risen over the last 20 years, and as technology develops, this trend is anticipated to continue. Scholars from fields such as computer science, economics, management, and business have made immense contributions. Currently, AI is employed in many financial applications such as automated wealth management, fraud detection, and market behavior prediction (Brynjolfsson & McAfee, 2014). Machine learning algorithms have proven remarkably effective in predicting stock market trends and identifying patterns in large datasets that cannot be detected by humans (Henrique et al., 2019; Nabipour et al., 2020; Patil et al., 2024). Similarly, financial institutions may now offer personalized customer support through chatbots and virtual assistants through natural language processing, which improves service quality and lowers costs (Bock et al., 2020; Engles & Bolze, 2020).\n\nDespite these developments, there are still few systematic studies on the development and research trends in the literature on AI in finance. Existing studies have often focused on specific AI technologies or their applications in particular areas of finance, such as trading or risk management (Cao, 2023; Dixon et al., 2020). However, there is still a lack of a thorough overview that maps its evolution, highlights its major topics, and describes new paths of inquiry. This gap accentuates the need to highlight AI and finance research using a bibliometric analysis. Applying statistical techniques to the study of scientific literature or bibliometrics can yield important information on the dynamics and organization of the subject of study (Aria & Cuccurullo, 2017). Bibliometric studies assist in determining the development of a field of study, as well as the relationships between various subjects and subfields, by examining trends in publication volume, citation patterns, and the most significant articles and authors.\n\nThe financial industry’s increasing reliance on AI technologies has resulted in both benefits and difficulties. On the one side, AI can increase customer satisfaction, reduce operating expenses, and enhance decision-making. However, there are additional hazards associated with the growing use of AI, including algorithmic biases, concerns about data privacy, and the possibility of job displacement in the financial services sector (Pal et al., 2021). As AI has become more integrated into the financial industry, research must address these concerns and find strategies to mitigate its negative consequences. Future studies should concentrate on the ethical implications of AI in finance, such as equity in algorithmic decision-making and transparency in the AI model (Kurshan et al., 2021).\n\nThe focus of this article is to fill this vacuum by offering a thorough overview of AI and finance research. The main aim was to determine the most referenced papers, significant authors, and important research issues in this field. The study also seeks to map the evolution of the sector and identify emerging patterns that could affect future use of AI in finance . This research is important because it will provide better knowledge of the academic progress in this field and identify areas for further study. The following research issues were addressed in the study to address the following research questions:\n\nQ1: How has the literature on AI and finance evolved till 2024?\n\nQ2: Which are the most productive journals, important articles, and renowned authors in AI and finance literature?\n\nQ3: What are the main tools, uses, and areas of study that influence the interaction between AI and finance?\n\nQ4: What are the challenges and future paths of AI and finance research?\n\nThe findings from this study could aid researchers in gaining a better view of the role of AI in finance, inform practitioners on the latest advancements, and assist policymakers in addressing ethical, operational, and regulatory concerns related to the field. This article is divided into six sections. We outline the process for locating, screening, and choosing relevant publications for the bibliometric study of AI in finance in the first section, which also presents the data and methodology. Using Bibiliometrix and VoSviewer software, we present a bibliometric overview in the second section. We created co-citation networks, cited significant articles and authors, highlighted the most productive journals, and identified publication patterns (Aria & Cuccurullo, 2017). The final section provides a comprehensive framework for the dominance of AI in the financial sector using the Textual, Contextual, Conceptual, and Methodological (TCCM)paradigm. In addition to offering insights into topics and subdomains, it also helps map the evolution of AI applications in finance. In the fourth segment, we examine the theme and future directions, looking at existing trends, gaps, and potential future research topics. The fifth section offers a synthesis of areas that require more research and opportunities for development as well as a synopsis of future study directions. The sixth section concludes with a review of the research’s limitations and a list of the key lessons learned, and finally discusses the implications of our findings.\n\n\n2. Methods\n\nWe employed a mixed review technique in this study, combining the TCCM framework with bibliometric review to identify research trends and propose future possibilities within the research context. The TCCM framework examines existing theoretical and research frameworks and suggests changes or the creation of new models (Paul & Rosado-Serrano, 2019). This approach is consistent with the design and content of the accepted review procedures (Bhukya & Paul, 2023). Furthermore, we incorporated inclusion and exclusion criteria (Bhukya & Paul, 2023) when choosing the materials for analysis. Articles from peer-reviewed journals in the Web of Science (WoS) database with an impact factor of at least one were included.\n\nThe selection follows a three-step process: i) identification of relevant documents, ii) screening of documents, and iii) final selection. This establishes the relevance and rigour of the materials required for the study. The theories, constructions, contexts, and methodologies in the literature were evaluated using the TCCM framework. Bibliometric analysis reveals information on cocitation networks, publishing trends, and citation patterns. We applied an integrated approach, that help us to uncover new topics and knowledge gaps for future research. This provides a broad picture of the evolution of AI applications in finance. This would establish a foundation for future theoretical and methodological advancements and provide useful recommendations for academics and specialists in the area.\n\nThe WoS bibliometric database (http://www.webofknowledge.com) was used to identify research articles relevant to AI and finance. The search terms included “artificial intelligence” “AI” and “finance” finance, which were applied to conduct title, abstract, and keyword searches. The initial query retrieved a total of n = 2476 documents connected to AI and finance research. Recognizing the possibility that not all documents would be directly relevant to the research scope, further screening was performed using predefined filters to ensure the selection of pertinent documents.\n\nA multilayered filtering process was employed to refine the document set and maintain its relevance to the study objectives. First, the scope was narrowed to publications categorized under the fields of ‘Economics,’ ‘Business Finance,’ ‘Management,’ and ‘Business, econometrics, and finance’ as depicted Figure 1. Second, only the final versions of the peer-reviewed journal papers published in English were included. The filtering process returned a reduced dataset of 629 documents. To ensure data quality, additional manual screening was performed to confirm the relevance of these articles to AI and finance research.\n\nFollowing comprehensive screening, 607 documents were finalized as highly relevant to the literature on AI in finance. Manual verification of the dataset was performed and each document provided substantial insights. These documents were included in the subsequent bibliometric analyses.\n\n\n3. Bibliometric overview\n\nAdvanced bibliometric analytic tools, such as Bibliometrix (https://www.bibliometrix.org/home/) and VOSviewer (https://www.vosviewer.com/), which are frequently used in bibliometric investigations, were employed in this study (Ingale & Paluri, 2020). A bibliometric analysis was conducted on the finalized dataset to uncover publication trends, influential works, and key contributors to the domain of AI in finance.\n\na) Trend Analysis: The analysis begins with a trend overview of AI and finance research, highlighting publication growth over time and identifying periods of significant research activity.\n\nb) Most Cited Articles: An overview of the most referenced papers in finance and AI literature is provided, highlighting significant research that has influenced the field.\n\nc) Leading Journals: The study identifies journals with the highest impact, which have published groundbreaking works in AI and its applications in finance.\n\nd) Productive Authors: Finally, the analysis highlights the most prolific and impactful authors who have significantly contributed to AI and finance research.\n\nThis methodological approach facilitates insights into existing trends and identifies areas for future research, thus offering extensive knowledge of the research landscape in AI and finance.\n\nSince the mid-1900s, the concept of AI has experienced sizable growth. At the Dartmouth Conference in 1956, John McCarthy first used the word to describe the making of machinery that might carry out assignments that normally required human intelligence (McCarthy et al., 1956). Over time, AI has been expanded to encompass machine learning, deep learning, and neural networks, moving away from its initial focus on rule-based systems and symbolic reasoning (Mohamed et al., 2020; Russell & Norvig, 2016). AI’s increasing capacity to evaluate enormous datasets, adjust to new knowledge, and produce remarkably accurate forecast insights is shown in this progression.\n\nAI’s transformative impact has been particularly profound in the financial sector, where its adoption has redefined traditional processes and decision-making paradigms. Financial institutions have leveraged AI for applications ranging from algorithmic trading and fraud detection to personalized customer services and risk assessment (Agrawal et al., 2018). For instance, AI powered algorithmic trading systems can process and analyze financial market data in real time, enabling high-frequency trades that maximize profitability (Baldauf & Mollner, 2020). Similarly, financial institutions can anticipate market patterns, identify possible weaknesses, and create plans to reduce losses by using AI-driven risk management systems (Cao, 2023; Jain, 2023).\n\nAI is essential for improving customer engagement and personalizing experiences in marketing and consumer finance. AI-powered advanced recommendation engines examine consumer behavior and preferences in order to make personalized financial product recommendations, enhance client loyalty, and foster stronger relationships (Davenport & Ronanki, 2018). Furthermore, chatbots and virtual assistants provide real-time assistance with natural language processing (NLP) capabilities to revolutionize customer service in banking and financial services (Coglianese & Lehr, 2019; Shin, 2019). Recent bibliometric analyses of AI in finance literature stresses its interdisciplinary nature and rapid expansion as a field of study. For instance, studies have identified key trends in AI applications within financial services, highlighting an emphasis on predictive analytics, real-time decision making, and automation (Dhamija & Bag, 2020). Bibliometric research has also revealed the central role of collaboration among researchers from diverse disciplines, thus reflecting the field’s complex and integrative challenges. In this study we have further explored the ethical considerations and governance challenges accompanying AI’s widespread adoption in finance, emphasizing the importance of balancing innovation with regulatory oversight (Li & Zhang, 2024; Ridzuan et al., 2024; Taeihagh, 2021).\n\nAI is a key force behind innovation in the financial industry because of its capacity to interpret unstructured data, identify hidden patterns, and make judgments on its own. Meanwhile, debates over fairness, transparency, and the possible replacement of human labor in finance-related positions have been sparked by its broad implementation (Cao, 2023; Pal et al., 2021). As AI develops further, its dual function as a tool to improve operational efficiency and ethical investigation highlights its great and complex effect on finance.\n\nThe status of scientific production for each year is shown in Figure 2 and Table 1. Our bibliometric research documents the scholarly investigation of AI in finance, identifying 607 papers published between 1993 and 2024, starting in the early 1990s. This area has shown consistent improvement, with a yearly growth rate of 3.49%. Throughout the first 25 years (1993–2017), academic output was relatively modest, with only 139 publications, averaging approximately 5.56 articles annually. However, this changed dramatically after 2018, with an exponential increase in the publication rates. From 2018 to 2023 alone, an average of 121.6 publications per year demonstrates the accelerating interest in AI applications within finance. The majority of research contributions result from this increase, suggesting that in recent years, the relationship between AI and finance has become a crucial topic of study.\n\nAn average of 15.73 citations per document and 30,726 references showed a growing volume of research in the area. Furthermore, international collaboration is prominent in this domain, with 45.63% of publications involving authors from multiple countries highlighting the global relevance of AI in reshaping financial systems. Major applications explored in the literature include risk management, trading algorithms, customer relationship management, and decision-making tools. Scholarly interest increased sharply between 2019 and 2023, coinciding with advances in automation, big data analytics, and machine learning. The relatively young age of documents (2.98 years on average) suggests that this is an emergent field, characterized by fresh insights and cutting-edge research. Despite the recent proliferation of studies, the field is still in its formative stages, with single-authored contributions comprising only 46 articles, indicating the collaborative nature of this research domain. The expanding adoption of AI technologies by financial institutions and fintech companies, along with the emergence of data-driven solutions, is expected to sustain and even amplify this growth trajectory. The sharp increase in publications after 2018 highlights the transformative capability in this area. As the financial sector continues to embrace AI-driven innovations, further academic exploration is anticipated, promising to enhance our insight into the role of AI in revolutionizing financial systems and practices.\n\nThe breakdown showed that 607 articles were published in 205 journals. We searched for journals with at least one publication and at least 25 citations to determine which were the most significant and active in furthering AI and finance research. 64 journals that satisfied the required limits were identified using this criterion ( Table 2). The journals were ranked according to the quantity of publications they published; the journal that published the most articles was ranked the highest. The rating was based on the overall number of citations earned by each publication, even if several journals had published the same number of articles. Our analysis indicates that Management Science, Journal of Banking & Finance, Technological Forecasting and Social Change, Finance analysis Letters, and Journal of Economic Dynamics & Control are the top five most productive publications for AI and finance research. The advancement of the literature in this field has been greatly aided by these journals. According to the ABDC journal rankings, these journals are notably ranked A or A, demonstrating their significance and the significant influence of the research they publish. Table 2 provides a thorough summary of the journals, along with their citation and publication counts.\n\nTo identify the most impactful contributions to this domain, we adopted a citation-based benchmarking approach, focusing on articles with at least 100 citations (Bhukya & Paul, 2023). This analysis identified ten seminal articles, which are detailed in Table 3. With an average of 36.89 citations annually (CPY), a research article (Das & Chen, 2007) published in Management Science has received 664 citations. The author (Altman et al., 1994), in the Journal of Banking and Finance, gathered 464 citations (14.97 CPY) by offering a comparative evaluation of neural networks and traditional methods for corporate distress diagnosis, a foundational contribution to predictive analytics in finance. Several other studies have also made profound contributions to the Journal of Economic Dynamics and Control (LeBaron et al., 1999) and received 386 citations (14.85 CPY) for their innovative exploration of time-series properties within artificial stock markets, bridging AI, and economic modelling. A nonparametric AI-driven method for pricing and hedging derivatives was presented (Hutchinson et al., 1994) in The Journal of Finance, which received 355 citations (11.45 CPY). More recently, the authors (Chod et al., 2020) highlighted the financial advantages of supply chain transparency and blockchain technology in Management Science, achieving 324 citations with an outstanding 64.80 CPY. The emerging significance of AI-driven decision making is further illustrated in the California Management Review (Huang et al., 2019) (200 citations, 33.33 CPY) and Finance Research Letters (Dowling & Lucey, 2023) (179 citations, 89.50 CPY). Despite being published only recently, the latter has demonstrated rapid scholarly engagement with AI in finance, emphasizing its critical role in shaping future research trajectories. The majority of these highly significant works were published in esteemed journals with ABDC classifications of A or A, including Management Science, The Journal of Finance, and the Journal of Banking & Finance. Their large number of citations highlights a vital contribution to the growth of AI applications in the financial industry. This has laid the groundwork for future research. A thorough overview of these studies is given in Table 3, which also highlights the variety of approaches, research topics, and consequences that have influenced the academic environment of financial and AI studies. This emphasizes that AI is becoming a more significant factor in risk management, market analysis, and financial decision-making.\n\nOur analysis revealed that 1966 writers contributed to the field of study. Nineteen played a significant role in developing the research area. Our aim was to identify the authors with the most cumulative citations and the most prolific authors. In terms of total citations (tc = 528) from 13 articles, Andrew W. Lo of the Massachusetts Institute of Technology stood out as the top contributor, highlighting his noteworthy influence in the field. With eight publications and 84 citations overall, Zhaobo Zhu dominated the list of authors with the most articles. Additional noteworthy contributors include Shasha Zhou and Yuangao Chen, each with seven publications and 211 and 176 cumulative citations, respectively, underscoring their strong influence in advancing academic discourse. Furthermore, researchers such as Maoyong Cheng (three publications, tc = 169) and Xingyang Lv (three publications, tc = 152) have also demonstrated focused and impactful research output. These contributions collectively reflect the dynamic and interdisciplinary efforts that drive the growth of AI and finance research. Figure 3, Figure 4, and Table 4 provide insightful snapshots of these leading scholars, emphasizing their pivotal roles in shaping the scholarly landscape.\n\nFigure 5 reveals the thematic structure of research on AI and Finance through a co-occurrence network in which distinct clusters of interconnected keywords are identified, each represented by a specific color. The largest cluster, highlighted in green, centers around “artificial intelligence” and includes closely linked terms like “machine learning,” “big data,” and “automation,” reflecting the widespread use of AI across diverse domains such as finance and technology. The red cluster emphasizes terms like “blockchain” and “cryptocurrency,” showcasing the amalgamation of AI with financial technologies, particularly in enhancing transparency, security, and digital innovation. The blue cluster focuses on “financial markets,” “risk assessment,” and “systemic analysis,” systemic analysis, demonstrating the use of AI in traditional financial research for predictive analytics and economic modelling. Additionally, smaller clusters, such as purple and orange clusters, capture niche areas such as behavioral analysis and decision-making systems. The multidisciplinary character of AI research is highlighted by these color-coded clusters, which integrate technological, financial, and economic development with computational advances. They also emphasized the crucial role that AI plays in tackling intricate problems in a variety of domains.\n\n\n4. TCCM analysis\n\nThe TCCM approach improves the methodological arrangement and evaluation of multidisciplinary research on AI in finance. Four categories were created based on the results highlighted in Figure 6. The study first educates readers by carefully examining both the well-established and new hypotheses that support role of AI in changing financial systems. Second, there has been discussion and critical analysis of the settings in which the most important research on AI applications in finance is carried out. Third, the defining characteristics of AI that enable its diverse applications in finance are outlined, highlighting its impact on operations and strategies. Fourth, the research methodologies employed to investigate role of AI in finance are reviewed, highlighting the tools and approaches used for data collection and analysis.\n\nThe analysis reveals six major hypotheses that explain how AI transforms financial innovation and decision making. The Efficient Market Hypothesis (EMH) explores how AI enhances the accuracy of financial market predictions and identifies inefficiencies that contribute to improved market efficiency (Anshari et al., 2021; Buckley et al., 2021; Fama, 1970; Kurshan et al., 2021). Behavioral Finance Theories examine the influence of AI-driven sentiment analysis on investor psychology and decision-making, highlighting the psychological underpinnings of financial behavior (Chartier et al., 2021). Agency Theory highlights AI’s potential to mitigate agency conflicts by enhancing transparency, monitoring, and corporate governance mechanisms, thereby reducing information asymmetry (Jensen & Meckling, 1976; Kalkan, 2024). Decision theory examines how AI streamlines intricate financial decision-making procedures, especially in domains such as investment strategies and risk management (Cao, 2023; Tversky & Kahneman, 1986). Network Theory illustrates AI’s significant role in systemic risk analysis, particularly through the modelling of financial networks, enabling a deeper understanding of interconnected risks (Battiston et al., 2016). Finally, the Resource-Based View (RBV) positions AI as a strategic organizational resource that firms leverage to gain competitive advantages, innovate, and drive long-term growth (Barney, 1991; Kitsios & Kamariotou, 2021; Machireddy et al., 2021). These theories offer a solid basis for comprehending the complex effects of AI on the financial industry to improve predictive analytics, decision-making procedures, and strategic management of financial institutions.\n\nThe literature on AI applications in finance spans diverse contexts, each contributing distinct insights into the transformative potential and the associated challenges of AI-driven innovation. Among these, the financial market context highlights AI’s application in algorithmic trading, market sentiment analysis, and fraud detection, showcasing its ability to enhance efficiency and security in trading environments (Baldauf & Mollner, 2020; Cao, 2023). In Corporate Finance, AI is considered for financial forecasting, capital structure optimization, and strategic investment decisions, demonstrating its value in improving corporate decision-making processes (Machireddy et al., 2021). The Banking sector leverages AI-powered solutions for credit risk assessment, customer relationship management, and the automation of loan approval processes, thereby enhancing operational efficiency and customer satisfaction (Jain, 2023; Singh & Arora, 2023). Within Insurance, AI contributes to streamlining underwriting, managing claims, refining actuarial risk models, and fostering precision and cost efficiency (Erem Ceylan, 2022; Rana et al., 2022; Zia & Kalia, 2022). The rise of FinTech showcases role of AI in developing innovative tools, such as robo-advisors, chatbots, and blockchain-driven systems, revolutionizing customer interactions, and transaction processes (Kashyap, 2023). Finally, the Sustainability context explores AI’s contributions to environmental, social, and governance (ESG) investments, green finance, and carbon market analytics, highlighting its critical role in supporting sustainable economic development (Hemanand et al., 2022; Macchiavello & Siri, 2022). These six contexts collectively demonstrate the breadth of AI’s impact on finance, operational efficiency, strategic decision-making, and sustainability initiatives.\n\nAI’s transformative impact of AI on finance is underpinned by its unique technical, functional, and strategic characteristics, which enable it to address complex challenges and unlock new opportunities. A key component of AI in finance is Data-Driven Insights, which use big data to identify trends, facilitate predictive analytics, and improve decision-making in a variety of financial fields (Go et al., 2020; Obschonka & Audretsch, 2020). Automation simplifies repetitive tasks, such as financial reporting, auditing, and trading, improves efficiency, and reduces operational burdens (Jain, 2023; Singh & Arora, 2023). The Scalability of AI allows its application to expand seamlessly across various financial sectors and global markets, demonstrating its adaptability and potential (Chen & Bellavitis, 2020; Jameaba, 2020). With Accuracy and Speed, AI delivers high-precision computations while accelerating complex financial processes, thereby ensuring timely and reliable outcomes (Cao, 2020, 2023; Jameaba, 2020). However, the use of AI also brings ethical challenges such as concerns about bias, equity, and transparency in AI-powered systems, which call for strong governance structures (Binns, 2018). AI also serves as a force for disruption, transforming traditional financial paradigms, fostering innovation, and driving new market dynamics (Kalkan, 2024). Together, these characteristics displays capacity of AI to enhance efficiency, reduce costs, and redefine strategies, making it a pivotal driver of financial innovation and evolution.\n\nAI research within finance domain has adopted a range of methodological approaches to investigate its multifaceted implications and applications. Empirical Studies show that machine learning algorithms perform predictive modelling and financial analysis, offering data-driven insights into market behavior and trends (Cao, 2023). Experimental Designs focus on testing AI-based solutions for critical functions, such as fraud detection, trading strategies, and risk management, enabling practical evaluations of effectiveness of AI (Kashyap, 2023). Simulation Models create artificial markets and scenarios, thus providing a framework for assessing systemic risks and market dynamics under controlled conditions (Battiston et al., 2016). Qualitative Research delves into stakeholder perceptions and attitudes toward AI adoption in finance, shedding light on behavioral and organizational factors (Ridzuan et al., 2024). Mixed Methods integrate quantitative and qualitative approaches, offering a holistic perspective of impact and potential of AI (Kitsios & Kamariotou, 2021; Machireddy et al., 2021; Tang, 2021). Network Analysis employs AI-driven graph analytics to map financial systems and uncover relationships, thereby enhancing the systemic understanding (Jain, 2023; Singh & Arora, 2023). Additionally, Systematic Reviews synthesize existing literature to identify emerging trends and research gaps, guiding future inquiries (Baldauf & Mollner, 2020; Cao, 2023). Despite considerable advancements, there are still gaps in the use of cutting-edge approaches to better grasp the revolutionary role of AI in finance, such as agent-based modelling and neuroscience (Go et al., 2020).\n\n\n5. Research Gaps and Future Directions\n\nThe TCCM framework identifies significant research gaps and proposes avenues for future exploration to enhance the understanding of AI’s role in finance. Theoretically, there is scope to integrate emerging frameworks, such as technological determinism and the adaptive markets hypothesis, to deepen insights into AI’s influence on financial decision-making (Kalkan, 2024). Contextually, applications of AI in microfinance, rural banking, and emerging economies remain underexplored, presenting opportunities to address unique challenges in underserved markets (Hemanand et al., 2022; Macchiavello & Siri, 2022). Ethical concerns, such as fairness, transparency, and explainability in AI-driven algorithms, require urgent attention to ensure accountability and alignment with ethical standards (Binns, 2018). Methodologically, adopting innovative approaches, including neuroscience and behavioral experiments, can provide novel insights into the cognitive and psychological dimensions of financial applications of AI (Go et al., 2020; Obschonka & Audretsch, 2020). Additionally, interdisciplinary research exploring intersection of AI with domains such as climate finance, blockchain, and global economic resilience can further expand its applications and address broader challenges (Barney, 1991; Kitsios & Kamariotou, 2021; Machireddy et al., 2021).\n\nFrom a country perspective ( Table 5), China leads research output with 337 documents, while the USA demonstrates the highest research impact with 4628 citations from 128 documents, highlighting its dominance in high-impact studies. England, with 75 documents and 1137 citations, also showed a significant influence. Among European nations, Italy (33 documents, 1082 citations) and France (55 documents, 675 citations) make notable contributions. In Asia, China stands out, followed by Taiwan (35 documents, 460 citations), and India (21 documents, 419 citations), underlining the region’s growing focus on AI-driven financial innovation. Smaller yet impactful contributions came from Vietnam (13 documents, 536 citations) and Malaysia (19 documents, 308 citations). Australia (34 documents, 515 citations) and Germany (29 documents, 535 citations) represent consistent efforts toward AI finance research. Emerging players such as South Africa (6 documents, 318 citations) and the UAE (7 documents, 312 citations) also highlight their involvement, albeit with fewer publications.\n\nThe Sankey diagram ( Figure 7) visualizes the evolution of AI and finance research themes over distinct periods, illustrating the dynamic progression of key topics. From 1993 to 2010, the focus was on prediction and neural networks, with predictive modelling in finance and the growing application of neural networks in decision-making. During 2011–2020, research diversified, with neural networks expanding into areas such as risk, volatility, and market studies. Themes such as growth, impact, and returns emerged, reflecting broader applications in financial performance and economic growth. The period from 2021 to 2024 marked a shift toward AI and technology, with an increased emphasis on the practical and managerial aspects of research alongside themes of information and management. The recent emergence of behavior as a key theme suggests a focus on decision making, consumer behavior, and organizational psychology.\n\nLooking ahead to 2025, the projected focus on determinants signals a growing interest in understanding the underlying factors that drive success or failure in various domains. While the rise of impact, information, and management indicates a move toward practical applications, themes such as neural networks remain consistent over time, reflecting their central role in the increase of AI and finance research. The future focus on determinants points to a trend toward deeper causal analysis to understand the factors shaping impact of AI on finance.\n\nThe research subjects in the fields of AI and finance are given by a thematic map ( Figure 8), which groups them according to two criteria: density (development degree) and centrality (relevance degree). Each of the four quadrants constituting the map represents a distinct topic. The high centrality and density of the motor topics (top-right quadrant) indicate well-developed topics that are essential to the field of study. Key topics in this quadrant include AI, Innovation, and Technology, which are pivotal for driving advancements within the domain. Themes with high density but low centrality are seen in the Niche Themes (top-left quadrant), signifying specialized fields with minimal ties to the larger research environment.\n\nTopics such as Overconfidence, Economics, Judgment, and Electricity, Spot Markets fall into this category, representing niche applications and behavioral finance aspects. The undeveloped Emerging or Declining Themes (bottom-left quadrant), such as value-at-risk, have low centrality and density, which indicates that current research has shown less interest in these subjects. Lastly, the bottom-right quadrant’s Basic Themes, which have high centrality but low density, stand for fundamental ideas such as risk, returns, markets, impact, performance, and information. These ideas are essential for financial analysis and investment studies, but they might need more work to realize their full potential.\n\nThe industry has seen a dramatic change as a result of the rapid development of AI, which has opened new avenues for risk management, predictive analysis, and more effective decision-making. The use of AI in financial operations is still developing, and a number of important areas require further research. As technology advances and the financial landscape changes, more research is necessary to fully understand how AI propels innovation in markets and financial institutions. A promising path toward enhancing operational effectiveness and financial stability is provided by the AI’s capacity to handle enormous amounts of data and deliver insights into dynamic environments. With increasing influence of AI, particularly in areas such as algorithmic trading, fraud detection, and financial forecasting, the following future research questions (FRQs) can guide further investigation into the role of AI in finance.\n\nFRQ1: How can AI-driven predictive models enhance decision-making in volatile financial markets, particularly during economic downturns or crises?\n\nFRQ2: How does the use of AI to financial decision-making raise ethical questions, particularly with regard to accountability, transparency, and fairness?\n\nFRQ3: What effects will AI deployment have on conventional risk management techniques and the part that human decision-makers play in these procedures in financial institutions?\n\nFRQ4: How can AI innovations improve financial inclusion, particularly in underserved or emerging markets?\n\nFRQ5: What are the longstanding effects of AI on investor behaviour and financial market dynamics, particularly regarding the automation of trading and advisory services?\n\nFRQ6: Can AI play a role in enhancing sustainability in finance by supporting green finance initiatives and responsible investment practices?\n\nAI in finance is driven not only by its technical capabilities but also by its potential to disrupt traditional financial models and improve efficiency. Future research can explore the interplay between AI technologies and behavioral factors that influence decision-making processes in finance. Key areas of interest include the following.\n\nFRQ1: How does AI-driven sentiment analysis affect investor psychology and market movements, particularly in volatile or uncertain periods?\n\nFRQ2: What role does AI play in reshaping financial advisory services, and how do consumers perceive the trustworthiness and effectiveness of AI-driven advice compared to traditional human advisors?\n\nFRQ3: How can AI be leveraged to improve decision-making under uncertainty, particularly in complex financial markets where human cognition may be limited?\n\nAs AI technology continues to evolve, its interaction with human behavior and cognitive processes in finance remains a critical area for future research. Understanding how AI enhances or challenges human decision-making and the ethical implications of these changes is crucial for shaping the future of finance. Research in this area should consider the potential of AI to not only optimize financial outcomes but also its role in influencing consumer behavior and financial practices.\n\nAI is used in a large range of financial products, from algorithmic trading to fraud detection, risk management, and financial forecasting. Quantitative methods, such as statistical analysis and machine learning models, are the mainstays of current research in this field. Model overfitting, data bias, and limited interpretability of sophisticated AI systems are some of the methodological problems that still exist. Future research can address these issues by implementing a greater variety of creative techniques to increase the precision, dependability, and interpretability of AI-driven financial models. Using text analytics and natural language processing (NLP) tools to examine vast volumes of financial data from many sources, such as business filings, social media, and financial news, is a possible path for methodological progress. Using named entity identification, topic modelling, and sentiment analysis, researchers can learn more about investor behavior, market mood, and patterns that affect financial decision making. These methods can provide more accurate predictions of market movements and risk factors while also addressing biases inherent in structured financial data.\n\nAdditionally, simulation methodologies such as agent-based modelling and fuzzy cognitive mapping offer promising approaches for understanding complex interactions in financial systems. These techniques allow for the modelling of dynamic financial environments where individual agents, such as investors or firms, interact under uncertain conditions. Research on how AI affects financial stability, risk propagation, and market behavior can be conducted using agent-based models. On the other hand, fuzzy cognitive mapping can offer a better understanding of systemic risk and role of AI in financial crises by visualizing and comprehending the interaction between AI-driven decisions and other macroeconomic factors. Lastly, qualitative approaches can be significant in comprehending the behavioral consequences of AI adoption, as AI continues to upend conventional banking practices. Stakeholder opinions about the use of AI in finance can be investigated using case studies, expert interviews, and interviews. The impact of AI on decision making, organizational behavior, and the future of financial advice services could be the main topics of discussion. Combining these qualitative insights with quantitative data can offer a holistic view of transformative potential of AI in finance.\n\n\n6. Implications\n\nOur research highlights the managerial implications for financial institutions and other stakeholders in the finance sector. Financial institutions should be mindful of AI’s potential to influence customer behavior in both beneficial and detrimental ways. While AI can drive efficiency and improve decision-making, its use in customer-facing applications must be approached with caution to avoid ethical concerns such as algorithmic bias or lack of transparency. Marketers, for example, should focus on promoting AI-based financial tools in ways that are transparent and aligned with consumers’ best interests, rather than relying solely on automation for decision-making.\n\nPolicymakers need to address the ethical and legal issues raised by AI in finance. It is imperative that governments and authorities put in place mechanisms that guarantee accountability, transparency, and justice in AI algorithms, given the widespread use of AI in decision-making. Oversight is required as AI systems in finance have become more sophisticated to prevent market manipulation, discrimination, and data privacy violations. Furthermore, regulators should focus on creating standards for AI literacy among consumers to help them understand the implications of AI-driven financial products/services.\n\nAI in finance has several significant ethical implications. Although AI systems can improve decision making, they can also reinforce pre-existing biases, raising concerns about equality and fairness. Ethics pertaining to the independence of AI-driven judgments, openness in algorithmic procedures, and protection of consumer rights must be addressed as AI continues to have an impact on the financial industry. Researchers and practitioners should pay close attention to these issues, ensuring that AI adoption in finance does not disproportionately affect vulnerable populations or widen existing financial disparities.\n\n\n7. Conclusion\n\nThis study has some limitations. First, while we have focused on impact of AI in finance, the rapidly evolving nature of AI technologies suggests that new research is needed to account for emerging trends and applications. Additionally, most of the reviewed studies focus on Western financial markets. This could restrict the extent to which our results can be applied in other areas. Future studies should examine the cross-cultural uses of AI in finance to determine how various markets react to AI-driven financial tools. Finally, although we have outlined the main ethical issues, further study is required to fully understand the long-term societal effects of AI in finance, especially regarding privacy, surveillance, and consumer autonomy. AI holds the prospect of transforming the financial sector by enhancing decision making, minimizing risks, and improving operational efficiency. However, as emphasized in our research, its implementation brings certain challenges, including ethical concerns, managerial complexities, and policy implications, all of which require responsible attention.", "appendix": "Data availability statement\n\nZenodo: AI and Finance, https://doi.org/10.5281/zenodo.14410427 (Singh, P. K, 2024).\n\nThis project contains the following underlying data:\n\n1. AI and Fin.bib\n\n2. AI fin.txt\n\nLicense: Data is available under Creative Commons Attribution 4.0 International\n\n\nReferences\n\nAgrawal A, Gans J, Goldfarb A: Prediction Machines: The Simple Economics of Artificial Intelligence. Harvard Business Review Press; 2018.\n\nAltman EI, Marco G, Varetto F: Corporate distress diagnosis: Comparisons using linear discriminant analysis and neural networks (the Italian experience). J. Bank. Financ. 1994; 18(3): 505–529. Publisher Full Text\n\nAnshari M, Almunawar MN, Masri M, et al.: Financial Technology with AI-Enabled and Ethical Challenges. Society. 2021; 58(3): 189–195. Publisher Full Text\n\nAria M, Cuccurullo C: Bibliometrix: An R-tool for comprehensive science mapping analysis. J. Informet. 2017; 11(4): 959–975. Publisher Full Text\n\nArner DW, Barberis J, Buckley RP: FinTech, RegTech, and the Reconceptualization of Financial Regulation. Northwest. J. Int. Law Bus. 2016; 37(3): 371–413.\n\nBaldauf M, Mollner J: High-frequency trading and market performance. J. Financ. 2020; 75(3): 1495–1526. Publisher Full Text\n\nBarney J: Firm resources and sustained competitive advantage. J. Manag. 1991; 17(1): 99–120. Publisher Full Text\n\nBattiston S, Caldarelli G, May RM, et al.: The price of complexity in financial networks. Proc. Natl. Acad. Sci. 2016; 113(36): 10031–10036. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBhukya R, Paul J: Social influence research in consumer behavior: What we learned and what we need to learn?–A hybrid systematic literature review. J. Bus. Res. 2023; 162: 113870. 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Reference Source\n\nMacchiavello E, Siri M: Sustainable finance and fintech: Can technology contribute to achieving environmental goals? A preliminary assessment of ‘green fintech’and ‘sustainable digital finance. Eur. Co. Financ. Law Rev. 2022; 19(1): 128–174. Publisher Full Text\n\nMachireddy JR, Rachakatla SK, Ravichandran P: Leveraging AI and Machine Learning for Data-Driven Business Strategy: A Comprehensive Framework for Analytics Integration. Afr. J. Artif. Intell. Sustain. Dev. 2021; 1(2): 127–150.\n\nMcCarthy J, Minsky M, Rochester N, et al.: A proposal for the Dartmouth summer research project on artificial intelligence.1956.\n\nMohamed A, Najafabadi MK, Wah YB, et al.: The state of the art and taxonomy of big data analytics: view from new big data framework. Artif. Intell. Rev. 2020; 53(2): 989–1037. Publisher Full Text\n\nNabipour M, Nayyeri P, Jabani H, et al.: Predicting stock market trends using machine learning and deep learning algorithms via continuous and binary data; a comparative analysis. IEEE Access. 2020; 8: 150199–150212. Publisher Full Text Reference Source\n\nObschonka M, Audretsch DB: Artificial intelligence and big data in entrepreneurship: a new era has begun. Small Bus. Econ. 2020; 55(3): 529–539. Publisher Full Text\n\nPal A, Tiwari CK, Behl A: Blockchain technology in financial services: a comprehensive review of the literature. J. Glob. Oper. Strateg. Sourc. 2021; 14(1): 61–80. Publisher Full Text\n\nPatil D, Rane NL, Desai P, et al.: Machine learning and deep learning: Methods, techniques, applications, challenges, and future research opportunities. Trustworthy Artificial Intelligence in Industry and Society. 2024; pp. 28–81. 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Publisher Full Text" }	[ { "id": "362857", "date": "03 Feb 2025", "name": "Saad Salih Hussein", "expertise": [ "Reviewer Expertise the systematic way of writing to present the researchers' ideas was credit for the paper" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article discusses a new aspect of the relationships between Artificial intelligence and finance, it gives, therefore, a rule of thump to the literature on accounting and finance, the researchers have used a sufficient amount of background articles to support their argument to prove the relationship between the main variables of this study, it is thus, this article has written carefully in the right path with all supported evidence to complete the paper argument.\nSummary of the Article The article provides a comprehensive bibliometric analysis of the intersection of artificial intelligence and finance, shedding light on its evolution, central themes, and potential research avenues which is welcoming. The study uses 607 Web of Science indexed papers and follows the Theory-Context-Characteristics-Methodology (TCCM) framework which is commendable. The research highlights key themes such as risk management, market efficiency, innovation, and emerging areas like ethical AI and AI-driven financial decision-making. The findings emphasize critical gaps in interdisciplinary methodologies, ethical considerations, and the need for more transparent AI systems in financial applications.\nStrengths of the Article Comprehensive Scope – The study successfully maps the evolution of AI in finance, providing a well-structured thematic analysis. Robust Methodology – The use of bibliometric techniques and the TCCM framework adds rigor to the research, ensuring a systematic approach. Relevance to Academia and Industry – The findings are valuable for researchers, practitioners, and policymakers, offering insights into the transformative role of AI in finance. Identification of Key Gaps – The study highlights crucial research gaps, particularly in ethical AI and methodological advancements, making it a strong foundation for future research.\nMajor Points for Improvement\n1. Expanding Practical Implications through empirical research– The findings highlight key trends in AI adoption within finance; however, further elaboration on the direct industry applications of these insights would enhance the study’s practical relevance. Providing specific examples of AI’s role in areas such as credit risk assessment, fraud detection, portfolio management, and regulatory compliance could help bridge the gap between research and practice.\nMinor Points for Improvement 1. Incorporating Recent Literature – The study is well-grounded in existing research; however, integrating more recent publications (2023–2025) would further enhance its timeliness. Including the latest studies on AI applications in finance, particularly in ethical AI and regulatory advancements, would ensure the findings remain current and relevant.\nNevertheless, the article can be accepted for indexing in bibliographic databases.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] }, { "id": "362855", "date": "04 Feb 2025", "name": "Rajeev Semwal", "expertise": [ "Reviewer Expertise Tourism Psychology", "Tourism Marketing", "Sustainable tourism Practice", "Tourism & AI", "Tourism and Machine Learning." ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n1. Is the work clearly and accurately presented and does it cite the current literature? Response: Yes Explanation: The paper is well-structured and provides a comprehensive review of the intersection between artificial intelligence (AI) and finance. The presentation follows a logical flow, beginning with an introduction to AI's impact on finance, a review of relevant literature, a detailed discussion of the bibliometric methodology, and a structured analysis using the TCCM framework. The paper effectively conveys its objectives, research questions, and findings without excessive complexity. The citations include a mix of foundational theories (e.g., Efficient Market Hypothesis, Decision Theory) and contemporary research, ensuring that the literature review remains current and relevant. The use of bibliometric tools such as VOSviewer and Bibliometrix further strengthens the credibility of the study, providing a systematic analysis of publication trends, key authors, and influential works.\nRecommendation: The clarity of the paper is commendable, and no major revisions are needed in terms of structure or citation quality. However, the introduction could benefit from a more concise summary of the key bibliometric trends identified, helping readers quickly grasp the significance of the study. Additionally, while the literature cited is extensive, the authors could briefly acknowledge any limitations related to potential publication bias, particularly the exclusion of non-English and non-Web of Science indexed studies.\n2. Is the study design appropriate and is the work technically sound? Response: Yes Explanation: The study employs a robust bibliometric approach, which is a widely accepted method for identifying research trends and knowledge gaps in a given domain. The authors use a well-defined process for data collection, screening, and analysis, ensuring methodological rigor. The adoption of the TCCM framework provides a structured way to categorize existing research based on theoretical perspectives, contextual applications, methodological approaches, and key characteristics. This framework enhances the study’s depth by not only mapping existing literature but also proposing future research directions. The reliance on the Web of Science (WoS) database ensures access to high-impact, peer-reviewed publications, lending credibility to the findings. The use of bibliometric tools (Bibliometrix and VOSviewer) for co-citation analysis, keyword mapping, and research impact assessment adds further technical validity.\nRecommendation: While the study design is appropriate, the authors could briefly discuss any potential biases associated with bibliometric analysis. For example, the exclusion of conference papers and preprints could mean that some emerging research trends are not captured. Additionally, acknowledging any limitations related to the reliance on citation metrics (which can be influenced by journal impact factors rather than intrinsic research quality) would enhance transparency.\n3. Are sufficient details of methods and analysis provided to allow replication by others? Response: Partly Explanation: The paper outlines the methodology in a structured manner, detailing the data collection process, the use of specific bibliometric tools, and the screening process for relevant articles. The inclusion of a three-step selection process (identification, screening, and final inclusion) ensures clarity in how studies were chosen. However, some critical details are missing that could impact replication. For instance, the exact parameters used in VOSviewer for network visualization (e.g., clustering thresholds, link strength criteria) are not mentioned. Similarly, while the TCCM framework is referenced, it is unclear how the classification of studies into its four components was conducted—was it manually coded, or was a software-assisted text analysis used?\nRecommendation: The authors should provide additional methodological details to enhance replicability. Specifically, they should:\nInclude a more detailed description of how bibliometric data was cleaned and processed. Specify the exact search terms and filters used in Web of Science.\n\n4. If applicable, is the statistical analysis and its interpretation appropriate? Response: Yes Explanation: The statistical analysis used in the paper is appropriate for a bibliometric review. The study effectively utilizes co-citation networks, citation count analysis, and research trend evaluations to identify influential works and key research domains. The thematic evolution analysis, which traces how AI and finance research has developed over time, is particularly useful in highlighting emerging research trends. The authors also provide a Sankey diagram to illustrate shifts in research focus, adding a strong visual representation of the field’s progression. The citation-based benchmarking approach used to identify high-impact studies is an established method in bibliometrics, and the interpretation of these results aligns well with broader trends in AI and finance.\nRecommendation: No major revisions are required for the statistical analysis. However, the authors could improve the discussion by briefly addressing potential limitations of citation-based impact metrics. For example, some highly cited papers might be review articles rather than empirical studies, and self-citations could also influence citation counts. Including a short paragraph on such limitations would add nuance to the discussion.\n5. Are all the source data underlying the results available to ensure full reproducibility? Response: Yes Explanation: The study ensures transparency by making its dataset publicly available on Zenodo, with a provided DOI link. This allows other researchers to access the raw bibliometric data used in the analysis, facilitating reproducibility. The inclusion of citation details, thematic mappings, and network visualizations further supports the integrity of the study. Additionally, the authors utilize widely accepted bibliometric tools (VOSviewer and Bibliometrix) for analysis, making it easier for others to replicate their methodology. The structured approach to data selection, processing, and screening ensures that all source materials are well-documented.\nRecommendation: While data accessibility is well-addressed, the authors could enhance reproducibility by Providing a step-by-step guide or supplementary material outlining how to replicate the analysis using the shared dataset. Clarifying whether any pre-processing scripts or software configurations (e.g., parameter settings in VOSviewer) are included in the repository.\n6. Are the conclusions drawn adequately supported by the results? Response: Partly Explanation: The conclusions summarize the study’s key findings well and highlight important research gaps. The identification of future research directions is particularly useful, as it provides a roadmap for scholars interested in AI and finance. However, while the paper discusses research gaps and trends, it does not sufficiently address practical implications for financial institutions, policymakers, or industry practitioners. Given the relevance of AI in real-world financial applications, a discussion on how financial institutions can use these insights would enhance the paper’s impact. Additionally, the ethical implications of AI in finance—such as bias in AI-driven decision-making and the risks of algorithmic trading—are briefly mentioned but not explored in depth.\nRecommendation: Expand the discussion on practical implications for financial decision-makers and policymakers. Provide a clearer link between the identified research gaps and potential industry applications.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [] } ]	1	https://f1000research.com/articles/14-122
https://f1000research.com/articles/12-1092/v1	01 Sep 23	{ "type": "Research Article", "title": "'It’s become a theatre’: relational experiences of family carers and people with Amyotrophic lateral sclerosis (ALS) after cognitive impairment emerges", "authors": [ "Marit Sofie Oseland", "Unni Sveen", "Tina Taule", "Marit Sofie Oseland", "Tina Taule" ], "abstract": "Background: Amyotrophic lateral sclerosis (ALS) can lead to emotional and psychological distress between patients and their family carers. Many people with ALS develop cognitive impairment, which limits their ability to process complex information, interact, and communicate. This cognitive decline adds to caregiver burden. Few studies have explored interpersonal relations between people with ALS and their carers. Aim: To better understand how ALS-associated cognitive impairment influences close relations. Methods: Individual semi-structured in-depth, interviews were conducted once, with four patients and four family carers. Thematic analysis was used. Results: Increased distance of close relations was identified as the core theme. Differences and similarities within the data were identified according to the subthemes, (1) Everyday life together but apart: a demanding role to play, and (2) Coping with a lost future: living in the ‘normal’ present and searching for hope through a well-lived life. Conclusions and significance: Cognitive impairment following ALS can lead to increased relational distance between patients and their family carers. To ease their burden, professionals should recognize patients’ and carers’ relational issues and grief at an early stage. Focusing on their occupational identity and highly valued occupations that are still-accessible may help patients and carers regain meaning in everyday life.", "keywords": [ "Amyotrophic lateral sclerosis", "Biographical disruption", "Everyday life", "Interaction", "Interview", "MND", "Motor neuron disease", "Occupational identity", "Qualitative", "Thematic analysis", "Occupational Therapy" ], "content": "Introduction\n\nBeing diagnosed with Amyotrophic lateral sclerosis (ALS) is described as a major traumatic experience, characterized as a ‘biographical disruption’.1 The complexity and severity of the disease can lead to great emotional and psychological strain, affecting both patients and their family carers.2,3 According to Bury,4 a biographical disruption implies that the individual’s life expectations and future plans must be reassessed and that the structure of the person’s everyday life becomes unpredictable. Everyday rules and reciprocity that exists in family relations may be disrupted in line with increased dependency.4 Progressive chronic illness qualifies as a very disruptive experience, one changing a person’s behaviour and expectations. This scenario suggests that when ALS leads to the inability to perform valued occupations, lost aspects of self can emerge, such as altered perceptions of competence, self-worth, and identity.5\n\nALS is a neurological disease with no cure, extremely variable life expectancy, and progressive loss of function.6 Research done in past decades shows that ALS is a multisystem disorder that, in addition to showing progressive degeneration of motor neurons, can lead to neuropsychological alterations.7,8 Approximately 50% of all people with ALS progress to cognitive impairment.6 Among these, 8-14% develop severe behavioural changes, which meet the criteria for the behavioural variant of frontotemporal dementia (bv-FTD).9–11 Meta-analyses have documented that verbal fluency, language, verbal memory, and executive functions, including social cognition are affected.9,11 Common behavioural symptoms include apathy, disinhibition, loss of sympathy/egocentric behaviour, and perseverative and stereotyped behaviour.12,13 Cognitive and behavioural changes associated with ALS may impair patients’ ability to process complex information, interact appropriately with others, and communicate effectively.8,14 Patients’ and carers' experiences of loss related to disease progression and the prospect of nearing death often lead to greater grief. Grief is associated with symptoms of distress that, on top of the many other consequences of ALS, may interfere with occupational engagement and social interaction.15,16\n\nWhile it is unclear exactly what aspects of ALS affect caregiver burden,3,8,17 carers’ overall experience of burden is well documented,18 and the burden may increase when patients develop cognitive and behavioural impairment.3 A recent study,19 however, found that family caregiving in ALS is reciprocal, and that patients can also experience a ‘carer burden’. Psychological distress in the family related to providing emotional support to each other can arise, and people with ALS not wanting to be a burden is common. Others have found that the severity of ALS can disrupt patients’ personal roles and relationships, and that dependency relationships may help identify different illness trajectories.1 Foley et al.19 advocate investigating supportive roles that people with ALS play in their family to outweigh the highly present focus on caregiver burden in ALS-research.19\n\nMaintaining close relationships is important in order to cope with life crises and to be resilient.20 The degree of closeness in interpersonal relationships is a core dimension of every relationship, and it underpins relational communication.21 Given the array of possible negative outcomes in ALS, it is surprising that there is a paucity of research on how cognitive and behavioural changes in ALS affect interactions and personal relationships.22 Research including people with other neurodegenerative diseases, like high-grade glioma23,24 and primary progressive aphasia,25 shows that neurocognitive changes and communication difficulties can lead to strained relationships, involving increased relational distance, between the patient and their family carers. However, it is unknown how the cognitive and behavioural impairments in ALS might impact the closeness of patients’ relations with their family carers. There are other significant knowledge gaps on how to apply established knowledge about cognitive impairment in ALS to clinical management practices that benefit people with ALS and their carers.8,26 For example, ALS-specific interventions that promote holistic care of patients might aid carer’s psychological well-being,8,26 but such practices are not widely studied or implemented. Nevertheless, multidisciplinary teams in ALS clinics maintain heightened awareness of patients’ possible neuropsychological changes and provide relevant information and support so that patients and their carers can realize full lives as much as possible.27 Occupational therapists emphasize that to enable engagement in occupations with personal value, is essential for a person to experience meaning in everyday life.5,28 We lend support to the understanding that occupation is transactional, always connecting person and situation in its environmental context.29 Hence, occupational therapists should pay attention to how patients’ and carers’ personal relationships can exert influence on their occupational engagement. In the present study, we aimed to better understand how people with ALS and cognitive impairment, and their family carers experience close relations in everyday life.\n\n\nMethods\n\nTo ensure transparency, we report our qualitative study according to the consolidated criteria for reporting qualitative studies (COREQ).30 See supplement 1 in extended data for COREQ checklist.\n\nThe study was conducted in accordance with the Declaration of Helsinki.31 All procedures were evaluated and approved by the Regional Committee for Medical Research Ethics Western Norway, REK West (No. 2016/2187). All participants had received oral and written information about the study and signed a voluntary informed consent. Data was handled with confidentiality and stored in a secure research server. Participants are presented with pseudonyms in this manuscript.\n\nWe sought to collect thick descriptions of individual experiences to reach an in-depth understanding of the participants’ situation. A qualitative design with a thematical analysis32 underpinning paradigm of occupational science33,34 was appropriate to accomplish our research aim of exploring how people with ALS and their family carers experience everyday close relations.35–37\n\nEligible participants were already enrolled in the overarching main registered clinical study, led by the last author (TT) of this manuscript, entitled: Cognitive impairment in ALS: screening tools, experiences and prognosis38 between May 22, 2019, and June 01, 2021. This study sample comprises people diagnosed with ALS and their carers who were followed up at an ALS outpatient clinic in Western Norway. Included patients had to be native-Norwegian speakers so that they could understand the instructions and test situation, and to ensure accurate test-scores. Exclusion criteria included any non-ALS comorbidity in which a decline in cognitive function was the main feature and/or in which great difficulties in writing or reading were present. Patients included for interviews had to have a total score of 92 or less on the Norwegian version of the Edinburgh Cognitive and Behavioural ALS screen (ECAS-N)39; this cut-off score indicates cognitive impairment.39 ECAS-N has its purpose for clinical use and is considered appropriate for research. The researchers obtained a copyright license.39\n\nOf a total of 16 eligible people with ALS tested with the ECAS-N, eight scored equal or below 92. Of these, one patient declined to participate, and three were excluded because they had either no close family carers available to interview, or the recruiters (clinicians not involved in the research) evaluated that an interview situation could be demanding and increase their overall burden. According to the Strong-criteria12 that classify frontotemporal dysfunction in ALS into the subgroups; ALS cognitive impairment (ALSci), ALS behavioural impairment (ALSbi), ALS cognitive- and behavioural impairment (ALScbi), and patients with a combination of ALS and FTD (ALS-FTD), the results of the ECAS-N indicated that one patient met the criteria of ALSci because the patient showed executive dysfunction, including dysfunction in social cognition. One patient met the criteria of ALSbi because of reported apathy in combination with other behavioural change. The data material does not entail enough information to determine if any of the patients met the criteria of FTD. On the basis of our experience, the rich and detailed interview data provided by the included four patients and four carers, we determined that our study sample was sufficient to answer our research question. Two of the patients had difficulty speaking, so they used a communication aid. Characteristics of the included people with ALS and their carers are presented in Table 1.\n\n1 Personal identifying information of participants and their carers was protected by using fictive names in accord with the Declaration of Helsinki.34\n\n2 ECAS-N total cognitive score is 136, cut off scores for abnormality is 92.\n\n3 ECAS-N behavioural score ranges from 0-10 (0 indicating no behavioural change).\n\n4 ECAS-N psychosis score ranges from 0-3 (0 indicating no psychosis).\n\nIndividual semi-structured, in-depth interviews were conducted from October 2019 to April 2021. All the participants were approached by telephone and chose to be interviewed at home. The participants were interviewed once, face-to-face. Patients and their carers were interviewed at the same time, but in separate rooms. Interviewers were the first (MSO) and last authors (TT). The relationship between the participants and interviewers were solely related to the research. TT had met some of the participants in the ALS clinic, once, prior to the interviews, but after informed consent were signed. MSO met the participants at first when conducting the interviews. Due to government restrictions related to the Covid-19 pandemic, the interviewers wore a facemask when recommended.\n\nAll interviews were audio recorded and lasted from 43 to 71 minutes. We followed a study protocol inspired by Creswell.40 This comprised procedures for standardized data collection, safeguarding relevant information and transmission of information given to all participants. The protocol also included a lay introduction about the aim of the study, its purposes, and interviews; a pilot-tested semi-structured interview guide (supplement 2) developed by TT and the research group at Haukeland University Hospital (HUH); and a formal expression of gratitude to the participants’ participation and time spent. See supplement 3.\n\nThe interview topics mainly focused on three areas: (1) everyday life before and after the ALS diagnosis; (2) everyday situations, which are described as being challenging when suffering from ALS-specific cognitive impairment; and (3) healthcare in early phases following diagnosis. To obtain rich, unprejudiced, and descriptive responses, we used open-ended questions while always nudging the discussion toward the topic in question. The interviews began with one of the following opening questions: “How do you see your own situation?” “Can you describe a typical day?” To encourage more descriptive stories, we used follow-up questions like: “Can you describe a specific situation when … ?”. To encourage participants to relate any other experiences, we asked closing questions like: “Do you have any additional experiences of importance that we haven’t talked about?”\n\nWe used thematic analysis (TA) as set out by Braun and Clarke.32,41 Data were coded and thematized using NVivo12 qualitative data analysis software.42 TA uses a six-step analysis structure guide (described in the following paragraphs), permitting great flexibility regarding theoretical and epidemiological positioning, and individual choices for coding.32 During analysis, the researchers attempted to set aside their field-specific (e.g. occupational science) preconceptions and ALS expertise in trying to understand the participants’ experiences. This was important in our TA, as its inductive nature aimed to code the data without trying to fit it into a pre-existing coding frame or the researcher’s analytic preconceptions; it was ‘data-driven’.43\n\nThe first analysis step, familiarizing ourselves with the dataset, focused on reaching an overall understanding of the participants’ stories, and started already during data collection. Immediately after each interview, the interviewer wrote global reflection notes to characterize the setting, feelings that emerged, and early general thoughts about what was said. The interviewers consecutively transcribed the audio recording verbatim, eliminating names of people and locations to protect participants’ anonymity. The interviews contain potentially identifiable sensitive data about the patients’ cognitive function and relational issues within the participants family. Because ALS is a relatively rare diagnosis with large variation in disease trajectories, and because the hospital identified in our dataset treats a limited number of patients a year, full de-identification of the transcripts was not possible without removing information necessary to analyse the data.\n\nTranscripts were read at three levels: (1) holistically across all participants, (2) individually for each participant, and (3) in pairs (patient and carer together). Additional reflection notes, keywords, and candidate topics were created. The transcripts were not returned to the participants for comments and/or corrections.\n\nBefore moving to step two, two authors (MSO and TT) discussed and agreed on preliminary keywords (e.g., communication) that best characterized the dataset and made decisions that ensured the given theme captured the pattern of importance in relation to our research question. For example, we decided what was important based on interpretations on what was said and how it was said (e.g., expressed feelings), what triggered curiosity, and what was found surprising. This procedure and the rich data generated data-driven themes (inductive analysis) at a latent (interpretive) level.\n\nStep two is generating initial codes. The first author (MSO) started the coding process of step two after clarifications important to moving the analysis forward were agreed on. Examples of initial codes are presented in Table 2.\n\n\n\n• Has lost daily structure and control (autonomy)\n\n• Does not feel organized\n\n\n\n• The patient and carer have a long history together\n\n• The patient does not tolerate disagreements\n\n• The carer is tired of the patients’ changed behaviour\n\n• The patient has changed\n\nCodes generated for the entire dataset were discussed and agreed upon by all the authors. In the third step, searching for themes, relevant coded data were sorted into candidate topics. Some codes formed main themes, like Challenging relations. Others, like absent communication, formed sub-themes.\n\nBy step four, reviewing the themes, the topics were all processed. All proposed themes appeared in relation to what emerged to be the core theme, Increased distance of close relations.\n\nIn step five, defining and naming the themes, the themes were precisely defined, and names finalized. A detailed analysis of each theme’s core content was documented before a theory was connected to the data. To better understand how daily interactions might affect the participants’ close relations, we were inspired by the dramaturgical metaphors Erving Goffman uses to describe face to face interaction in everyday life,44 and his perspectives of stigma.45 Goffmans’ perspectives in relation to our findings are described in the first section of the discussion, Burden of disrupted roles and interaction. Due to theoretical limitations on experience of grief, we found it relevant to add the dual process model of coping with bereavement (DPM),46 and Bury’s theory of a biographical disruption as presented in the introduction.4 DPM has its foundation in theory on attachment and coping, and may help to better understand the normal process of grief and to recognise prolonged or complicated grief.46 DPM is central in the second section of the discussion in this manuscript, When the future becomes ‘lost,’ a well-lived life provides hope for the present.\n\nIn step 6, reporting the findings, analyses were completed by presenting the findings of the study here. The participants have not provided feedback on the findings.\n\n\nFindings\n\nOverall, our TA of the interviews revealed that ALS with associated cognitive impairment can lead to relational challenges. Increased relational distance between patients and family carers showed differences and similarities according to a core theme: Increased distance of close relations. Subthemes were characterized by (1) Everyday life together but apart: a demanding role to play, and (2) Coping with a lost future: living in the ‘normal’ present and searching for hope through a well-lived life. These themes will be considered in turn.\n\nParticipants reported experiencing tension between ‘losing self’ and ‘losing each other.’ They all described unwanted changes in the way everyday roles became distributed, as well as experiencing limited and demanding verbal communication and social interactions. Moreover, they struggled to cope with an existential change about a ‘lost future’ together. Increased relational distance was to both patients and carers caused by suppressing difficult feelings bubbling up from loss and occupational limitations. Having different experiences and approaches to one’s own life situation challenged the foundation of their relationship.\n\nEveryday life together but apart: a demanding role to play\n\nAll participants described being increasingly dependent and losing freedom to engage in meaningful occupations. Skewed responsibilities, challenging communication, different levels of power and ability to respond to one another caused an imbalance in the relationship, leading to more and more relational distance. Everyday roles as patients and carers were taken for granted. They seemed to know little about each other’s experiences. The patients reported being more dependent on others, mainly because of their physical limitations. The carers had been taken for granted in their caregiving role, hindering or ‘short-circuiting’ their own priorities. They depended on the patients’ willingness to accept their help to make them feel important and ease the caregiver burden. The patients, however, had difficulties accepting disease progression, affecting their desire to maintain their independence.\n\nDaily interactions in social settings between carers, patients, and others became complicated, because communication was missing, impaired, or challenging. Patients’ communication abilities were affected by impaired motor function, emotional lability, apathy or a lack of initiative or energy to speak. During the interviews, some patients had difficulty retrieving words or reflecting on context, and some tended to communicate ambiguously, using words that did not match expressed feelings. Patients had difficulties following discussions, and their carers had to explain their rationale, repeat themselves, and sometimes talk on behalf of the patient. Communication aids that two of the patients used were cumbersome, and they were uncomfortable with its artificial-sounding voice. Losing their expressive ability was like losing an important part of themselves; they could no longer say what they wanted in the way they wanted. ‘It is very sad, because it [communication aid] doesn’t say what I mean,’ Ester said. She and other patients often felt excluded or misinterpreted. Depending on others to help them communicate was impossible for most to accept. The carers were also sad and frustrated that their stricken family member could not participate in conversations as before. One carer said they were infuriated because the patient related to circumstances differently. Some carers found it difficult to stay calm and be compassionate during arguments, and then felt guilty when they expressed frustration.\n\nAll the participants were grieving over lost occupational possibilities and meaningful roles they were expected to fill. Spouses felt they had lost their compatible partner, while patients felt they could not meet the expectations of others or themselves. Some patients experienced severe limitations when doing familiar daily activities, like Hans who had difficulty with the recipe steps when making dinner. These difficulties were, however, partly invisible to his wife, who said: ‘No [his short-term memory loss] doesn’t affect him …. no, like, he does everything he is supposed to do.’ Ester, who communicated with a communication aid, explained how her ability to be a fine grandmother had evaporated:\n\nInterviewer: Can you tell [me] something from the last time you were together with your grandchildren?\n\nEster: (Silence for over two minutes while typing on her communication aid and having a crying facial expression) … Last weekend we were together, and when the one-year-old looked at me and said, ‘hi hi’, and I couldn't answer.\n\nEster felt that forming a personal relationship with her grandchildren was impossible. Lost contact with her grandchildren amplified her grief and made her feel she was losing her social identity. Her experience was similar to the carers’ experience of watching their loved ones ‘disappear,’ and in some cases, ‘turn into someone unrecognizable.’ ‘It’s just like a flower that’s withering,’ Lise, daughter-in-law, said. The carers, however, also felt that they sometimes had become invisible. Everyday life was organized around the patient’s needs, causing some carers to feel little emotional support. Berit, a spouse, said in despair: ‘I had to ask for a hug’ when discussing how she was sick and needed support. This spouse also explained how the patient lacked initiative and interest, in contrast to before his cognitive impairment emerged. If she did not organize activities, he just lied on the sofa or walked around doing nothing. The patient, Tom, however, denied having any difficulties, explaining occupational limitations with natural causations (e.g. retirement). He said: ‘You know that thing with the disease […], it doesn’t affect my daily life at all. I don’t worry … […] so far, so good.’ He trivialized symptoms and expressed unrealistic thoughts about the future.\n\nTom and other patients deliberately leaned on their carers but lacked the capacity to acknowledge those efforts. Most carers felt ‘tied’ to the caregiving role, putting their own life on hold. Stress arose from worrying, having to be vigilant, and disregarding their own needs. ‘I feel like an executioner sometimes,’ Irene, spouse, said, referring to her guilt when trying to prioritize her own needs and desires. Lise, daughter-in-law felt bad for her mother-in-law, who ‘is in a prison,’ but also felt being ‘chain [ed]’ to her. She described spending hours helping her with chores and personal activities, expending extra time and effort to maintain a positive atmosphere, all to no avail. However, one spouse, Niklas, felt that the caring role was normal, not burdensome: ‘So, we try to make the best possible out of it [..], and for me, I don't feel that it's any bother to support her … for her to have the best situation possible.’ Niklas had open and good social support during the days, which seemed to explain his positive experience.\n\nWhether the patients acknowledged disease issues or not, most did not want to publicize the diagnosis. They felt ashamed and pretended they were not really affected much. Lise, daughter-in-law explained how they tried to maintain a façade of civility in everyday life: ‘It has become a theatre, like wearing a mask. That hurts. It’s the worst!’ When patients avoided exposing their disabilities, their carers’ efforts went unrecognized, leaving them feel alone with a heavy burden. Most patients, however, were afraid of becoming a burden to others. They resisted ‘whining,’ and often rejected unprompted help from carers to maintain their independence and sense of self-sufficiency and autonomy. Yet, most patients expected that their carers were available to help them when needed. Some carers felt they had to guard the patients, treating them like children. Lise, daughter-in-law said ‘because we are standing there with widespread hands (pulls her arms out to demonstrate) just like an octopus. “What do you want me to do? [we carers say]” “No. Don't want any help [patient says].”’. Lise found it hard to play a supportive role. Like other carers, she wished the patient would accept the disease and graciously accept help. For most participants, daily life became a tug-of-war between trying to hold on to oneself and doing what they thought was best for the other.\n\nCoping with a lost future: living in the ‘normal’ present and searching for hope through a well-lived life\n\nAll participants emphasized their previous active and social life. Adjusting to the new existence with ALS combined with a lost future was difficult for both patients and their carers. Despite somewhat different approaches, all participants tended to avoid the unpleasant and strived to think positively. They identified with lived lives and held onto what they could still do. Most focused on familiar practicalities of daily living and concentrated on one thing, one day at a time. They found meaning and hope in the past.\n\nMost participants found the future frightening and avoided talking about it. ‘I know how it goes, and I know how it looks, […] but I don’t dare to think ahead,’ Berit, spouse, said. Like the patients, she and most carers did not want to ‘meet trouble halfway.’ Tom, for example, said he wanted to live ‘blissfully ignorant.’ Future aspects seemed unachievable. He tended to relate only to what was concrete and manageable at the moment, like taking his pills and dealing with requests like ‘do as [he] is told.’ By avoiding the future, as it were, the participants could live as normally as possible. Irene, spouse, said: ‘I try to keep daily life as it used to be.’ Similarly, several participants talked about how everyday life is mostly the same. However, to Lise, daughter-in-law this avoidance of the future and emotional conversations was as a ‘double burden.’ She expressed hopelessness: ‘It’s just like I’m in a tunnel … There is not much light over there,’ and highlighted an unrealized longing to talk about death and to be able to share the negative feelings of grief and fear. Her mother-in-law, Ingrid, however, resisted becoming a burden by focusing on positivity.\n\nIn conversations the participants talked about concrete, familiar things in daily life: what one could see, touch, and sense. Despite experiencing severe loss and limitations, most participants recalled remaining shared activities. They could sit on the porch together, enjoy the view, and watch the grandchildren play. They all clung to the hope of what was normal. Patients found meaning in what they could still do for others. Some tried to maintain their usual activities, for example, by going from reading articles as they did before to reading poetry now. However, some activities could not be replaced. Hans said: ‘To walk with a four-wheeler on the pavement … like 50 meters … That’s not a true experience for me.’ Experiencing nature had been so important to him that he now found it impossible to enjoy and perceived it only as a ‘defeat’ when trying to adjust. He replaced these adventures with daydreaming, as shown in the following excerpt:\n\nWhen I'm […] half-sleeping, … then I'm back in the mountains […] (Last time) I was with a friend at a cabin… […] It was midsummer. We lit fires… I rowed across the lake. And he blew the bow horn and I (cries) answered. And walked like a hare uphill… yes (cries). It was…, it was early in the morning and … the sun rose… and shone on [that hill] (points at a picture) […] That was a great experience.\n\nHans’ reimagining his adventures gave him joy; remembering how it used to be allowed him to joyfully indulge in nostalgia. Nature experiences and the companionship he felt became real in his imagination. It seems like the past created hope for the present and contributed to patients’ ability to hold on to self.\n\nAll participants said that their history became purposeful for creating meaning for the present. The patients emphasized what they had done and talked about what they had accomplished in life with pride: ‘I have been to all the mountains in the area’ (Tom). ‘I worked until I was 75’ (Ingrid). They perked up when talking about hobbies they had engaged in and how they had been a helpful resource to others. Patients reported the need to maintain self-identity by telling their story. Spouses held onto who they were as a couple by remembering shared experiences. All carers emphasized who the patients were prior to the ALS diagnosis, and by helping them engage in activities valuable to them, they solidified their identity. They also safeguarded the patient's identity throughout the course of the disease by telling their story to others and by communicating on their behalf so that they felt included in social settings. All participants stuck to the everyday hopes of ‘normal’ days, and by cherishing memories, they held onto their identity.\n\n\nDiscussion\n\nIn this study, we explored how people with ALS and cognitive impairment, and their family carers, experience close relations in everyday life. Our thematic analyses revealed that ALS and associated cognitive impairment may lead to increased relational distance between patients and significant others. Changes in everyday roles, limited and demanding daily interactions, and difficulties in coping with a ‘lost’ future disrupted the participants’ close relationships. Given the lack of previous qualitative studies on how ALS-specific cognitive impairment impacts social interaction,22,47 these findings, to our knowledge, are new. Current theory prompts our interpretations, as follows.\n\nThe participants’ stories in the present study are consistent with the characterization of living with ALS as a ‘biographical disruption’.4 Experiences like lost ability to perform valued occupations strongly associated with self-worth and identity, might explain why our patients tended to avoid conversations about their disease or felt uneasy when meeting others. The participants’ everyday roles that became disrupted because of the disease and the ensuing loss of autonomy degraded the interactions between them. Tense feelings tended to cause patients and carers to avoid talking to each other. This disengagement in conversations was partly motivated by the idea that talking about negativities would cause more burden to their significant other. Patients also may have been incapable of handling the complexities of the disease, which manifested as silence. The patients were heavily burdened and felt that they were losing their sense of self, especially after becoming anarthric. The latter also seemed to be why they tended to avoid or complicate conversations and one of the main reasons behind participants’ lost roles and social possibilities. This is consistent with another study that showed patients with bulbar ALS losing power and independence.1 The narratives in our study also suggest that losing the ability to participate in conversations due to language (cognitive) difficulties or executive impairment, amplified the experience of lost control in daily interaction, and lead to a feeling of outsider-ness – but possibly without the ability to recognize, admit or talk about this feeling.\n\nSpoken language is central for maintaining communication and a thriving relationship.48 When people with neurological diseases lose the ability to speak, as in ALS, family-patient relationship is challenged. Qualitative studies of carers’ experiences with people with ALS who develop language or speech difficulties, have not been done, to our knowledge. Pozzebon et al.25 found that when spouses of people with primary progressive aphasia, became disconnected in their spousal relationship, and they had to readjust their sense of self. Similarly, carers in the present study reported that being unable to speak with the patient effectively added a second burden on top of the disease burden. It is unclear whether lack of communication was also a ‘double’ burden to the patients. Maintaining relationships is critical for patients’ well-being.1 However, our results do not allow us to determine whether the extent or content of communication between patients and carers defines how patients feel about the quality of their relationship. Patients may feel excluded, because their communicative abilities were reduced compared to others, effectively leading to little social participation. The patients’ increased burden due to anarthria demonstrates how important language and speech are to forming and maintaining identity. Alienation and loss of identity may explain why the patients hesitated using communication aids with an artificial-sounding voice. According to Goffman,45 functional disease-related loss forces a person to reorganize their biographical past. As with the patients in our study, if patients do not recognize themselves anymore, they may express ‘disapproval of self.’ Goffman45 argues that impaired speech is a ‘stigma symbol,’ one highly visible to others. Every time patients try to speak, they are reminded of their stigma. Patients in this study had difficulties speaking, in addition to having impaired non-verbal communication; these may have intensified this stigmatization and contributed to a loss of social identity.45 Additionally, when the patients have cognitive impairments that reduce their ability to effectively learn and use technical aids, this complicates their possibilities to participate in conversations.\n\nIn relationships, differences in opinions may arise from misunderstandings. A divergence in quality-of-life perspectives between people with ALS and their carers sometimes occurs because of misunderstanding each other’s experiences.49 These findings prompt clinicians to more prominently emphasize better communication between patients and carers. Our study, however, indicates that mutual dialogue exchanges about issues affecting their well-being might be difficult when patients suffer from cognitive and/or language impairments. Patients’ impaired ability to reflect on, to recognize others’ state of mind, or to comprehend complexities may make conversations more difficult. In ALS-related cognitive impairment, we observed that patients lost the ability to apply formerly effective strategies that are essential for interacting with others. They also lost the ability to interpret covert signals from the carers when interacting. According to Goffman,44 this loss will lead to disrupted ‘team-play’. Impaired cognitive abilities may affect patients' capability to act loyally, disciplined, and with care, which Goffman44 emphasizes as essential qualities for team members to feel united.44\n\nThe increased relational distance between participants in the study increased the burden to both patients, who felt excluded when losing control, and to their carers, who had more responsibilities and felt lonely. Our results correspond with previous research, suggesting that patients’ dependence on family could lead to interpersonal conflicts19 and that patients rated themselves more of a burden than did their carers.49 Findings in the present study is supported by Johnson et al.49 who suggest that misunderstandings and miscommunication between patients and their carers can trigger potential stressors that may influence one’s well-being. Disruption in personal roles and relational changes was also reported in a recent study of people with ALS,1 but in contrast to our findings, some patients experienced improved relationships with their carers. In contrast to a study in which identified caregiving between people with ALS and their family as bi-directional —leading to the patient also experiencing carer burden19—we observed that one-way support was overwhelmingly from carers toward patients. Possible differences in patients’ cognitive impairments in the two studies may underlie this difference.\n\nThe effects of carers’ worry about their own health that we observed are in line with what has been reported previously.18 However, when patient and carer have a strong and close relationship, we noted that the burden and disruption overall was eased. The importance of maintaining close relationships when coping with ALS have also been described by others,50 and this point is well established in applied and social psychology.51,52 Also, the quality of the carer-patient relationship appears to have a direct impact on the carers’ grief intensity after the patient dies, suggesting that difficult relationships might increase the risk of complicated bereavement.53 By contrast, good quality relationships can ease the bereavement.16 Our findings suggest that healthcare teams should focus on helping patients and their carers maintain a close relationship as the disease progresses. Stroebe et al.16 argue that former research on attachment54–56 shows that good relational quality between a dying patient and a bereaved importantly influences the outcome for the bereaved. Since good relations, high quality of life, effective coping, and resilience in severe illness20 are important, healthcare professionals need to provide helpful preventive and supportive procedures to address relational issues at an early stage. How to effectively handle relational challenges in ALS is unclear. Given the limited support patients gave to carers in this study, and due to the importance of emotional support for carers when coping with grief,57 clinicians could encourage carers of people with ALS to seek social support outside of the patient-carer dyad and to prioritize important social relations. Our findings suggest that some carers will need professional support. Their stories about how they struggled because they de-prioritized themselves in favour of the patients’ needs demonstrate that carers could benefit from occupational therapy intervention involving strategies to increase occupational balance and prioritize occupations with high personal value. Moreover, tailored information, based on cognitive test results, may help carers to better understand subtle cognitive impairment and behavioural changes of patients, which may ease caregiver burden. Carers’ increased understanding might have a positive influence on patients, leading to fewer relational conflicts. Similarly, appropriately tailored information for patients may help them understand and participate in interactions.\n\nVirtually all participants avoided mentioning anything about future aspects of life, especially the patients. This denial and avoidance is in line with research showing that cognitive impairment amplifies this tendency.1 Patients’ avoidance of the abstract future might be due to faulty reasoning resulting from their cognitive impairment, which is consistent with the cognitive profile of ALS.11,12 Alternatively, it might represent a survival strategy, a way to avoid the unpleasant.\n\nFocusing on positive aspects of life and recalling good memories seemed to help participants regain meaning and instil renewed hope. Ozanne and Graneheim58 found that ALS caused patients and their spouses ‘lose their foothold.’ As with our participants, they found that fear of the unknown caused patients and spouses to struggle with comprehending the diagnosis.58 Shifting focus to familiar things, like positive memories and still accessible and meaningful activities, seemed to ease this feeling. A tendency to find meaning and resilience by reflecting on the past has also been described in patients with primary progressive aphasia,25 a neurodegenerative disease similar to ALS in certain respects.59,60\n\nMost patients and carers in the present study had somewhat opposing perspectives of their life situation, grieving and coping differently. While some appeared totally unaware of their loss, only focusing on positive aspects and daily practicalities, others tended to oscillate between hurting and orientating towards aspects that ‘normalized’ the days. In the dual-process model of Stroebe and Schut,46 this oscillation is the ‘normal’ way of coping and most likely a healthier way of dealing with bereavement. Participants’ experiences of anticipatory grief and grief over a ‘lost’ self and lost fellowship can be understood in terms of theories of bereavement. Bereavement is associated with a higher risk of physical and psychological health issues.16 The dual-process model of bereavement may relate to adaptive versus maladaptive coping.46 However, there appears to be little evidence describing ‘normal’ coping in grieving people with a fatal disease and cognitive impairment, as in ALS. When a person who has cognitive impairments lack the capacity to process abstract and complex information, their singular focus on pleasant things may represent a necessary coping strategy. Nonetheless, how one person in a relationship copes will influence the other, and when they have different coping styles, relationships can become challenging.46 The hypothesis that different coping styles intensify relational challenges between patients and their carers46 strengthens our argument that healthcare professionals have a responsibility to provide early support to patients and their carers, if necessary providing separate and individual support. Healthcare professionals need to identify who might be at risk of a complicated bereavement arising from prolonged intense grieving. Strada15 stresses the importance to recognize early on both patients’ and carers’ grief and psychosocial issues to ease the burden throughout the disease trajectory, which is a relevant application consistent with our observations.\n\nOur findings indicate that patients and their carers may have separate needs when it comes to follow-up help during disease progression. However, all participants in the present study revealed a strong sense of occupational identity.61 Patients and carers shared the approach of finding resilience by recalling good memories while aiming to ‘normalize’ their days. They reported how everyday things can have great impact, creating hope for the present. With a transactional understanding of occupation,62–64 participants’ experiences and behaviours occur in the dynamic context of their past and present, all intertwined in a holistic relationship with objective conditions and subjective experiences. Their history impacts the creation of meaning in the present, and patients’ experiences and behaviour in daily life affect the carers’ and vice versa. Thus, professionals should encourage patients and carers to reflect on their history together. Occupational therapists may highlight their occupational identity, and like Hammel5 argues, focus on meaningful more willingly than purposeful occupations when aiming to help patients and carers to regain a sense of meaning in everyday life.\n\nThe reflexive evaluation approach of Stige et al.65 emphasize researchers engagement, processing, interpretation, critique related to materials and respective sociocultural and academic discipline, the usefulness and relevance of the research and ethical considerations. The approach encouraged us to provide a reflexive dialogue throughout the research and influences our methodological evaluation as followed. The researchers who carried out the study are occupational therapists with ALS-specific clinical experience. Hence, the course and presentation of this study may reflect the researchers’ engagement with the ALS clinic. First author (MSO) was inexperienced as researcher and conducted the study as part of a master’s degree. The second author (US) is professor with PhD and multiple qualitative publications, and last author (TT) has PhD and extended experience as a researcher within the field of ALS. Throughout the study, discussions within the research group helped contextualize and minimize the undue influence of preconceptions and clarify the research focus. Using TA to analyse the content of the interviews provided a systematic and rigorous, yet flexible thematic analysis.32,41 The complexity of ALS challenged the analysis. Interpretations of possible motor- or cognitive causations in relation to the data, may not always be distinguished. Misinterpretations may have occurred because of patients’ impaired cognitive ability to reflect on their situation, patients’ communication difficulties, and/or potential emotional stress related to a worsening crisis. Participants may have been reserved about revealing all relevant information because of familial fealty or fear of losing or damaging their necessary relationship with the hospital involved in the research. On the other hand, a strength of our study is that all patient-participants had indications of cognitive impairment, and some were with severe speech impediments, rarely addressed in ALS research. Our study presented perspectives from both patients and carers, an underrepresented design that provided new insights. Finally, participants provided rich, descriptive narratives, permitting sufficient data to identify themes.\n\n\nConclusions\n\nOur findings reveal that cognitive impairment in ALS is associated with increased relational distance between patients and their family carers. This situation emerged from newly skewed responsibilities and occupational possibilities, disparate ability to support each other in the dyad, and coping with a ‘lost’ future. The tension between losing self and losing fellowship appeared to interfere with daily interactions. Patients and carers had different coping strategies, while at the same time they reflected on their shared history, focusing on the positive aspects and practicalities of daily living. To varying degrees, these changes provided renewed meaning and hope for the present.\n\nOur findings prompt multidisciplinary ALS teams to focus on relational issues and grieving of patients and carers at an early stage of care. Occupational therapists should aim to facilitate the process of constructing meaning by highlighting patients’ occupational identity. Keeping in mind these initial observations, we encourage further research on specific approaches that facilitate patients’ and carers’ efforts to maintain a close, thriving relationship throughout the ALS disease trajectory.", "appendix": "Data availability\n\nRestricted data\n\nDue to ethical and legal restrictions 66 the raw underlying data cannot be made available to publish. This study involves human research with descriptive sensitive data that may not be fully anonymized without eliminating essential information to understand the analysis. The participants were informed that no identifiable data would be published, as approved by the Data Privacy Unit at Haukeland University Hospital, Bergen, Norway (reference numbers 2016/3166) when the study was accepted.\n\nAny data request may be sent to Health Bergen HF, Orthopaedic clinic, by clinic director Kjell Matre at e-mail postmottak@helse-bergen.no (https://helse-bergen.no/en/avdelinger/ortopedisk-klinikk ).\n\nThis study contains the following extended data, https://doi.org/10.5281/zenodo.8126168. 67\n\n• Supplement 1: Completed COREC checklist.\n\n• Supplement 2: Pilot-tested semi-structured interview guide.\n\n• Supplement 3: Interview protocol with introduction and formal gratitude to the participants.\n\nData are available under the Creative Commons Attribution 4.0 International license (CC-BY 4.0):\n\nNVivo was used as a tool for manually analysing data. NVivo is a proprietary, commercial software. 42 QualCoder is an alternative free and open-source software that may provide equivalent functions appropriate for use in thematic analysis. 68\n\n\nAcknowledgements\n\nOur gratitude goes to the participants for generously sharing their experiences.\n\n\nReferences\n\nCipolletta S, Gammino GR, Palmieri A: Illness trajectories in patients with amyotrophic lateral sclerosis: How illness progression is related to life narratives and interpersonal relationships. J. Clin. Nurs. 2017; 26(23-24): 5033–5043. Publisher Full Text\n\nOskarsson B, Gendron TF; Staff NP: Amyotrophic Lateral Sclerosis: An Update for 2018. Mayo Clin. Proc. 2018; 93(11): 1617–1628. Publisher Full Text\n\nde Wit J , Bakker LA, van Groenestijn AC , et al.: Caregiver burden in amyotrophic lateral sclerosis: A systematic review. Palliat. Med. 2018 Jan; 32(1): 231–245. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBury M: Chronic illness as biographical disruption. 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Publisher Full Text" }	[ { "id": "251640", "date": "23 Mar 2024", "name": "Camille Paynter", "expertise": [ "Reviewer Expertise Longitudinal qualitative research", "motor neurone disease", "communication and cognitive impairment", "implementation science" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for the opportunity to review this manuscript. The authors present important work in the area of ALS, and how people living with ALS and their family carers react to cognitive change. This is important work especially in the context of clinical advances in understanding the cognitive sequalae of ALS and the impact it has for those affected by ALS.\nThe manuscript presents interesting, qualitative research. The manuscript would benefit from some minor written/typographical refinement or reorganisation, clarification and/or revision in relation to the methodology, a review of the results section to provide data to support findings and support the development of themes. The Discussion section is lengthy and would benefit from editing and revision. Suggestions are provided.\nGeneral Authors may wish to consider their use of “patients”. “People living with ALS” is ‘person-first’ language and is recognised as a recommended way to speak about people with or about disability. Both “carers” and “family carers” are used throughout; consistent terminology would improve readability.\nIntroduction The authors present a succinct introduction to the topic and provide a rationale for their study. The third paragraph would benefit from revision to improve clarity. The first sentence presents as slightly contradictory (starting with ‘unclear’ evidence although quite a lot has been published in the area of carer burden as the authors have referenced). The last two sentences require revising to clarify the authors’ intended meaning.\nMethods Design\nThe authors are commended for reflecting on the paradigm underpinning their research. The reference #34 should be attributed to the qualitative design and not occupational science.\nData analysis The authors report they used TA as set out by Braun and Clarke 2006. The authors may wish to consider reviewing Braun and Clarke’s more recent publications. Since the inaugural 2006 paper, Braun and Clarke have published a number of papers and book chapters to guide researchers in producing methodologically coherent TA and reflexive TA. I believe it will strengthen your paper if your approach to analysis more closely aligns with your theoretical positioning.\nThe authors report the data analysis undertaken allowed “theoretical and epidemiological” flexibility, and describe that theory was connected to the data. This information relates to the study’s epistemology and methodology and would be appropriate to include in the ‘design’ section. However, an epidemiological approach does not seem congruent with Goffman. This reviewer is unfamiliar with Goffman and was unable to obtain the texts referenced, therefore this comment is based on brief online information available and I acknowledge may not be completely accurate. Regardless, not all readers will be familiar with Goffman therefore some clarification on the approach may be helpful for readers.\nThe authors report the three topic areas of the interview and provide the interview guide as supplementary material which is always helpful for other researchers. It would be helpful to understand why the data regarding “healthcare in the early phases” is not included in your findings.\nFindings The Findings section would benefit from inclusion of more data (ie., rich descriptions) to support your findings. Often the findings are generalised to all participants and contain, what appears to be, interpretation of participants’ feelings (eg., describing participants as sad, rather than reporting what the participants said).\nThe authors present thick information in the two themes which may benefit from the inclusion of sub-themes to improve readability. At times there is inconsistent emphasis given to examples. The second theme would benefit from further work to justify how the theme was developed from the data. It was difficult to identifying information related to ‘searching for hope through a well-lived life’.\nDiscussion The authors have written a lengthy discussion which would benefit from editing and revision. It may be helpful to focus on three areas in the first instance. Firstly, the discussion introduces new information and topics regarding the findings from the interviews. Typically, a discussion focuses on explaining, evaluating and interpreting results and how they relate to the literature review, and do not introduce new information. Secondly, there seems to be an epistemological incongruity; the authors’ integration and evaluation of results using ‘epidemiology flexibility’ together with the anthropological and sociological stance of Goffman does not seem consistent and would benefit from explanation/clarification. The reviewer has already declared a lack of knowledge of Goffman however the reported views of disability as a ‘stigma’ does not appear (on face value) consistent with current opinions of inclusion. The link to the stated occupational therapy paradigm (ref Hitch et al 2014) in the methodology was not clear in the discussion. Lastly, the clinical symptoms of ALS, and the associated cognitive impairments described in the introduction were not clearly integrated in the discussion. I would also direct the authors to papers written by Paynter, Mathers, Gregory, Vogel & Cruice (2019-2022) [1] who explored the impact of communication and cognitive impairment on healthcare involvement for people living with MND and carers.\nMethodological considerations The reflexive information provided in this section may be more appropriate to include in the methods section. The strengths and limitations of the current study would be clearer for the reader. The authors may wish to consider editing the second last sentence to report “perspectives from people with ALS with cognitive impairment and carers” to more accurately reflect extant literature.\nConclusions The authors’ report helpful clinical recommendations for allied health professionals.\nCongratulations to the authors for focusing on an important topic which may have application beyond ALS.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "13079", "date": "23 Jan 2025", "name": "Marit Sofie Oseland", "role": "Author Response", "response": "Dear Dr. Paynter. We would like to express our gratitude for your thorough review and valuable feedback. We are thankful for the opportunity to improve and enhance the clarity of our manuscript. Assorted below, you will find our responses to the comments with the changes that we made. General Comment: Authors may wish to consider their use of “patients”. “People living with ALS” is ‘person-first’ language and is recognised as a recommended way to speak about people with or about disability. Both “carers” and “family carers” are used throughout; consistent terminology would improve readability. Answer: We have exchanged the use of “patients” with “persons with ALS” and chosen to be consistent using “family carers” throughout the manuscript. Introduction Comment: The authors present a succinct introduction to the topic and provide a rationale for their study. The third paragraph would benefit from revision to improve clarity. The first sentence presents as slightly contradictory (starting with ‘unclear’ evidence although quite a lot has been published in the area of carer burden as the authors have referenced). The last two sentences require revising to clarify the authors’ intended meaning. Answer: As suggested, we have tried to clarify the third paragraph by editing the first and last part of the paragraph. We have expanded the paragraph to improve clarity and added related information we find important to help the reader to understand. We hope our intended meaning is clarified. Methods Comment: The manuscript would benefit from some minor written/typographical refinement or reorganisation, clarification and/or revision in relation to the methodology Answer: We have made some minor typographical changes to the methodology, in addition to the clarifications and reorganizations mentioned more specific in the comments below. Design Comment: The authors are commended for reflecting on the paradigm underpinning their research. The reference #34 should be attributed to the qualitative design and not occupational science. Answer: Clarifications have been made by reorganizing the text. Reference #34 (Hitch) refers to occupational science. To clarify when we are referring to qualitative methods, and when we are referring to occupational science, we have moved the part about occupational science to the last paragraph in the introduction where we present our theoretical preconception. Data analysis Comment: The authors report they used TA as set out by Braun and Clarke 2006. The authors may wish to consider reviewing Braun and Clarke’s more recent publications. Since the inaugural 2006 paper, Braun and Clarke have published a number of papers and book chapters to guide researchers in producing methodologically coherent TA and reflexive TA. I believe it will strengthen your paper if your approach to analysis more closely aligns with your theoretical positioning. Answer: Thank you for your awareness of the scarcity of references to Braun and Clarkes’ more recent publications. For the analysis we did indeed make use of some of their newer publications, and we agree that it is appropriate to add newer publications to the reference. We also realize that it is more accurate to refer to Reflexive thematic analysis rather than solely thematic analysis, as the authors prefer. However, we believe that the original paper describing the method steps that Braun and Clark set out in 2006, still stand as the main reference to understand how we produced the analysis. We have elaborated on how theory is used, and its relevance for the process of analysis/when generating themes. Comment: The authors report the data analysis undertaken allowed “theoretical and epidemiological” flexibility, and describe that theory was connected to the data. This information relates to the study’s epistemology and methodology and would be appropriate to include in the ‘design’ section. However, an epidemiological approach does not seem congruent with Goffman. This reviewer is unfamiliar with Goffman and was unable to obtain the texts referenced, therefore this comment is based on brief online information available and I acknowledge may not be completely accurate. Regardless, not all readers will be familiar with Goffman therefore some clarification on the approach may be helpful for readers. Answer: We are sorry about the typographical error that led to this misunderstanding. Our intention was to refer to how the reflexive thematic analysis by Braun and Clark allowed for epistemological flexibility (flexibility to make individual choices about theoretical positioning) when making choices for our analysis. We have chosen to remove the sentence about theoretical and epistemological flexibility in order to avoid further misunderstandings. Clarifications in regard to Goffman, and how his theory is used for analysis of the data, is made where we describe step five in the reflexive thematic analysis. We hope these clarifications made is helpful to understand our analysis better. Comment: The authors report the three topic areas of the interview and provide the interview guide as supplementary material which is always helpful for other researchers. It would be helpful to understand why the data regarding “healthcare in the early phases” is not included in your findings. Answer: The findings regarding healthcare were planned to be presented in another article. We have added a sentence in the manuscript for clarification. See Data collection, last paragraph. Findings Comment: The Findings section would benefit from inclusion of more data (ie., rich descriptions) to support your findings. Often the findings are generalised to all participants and contain, what appears to be, interpretation of participants’ feelings (e.g., describing participants as sad, rather than reporting what the participants said). Answer: Thank you for making us aware of how our findings could be improved. We have had a thorough review of the findings-section. We hope the revisions we have made, makes the section more precise as well as consistent with presenting the findings as presented by the participants rather than interpretations of the participants feelings. Moreover, we hope our changes to the section clarifies the differences and similarities between the participants’ experiences. We have added more examples and quotations from the participants to support the findings. Comment: The authors present thick information in the two themes which may benefit from the inclusion of sub-themes to improve readability. At times there is inconsistent emphasis given to examples. The second theme would benefit from further work to justify how the theme was developed from the data. It was difficult to identifying information related to ‘searching for hope through a well-lived life’. Answer: After reviewing each theme and looking into the data again, we realize that our data does not fully support the identification of the theme “Searching for hope through a well-lived-life”. Our analysis reveals that this theme is about holding on to self and identity rather than searching for hope. “Searching for hope…” cannot be justified by the participants’ stories. We have therefore decided to revise the theme, now identified as “Coping with a lost future”. To increase readability, we have added three sub-themes to the first main theme, and two sub-themes to the second main theme. Discussion Comment: The authors have written a lengthy discussion which would benefit from editing and revision. It may be helpful to focus on three areas in the first instance. Firstly, the discussion introduces new information and topics regarding the findings from the interviews. Typically, a discussion focuses on explaining, evaluating and interpreting results and how they relate to the literature review, and do not introduce new information. Answer: We have made some major reorganization of the information in the discussion. We have tried to highlight the most important findings, and we have eliminated new information from the data that had not been mentioned before. Moreover, some this new information has been integrated from the discussion to the findings section. We hope the discussion is now easier to follow, and that you like revisions and reorganisations that we have made. Comment: Secondly, there seems to be an epistemological incongruity; the authors’ integration and evaluation of results using ‘epidemiology flexibility’ together with the anthropological and sociological stance of Goffman does not seem consistent and would benefit from explanation/clarification. The reviewer has already declared a lack of knowledge of Goffman however the reported views of disability as a ‘stigma’ does not appear (on face value) consistent with current opinions of inclusion. Answer: Again, we are sorry about the typographical error that led to the misunderstanding regarding the epistemology of this study. We believe our revision clarify that this is not an epidemiological study. We realize that we have not succeeded in our intention to illustrate how the participants’ stories aligned with Goffmans’ description of Stigma. Therefor we have decided to withdraw the focus on this theory. Comment: The link to the stated occupational therapy paradigm (ref Hitch et al 2014) in the methodology was not clear in the discussion. Answer: We have elaborated conceptions of occupational science described by Hitch in connection with the discussion of our findings. See first and last paragraph under the heading When the future becomes lost in the discussion. We hope our revision was clarifying. Comment: Lastly, the clinical symptoms of ALS, and the associated cognitive impairments described in the introduction were not clearly integrated in the discussion. Answer: Thank you for making us aware. We have now integrated relevant information about the associated cognitive impairments in ALS to the findings in the discussion. See Burden of disrupted roles and interaction, second and fourth paragraph. See also the last part of the second paragraph in When future becomes lost. Comment: I would also direct the authors to papers written by Paynter, Mathers, Gregory, Vogel & Cruice (2019-2022) [1] who explored the impact of communication and cognitive impairment on healthcare involvement for people living with MND and carers. Answer: Thank you for recommending these interesting and highly relevant papers. We have added some arguments based on you and your colleges’ research to our discussion. See paragraph four under the heading Burden of disrupted roles and interaction in the discussion. Methodological considerations Comment: The reflexive information provided in this section may be more appropriate to include in the methods section. The strengths and limitations of the current study would be clearer for the reader. The authors may wish to consider editing the second last sentence to report “perspectives from people with ALS with cognitive impairment and carers” to more accurately reflect extant literature. Answer: As suggested, we have moved the information about the reflexive evaluation to the method section, more specifically in the paragraph about design. Moreover, we have followed your suggestion to edit the sentence to report “… perspectives from both persons with ALS with cognitive impairment and family carers”. Conclusions Comment: The authors’ report helpful clinical recommendations for allied health professionals. Congratulations to the authors for focusing on an important topic which may have application beyond ALS. Answer: Thank you for acknowledging the importance of the topic of our research. Your feedback has been helpful in improving this manuscript, and we hope that it now is applicable to be considered for indexing. Best regards, Marit Sofie Oseland" } ] }, { "id": "267803", "date": "12 Jun 2024", "name": "Nicolò Zarotti", "expertise": [ "Reviewer Expertise Neurodegenerative diseases", "amyotrophic lateral sclerosis", "Parkinson's", "Huntington's disease", "multiple sclerosis", "mixed methods", "qualitative methods." ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for asking me to review this article on relational experiences of family caregivers and people with ALS who experience cognitive impairments. The article would potentially be of interest for the field and the readership of the journal. However, I believe a number of major issues prevent it from being indexed at this stage:\n- The sample size is very limited. While large sample sizes are normally not required in thematic analysis, this study only enrolled 4 participants for each type (people with ALS and caregivers) to explore a construct (relational experiences) which is arguably conveyed fully only by dyadic data. In other words, the effective total sample size of this study is only of 4 'relational participants’, which is very unlikely to be sufficient to obtain data saturation or, in the authors' words, \"thick descriptions of individual experiences to reach an in-depth understanding of the participants’ situation\". Indeed, no actual justification or rationale is provided in favour of this sample size, apart from a vague sentence mentioning \"rich and detailed interview data\" before the data are even presented.\n\n- The authors spend almost an entire page to describe how their analysis was carried out inductively, only to add a whole series of theoretical underpinnings in step five (i.e., Goffmans and DPM) which clearly made at least part of the analysis deductive. While TA allows for both inductive and deductive approaches to be carried out simultaneously, a significant lack of clarity (and potentially methodological understanding) transpires from the Methods section.\n\n- Despite what the authors claimed, their data are in fact not rich. The Findings section is barely two pages long, covering only one overarching theme split into two sub-themes. If this is really all that emerged from the interviews, it is hard to believe it was not due to the very limited sample size.\n- The Discussion section is far longer than the Findings, which makes me wonder how the participants managed to draw so many points from such a limited data set.\n\nOverall, the manuscript cannot be considered for indexing in its current limited form. The authors should carry out further in-depth interviews with additional participants and a more thorough data analysis, thus allowing for a more comprehensive and methodological robust contribution to the literature.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No", "responses": [ { "c_id": "13080", "date": "23 Jan 2025", "name": "Marit Sofie Oseland", "role": "Author Response", "response": "Dear Dr. Zarotti. We would like to express our gratitude for the thorough review and valuable feedback. We are thankful for the opportunity to improve and enhance the clarity of our manuscript. Assorted below, you will find our responses to the comments with the changes that we made. Comment: The sample size is very limited. While large sample sizes are normally not required in thematic analysis, this study only enrolled 4 participants for each type (people with ALS and caregivers) to explore a construct (relational experiences) which is arguably conveyed fully only by dyadic data. In other words, the effective total sample size of this study is only of 4 'relational participants’, which is very unlikely to be sufficient to obtain data saturation or, in the authors' words, \"thick descriptions of individual experiences to reach an in-depth understanding of the participants’ situation\". Indeed, no actual justification or rationale is provided in favour of this sample size, apart from a vague sentence mentioning \"rich and detailed interview data\" before the data are even presented. Answer: We acknowledge that the sample size is limited, and we have mentioned our limited sample size in our section of methodological considerations. Due to the underrepresentation of studies including perspectives of both persons with ALS and family careers in the same study, and a paucity of studies with perspectives from people with cognitive impairment, we find the study, although with a small sample size, important – and may be a basis for further research. What makes a sufficient sample size in qualitative research is also debated. Malterud [1], which we refer to in our manuscript, emphasizes that it is the information strength within the sample that determines how many participants is sufficient, and that if the data has high information strength, between four and seven participants may provide sufficient rich material. It is also worth mentioning that our choice of including perspectives from both persons with ALS and family careers, and to analyse the data on different levels, has made the analysis more complex. Comment: The authors spend almost an entire page to describe how their analysis was carried out inductively, only to add a whole series of theoretical underpinnings in step five (i.e., Goffmans and DPM) which clearly made at least part of the analysis deductive. While TA allows for both inductive and deductive approaches to be carried out simultaneously, a significant lack of clarity (and potentially methodological understanding) transpires from the Methods section. Answer: We have made some changes to improve the clarity of our analysis and use of theory. We decided to remove statements about use of theory inductively during the analytic process due to the different understandings about this concept in qualitative literature, and to clarify the methodological approach that was carried out. To avoid premature and dominating explanations to the results, it was, however important to state our field specific and theoretical preconception before starting the data collection. We acknowledge that no researcher can fully part from their preexisting convictions. We hope our revision has improved the clarity to differentiate between theoretical preconceptions and theory used to analyse data. We are sorry about the typographical error where we write “epidemiological flexibility” instead of “epistemological flexibility”. This error may have led to unnecessary misunderstandings/confusion. Comment: Despite what the authors claimed, their data are in fact not rich. The Findings section is barely two pages long, covering only one overarching theme split into two sub-themes. If this is really all that emerged from the interviews, it is hard to believe it was not due to the very limited sample size. Answer: We realize that the themes generated covers many aspects and may have been difficult to follow. To increase readability and to clarify our findings, we have added three sub-themes to the first main theme, and two sub-themes to the second main theme. We have also added more examples and quotations from the participants to support the findings, and to justify that the participants provided rich descriptions to answer the research question. We have had a thorough review of the findings section. We hope the changes we have made to the section clarifies the differences and similarities between the participants’ experiences. After reviewing each theme and looking into the data again, we also realize that our data does not fully support the identification of the theme “Searching for hope through a well-lived-life”. Our analysis reveals that this theme is about holding on to self and identity rather than searching for hope. “Searching for hope…” cannot be justified by the participants’ stories. The theme has therefor been revised and is now identified as “Coping with a lost future”. Comment: The Discussion section is far longer than the Findings, which makes me wonder how the participants managed to draw so many points from such a limited data set. Answer: We have added data to support our findings and revised the findings section. We have also made a quite large reorganization and editing of the discussion. We hope the changes we have made, now makes the manuscript easier to follow, and that our findings are more trustworthy in relation to our discussion. Comment: Overall, the manuscript cannot be considered for indexing in its current limited form. The authors should carry out further in-depth interviews with additional participants and a more thorough data analysis, thus allowing for a more comprehensive and methodological robust contribution to the literature. Answer: To carry out further interviews with additional participants is not possible within this study, but we encourage future research to address the same topic to add to todays’ scarce knowledge. Rearrangements of our findings and inclusion of more examples from the data is done to meet some of reviewer’s critique. We acknowledge that the small sample size is a limitation in this study. In the revised manuscript we have stated our limited sample size as a limitation of this study in the section of methodological consideration. However, we lend support to qualitative research method that justifies our sample size (1). We believe the data was sufficient to answer our research question, and due to the very scarce research existing in this field, we believe our findings may be an important basis for further research. Finally, thank you so much for revising this manuscript with valuable comments to enhance the clarity of the manuscript. Your feedback has been important to improve the article. We hope it is now sufficient to be considered applicable for indexing. Best regards, Marit Sofie Oseland 1. Malterud K, Siersma VD, Guassora AD. Sample Size in Qualitative Interview Studies: Guided by Information Power. Qual Health Res. 2016 Nov;26(13):1753-1760." } ] } ]	1	https://f1000research.com/articles/12-1092
https://f1000research.com/articles/13-1080/v1	20 Sep 24	{ "type": "Systematic Review", "title": "A systematic review of Streptococcus Mutans and Veillonellae species interactions in dental caries progression: Positive or Negative impact?", "authors": [ "Faizul Hasan", "Hendrik Setia Budi", "Rajesh Ramasamy", "Tantiana Tantiana", "Rini Devijanti Ridwan", "Ervina Restiwulan Winoto", "Prawati Nuraini", "Juni Handajani", "Ariadna Adisattya Djais", "Silvia Anitasari", "Faizul Hasan", "Rajesh Ramasamy", "Tantiana Tantiana", "Rini Devijanti Ridwan", "Ervina Restiwulan Winoto", "Prawati Nuraini", "Juni Handajani", "Ariadna Adisattya Djais", "Silvia Anitasari" ], "abstract": "Background The interaction between Streptococcus mutans (S. mutans) and Veillonella species (Veillonella spp.) is unclear. This study aims to investigate the interaction between S. mutans and Veillonella spp. on caries development using systematic review.\n\nMethods This systematic review was accorded to the guideline of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Three electronic databases, namely PubMed, Embase, and the Cochrane library, were used to conduct a systematic search for eligible studies from their inception until July 18, 2023. PROSPERO registration number was No. CRD42023445968.\n\nResults We initially identified 4,774 articles. After eliminating duplicates and irrelevant articles, 11 studies met the inclusion criteria. The studies revealed important aspects of the relationship between S. mutans and Veillonellae spp. in dental caries. One significant finding is that Veillonellae spp. can affect the acid production capacity of S. mutans. Some studies indicate that Veillonellae spp. can inhibit the acid production by S. mutans, potentially reducing the cariogenic process. Another aspect is the competition for substrates. Veillonellae spp. utilize lactic acid, which is a by product of S. mutans metabolism, as a source of carbon. This metabolic interaction may decrease the availability of lactic acid for S. mutans, potentially influencing its cariogenic potential.\n\nConclusions This systematic review highlights the emerging evidence on the interaction between S. mutans and Veillonellae spp. in dental caries. The findings suggest that Veillonellae spp. can modulate the acid production, and substrate competition of S. mutans, potentially influencing the cariogenic process.", "keywords": [ "dental caries", "Streptococcus mutans", "Veillonellae species", "lactic acid", "substrates competition" ], "content": "Introduction\n\nThe oral cavity is a habitat that provides a diversity of microbial species, and it is estimated that more than 700 species of bacteria are present in the oral cavity.1 The teeth, tongue, cheeks, gingival sulcus, tonsils, and palate provide a favourable environment for microorganisms to thrive. The oral cavity’s surface is coated with many bacteria in dental plaque, known as a dental biofilm.2,3 The main oral bacteria are gram-positive and gram-negative, followed by aerobic and anaerobic. The commensal flora works in harmony with the host, but this relationship can become disharmonious due to changes in the microenvironment (microenvironment), resulting in disease states. Predominant oral diseases such as caries and periodontal disease are caused by microflora that are not in line with the host (dysbiosis).4 The role of beneficial bacteria is to prevent invasion of pathogenic bacteria.1 Polymicrobial community in oral biofilms include Streptococcus, Actinomyces, Lactobacillus, Veillonellae, Neisseria, and Eubacterium.5 This biofilm can thrive in homeostasis with a human host but is also the cause of the two most common human diseases, dental caries and periodontitis.6,7\n\nStreptococcus mutans (S. mutans) is a normal flora in the oral cavity, including gram-positive facultative anaerobes. In certain circumstances, these bacteria can turn into pathogens due to predisposing factors, namely oral hygiene.8 Dental caries is caused by multifactorial, one of which is food left on the surface or between the teeth. Sweet food with high glucose, such as carbohydrates, candy, sugar and other sweet foods, will form a layer of plaque (dental biofilm) on the tooth surface as a colony for a multi microorganism.9 Dental caries and plaque are among the most common diseases worldwide and are caused by a mixture of microorganisms and food.10 Acid-producing bacteria, especially S. mutans, will colonize the tooth surface and cause damage to the hard tooth structure due to the fermentation of carbohydrates into sucrose and fructose.11 Lactic acid formed by S. mutans bacteria in plaque will cause demineralization of tooth enamel and decrease saliva acidity (pH), resulting in caries over time.12\n\nHowever, lactic acid is a source of life for other bacteria in the vicinity, such as Veillonellae species (Veillonellae spp.) and is closely related to lactic acid-producing bacteria.13,14 Bacteria in the oral cavity will reduce high concentrations of nitrate in saliva to nitrite, and nitric oxide.15 Veillonela spp. is a gram-negative anaerobic bacteria that can convert lactic acid into weak nitric acid (NO3-), which is then reduced to produce nitrite (NO2-), and nitric oxide (NO) which is a source of defence in the oral cavity against pathogenic bacteria and raises the pH of the oral cavity.16,17 This process is known as the nitrate-nitrite-NO pathway.18 The biological activity of nitrite is lower than that of NO, while nitrate has no biological activity. The half-life of NO is very short, so it only has activity around its biosynthetic site.19\n\nThe symbiosis between bacteria can certainly benefit or harm the host. Veillonella spp. may reduce lactic acid that causes dental caries produced by S. mutans. However, there is a lack of pooled evidence investigating the interaction between S. mutans and Veillonella spp. on caries development using systematic review. Therefore, this systematic review examined the interaction between S. mutans and Veillonella spp. on caries development.\n\n\nMethods\n\nThis systematic review was accorded to the guideline of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.20 The study registration number was CRD42023445968 on the International Prospective Register of Systematic Reviews website. Three electronic databases, namely PubMed, Embase, and the Cochrane library, were used to conduct a systematic search for eligible studies from their inception until July 18, 2023. We used the following keyword combinations to search for articles: (“Streptococcus mutans”) OR (“S. mutans”) AND (Veillonella) OR (“Veillonella spp”) AND (“Dental Caries”) OR (“Tooth Decay”), the searching strategies were listed in Table 1. In addition, the reference lists of the eligible articles were manually searched to identify additional relevant publications.\n\nWe included full-text studies that fulfilled the following criteria: (1) individuals with dental caries, early childhood caries (ECC), or root caries, compared or not with a control group without caries; (2) reported the interaction between Streptococcus mutam and Veillonella in dental caries; and (3) the study employed a cross-sectional, case–control, prospective, retrospective, or randomized controlled. We defined the dental caries by Decay-missing-filled teeth index (DMFT) or other standard instrument used to define the dental caries. There were no language or publication date restrictions.\n\nTwo investigators (H.S.B. and F.H.) searched the electronic databases independently and screened and reviewed the qualified publications. The third investigator (R.D.R.) assisted in resolving any discrepancies through discussion.\n\nStudy outcome\n\nTo assess the methodological quality of the included studies, we used the Joanna.21 We scored each item as “yes,” “no,” “unclear,” or “not applicable”.\n\nData extraction and synthesis\n\nTwo reviewers (H.S.B. and F.H.) extracted data and evaluated the included studies independently. Any differences were resolved through discussion. We extracted the first author’s name, publication year, study location, study design, sample demographics, sample size, and the interaction betweem Steptococcus mutan and Veillonella in dental caries. All data were presented in tables.\n\n\nResults\n\nAs presented in Figure 1, we initially identified 4,774 articles. After eliminating duplicates and irrelevant articles, 11 studies met the inclusion criteria. We added 1 studies from other sources. Five studies were excluded by reason were presented in Table 2. In total, there were 7 studies were included for the systematic review.\n\nAmong the included studies, there were 408 participants in total. The age was ranges from 1 to 3.89 years old. Five studies were conducted in United State of America and the two studies were in Hong Kong and Indonesia. Other detail of participant characteristics were presented in Table 3.\n\nTable 4 depicted the studies characteristic. For the caries type, there were 4 studies were ECC type, and 3 studies were severe ECC. The definition to detect caries criteria was using DMFT, DMFS, white spot, gingivital index, and caries dentition criteria.\n\nThe studies revealed important aspects of the relationship between S. mutans and Veillonellae spp. in dental caries. One significant finding is that Veillonellae spp. can affect the acid production capacity of S. mutans. Some studies indicate that Veillonellae spp. can inhibit the acid production by S. mutans, potentially reducing the cariogenic process.\n\nAnother aspect is the competition for substrates. Veillonellae spp. utilize lactic acid, which is a by product of S. mutans metabolism, as a source of carbon. This metabolic interaction may decrease the availability of lactic acid for S. mutans, potentially influencing its cariogenic potential.\n\nLimited evidence suggests that Veillonellae spp. might have an impact on the host immune response and modulate the inflammatory processes associated with dental caries. Further research is necessary to understand the specific mechanisms involved in these interactions.\n\nThe meta-analysis cannot be performed due to the limitation of the number of included studies.\n\nMost studies used a cross-sectional study design. Of these, 4 studies did not state their strategies for addressing confounding factors. All studies measure outcomes in a valid and reliable manner. Other details regarding the methodological quality of studies are summarized in Table 5.\n\n\nDiscussion\n\nThis systematic review highlights novel findings about the interaction of Veillonellae spp. and S. mutans in dental caries. The results imply that Veillonellae spp. can control the substrate competition and acid production of S. mutans, potentially affecting the cariogenic process. This interaction may also be influenced by host-microbe interactions. Because our study implied rigorous methodology, hence, the finding should be highly considered.\n\nStreptococcus mutans is a bacterium commonly found in the human oral cavity and is known for its role in dental caries formation.22 However, recent studies have shown that Veillonellae, anaerobic bacteria commonly found in the oral cavity, play a role in inhibiting this caries progression.23 Veillonellae, on the other hand, are anaerobic bacteria that thrive in the same environment. Studies have shown that these two bacteria have a mutually beneficial relationship.24\n\nStreptococcus mutans is known for its ability to ferment dietary carbohydrates, producing acids as by products. These acids can lead to the demineralization of tooth enamel, increasing the risk of dental caries.25 However, Veillonellae have been found to metabolize the lactate produced by S. mutans.26 Lactate is a key component of the acid production process.27 By lowering the acidity, Veillonellae contribute to maintaining a more balanced pH level,28 which is crucial for oral health and prevents enamel demineralization.29\n\nFurthermore, the presence of Veillonellae has been shown to inhibit the growth and colonization of other potentially harmful bacteria in the oral cavity. This further emphasizes the beneficial role of Veillonellae in maintaining oral health. The exact mechanisms by which Veillonellae inhibit the growth of these harmful bacteria are still being studied, but it is believed that they compete for resources or produce antimicrobial substances. The symbiosis between S. mutans and Veillonellae plays a significant role in maintaining the homeostasis of the oral microbiome.30,31\n\nThe relationship between Veillonella spp. abundance and dental caries (specifically Early Childhood Caries or ECC) is not entirely consistent across all studies. While some studies have reported lower levels of Veillonella in caries-free individuals compared to those with ECC, other studies have reported different findings. In some research, lower levels of Veillonella spp. have been associated with a higher risk of dental caries, including ECC.32 This could be because Veillonella, as an acid-resistant bacteria, plays a role in modulating the oral environment and reducing acidity, which is beneficial in preventing dental caries. On the other hand, other studies have shown contrasting results, reporting either higher levels of Veillonella or no significant difference in its abundance between caries-free children and those with ECC.33\n\nSome studies have shown a higher abundance of Veillonella in caries subjects compared to control subjects, suggesting a potential role of Veillonella in caries progression. On the other hand, other studies have found no significant difference in Veillonella levels between the two groups. The difference in Veillonella abundance between caries subjects and controls could be attributed to several factors related to the oral microbiome and the development of dental caries. The oral microbiome is a complex ecosystem consisting of various bacterial species, and its composition can be influenced by multiple factors, including diet, oral hygiene practices, genetics, and environmental factors.34\n\nThe potential reasons for the difference in Veillonella amount between caries subjects and controls are diet, oral hygiene practices, acidity (pH), host genetics and immune and disease progression response. The type and frequency of dietary sugar intake can influence the abundance of different bacterial species in the oral cavity. High sugar consumption provides more food for acid-producing bacteria like S. mutans, which can lead to a shift in the microbial balance.35 As Veillonella can utilize metabolic by products of acid-producing bacteria, its abundance may change in response to variations in sugar consumption. Regular and effective oral hygiene practices, such as brushing and flossing, can help maintain a healthier oral microbiome by reducing the accumulation of plaque and the growth of cariogenic (caries-causing) bacteria. Inadequate oral hygiene may promote the growth of cariogenic bacteria at the expense of acid-resistant bacteria like Veillonella. Dental caries development is associated with a decrease in oral pH due to acid production from certain bacteria. Veillonella is known to thrive in low-pH environments and can help modulate the acidity in the oral cavity. Consequently, its abundance may be affected by changes in pH levels caused by the presence of cariogenic bacteria.10 Individual variations in host genetics and immune responses can influence the composition of the oral microbiome and susceptibility to dental caries.36 The interactions between the host and specific bacterial species, including Veillonella, might impact its abundance in the oral cavity. Disease progression, dental caries is a dynamic process. As the disease progresses, the oral environment changes, which can lead to shifts in the composition of the oral microbiome, including Veillonella.\n\nTo understand the specific reasons for the difference in Veillonella abundance between caries subjects and controls, need to conduct comprehensive studies that take into multiple factors and potentially control for confounding variables. It is important to note that the conflicting results may be due to various factors, such as differences in study design, sample size, and methodology. Additionally, the oral microbiome is highly complex, and the interaction between different microorganisms may also influence the progression of caries. Further research is needed to fully elucidate the specific interactions and mechanisms involved in this symbiotic relationship between S. mutans and Veillonellae. Such knowledge could potentially lead to the development of targeted therapies or probiotics that promote the growth of Veillonellae to prevent or slow down the progression of dental caries.\n\n\nConclusion\n\nThis systematic review highlights the emerging evidence on the interaction between S. mutans and Veillonellae species in dental caries. The findings suggest that Veillonellae spp. can modulate the acid production, and substrate competition of S. mutans, potentially influencing the cariogenic process. Additionally, host-microbe interactions may play a role in this interaction. Further research, including well-designed in vitro and in vivo studies, is needed to fully understand the mechanisms underlying this interaction. The knowledge gained from such investigations could pave the way for novel preventive and therapeutic strategies targeting the interaction between S. mutans and Veillonellae species to manage dental caries effectively.\n\n\nEthics and consent\n\nEthical approval and consent were not required.", "appendix": "Data availability\n\nNo data are associated with this article.\n\nPRISMA checklist https://doi.org/10.5281/zenodo.11213481\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nJoanna Briggs Institute Critical Appraisal Tools can be assessed here: https://jbi.global/critical-appraisal-tools\n\n\nAcknowledgment\n\nWe express our gratitude to Airlangga University and The Indonesian Ministry of Research, Technology and Higher Education (Ristekdikti) for their generous financing, which has facilitated the successful completion of this research project.\n\n\nReferences\n\nDeo PN, Deshmukh R: Oral microbiome: Unveiling the fundamentals. 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How Fermented Foods Feed a Healthy Gut Microbiome. Cham: Springer; 2019; pp. 171–191\n\nTakahashi N: Oral microbiome metabolism: from “who are they?” to “What are they doing?”. J. Dent. Res. 2015. Dec; 94(12): 1628–1637. PubMed Abstract \| Publisher Full Text\n\nRibeiro AA, Paster BJ: Dental caries and their microbiomes in children: what do we do now? J. Oral Microbiol. 2023 Apr 10; 15(1): 2198433. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nTheodorea CF, Diven S, Hendrawan D, et al.: Characterization of Oral Veillonella Species in Dental Biofilms in Healthy and Stunted Groups of Children Aged 6–7 Years in East Nusa Tenggara. Int. J. Environ. Res. Public Health. 2022; 19(21): 13998. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMeyer F, Enax J, Epple M, et al.: Cariogenic Biofilms: Development, Properties, and Biomimetic Preventive Agents. Dent. J (Basel). 2021 Aug 3; 9(8): 88. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nZhang Y, Wang X, Li H, et al.: Human oral microbiota and its modulation for oral health. Biomed. Pharmacother. 2018; 99: 883–893. Publisher Full Text\n\nAkimbekov NS, Digel I, Yerezhepov AY, et al.: Nutritional factors influencing microbiota-mediated colonization resistance of the oral cavity: A literature review. Front. Nutr. 2022 Oct 20; 9: 1029324. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nDame-Teixeira N, de Lima AKA , Do T, et al.: Meta-Analysis Using NGS Data: The Veillonella Species in Dental Caries. Front. Oral Health. 2021 Oct 22; 2: 770917. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nChen X, Daliri EB, Kim N, et al.: Microbial Etiology and Prevention of Dental Caries: Exploiting Natural Products to Inhibit Cariogenic Biofilms. Pathogens. 2020 Jul 14; 9(7): 569. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSedghi L, DiMassa V, Harrington A, et al.: The oral microbiome: Role of key organisms and complex networks in oral health and disease. Periodontol. 2000. 2021 Oct; 87(1): 107–131. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBradshaw DJ, Lynch RJ: Diet and the microbial aetiology of dental caries: new paradigms. Int. Dent. J. 2013 Dec; 63(Suppl 2): 39–47. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nEsberg A, Haworth S, Kuja-Halkola R, et al.: Heritability of Oral Microbiota and Immune Responses to Oral Bacteria. Microorganisms. 2020 Jul 27; 8(8): 1126. PubMed Abstract \| Publisher Full Text \| Free Full Text" }	[ { "id": "350944", "date": "28 Dec 2024", "name": "Yifei Zhang", "expertise": [ "Reviewer Expertise Oral microbiology" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe main defect of this review is that the author only included clinical research literature and can only draw relevant conclusions, but could not draw causal conclusions, which need robust experimental data.\nBesides, there are some misunderstandings about basic concepts, which may affect the quality of the article. For example:\n“The main oral bacteria are gram-positive and gram-negative, followed by aerobic and anaerobic”\n\nGram-stain reflects the cell wall structure, while aerobic/anaerobic reflects the growth characteristics.\nPolymicrobial community in oral biofilms include Streptococcus, Actinomyces,\nLactobacillus, Veillonellae, Neisseria, and Eubacterium.5 This biofilm can thrive in homeostasis with a human host but is also the cause of the two most common human diseases, dental caries and periodontitis\nThose bacteria are not the main members that causing periodontitis.\nStreptococcus mutans (S. mutans) is a normal flora in the oral cavity, including gram-positive facultative anaerobes. S. mutans is a species.\nIn certain circumstances, these bacteria can turn into pathogens due to predisposing factors, namely oral hygiene.\nOral hygiene is a predisposing factor? What does it mean?\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Partly\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Partly\n\nIs the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required.\n\nAre the conclusions drawn adequately supported by the results presented in the review? No\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable", "responses": [ { "c_id": "13121", "date": "13 Jan 2025", "name": "Hendrik Setia Budi", "role": "Author Response", "response": "We appreciate the reviewer's insightful comments and constructive feedback. We will now address the specific concerns raised. The incorporation of clinical research literature and the constraints in establishing causal conclusions. The reliance on clinical research literature presents limitations that restrict the capacity to draw causal conclusions. The manuscript explicitly outlines this limitation. The revised text includes a discussion highlighting the necessity of robust experimental data to support causal inference. Misinterpretation of Fundamental Principles: Gram stain and growth characteristics: Thank you for highlighting the inaccuracies in the phrasing related to gram-positive/negative and aerobic/anaerobic bacteria. The statement has been revised to clarify that gram-stain indicates cell wall structure, whereas aerobic/anaerobic pertains to growth characteristics. The revised text states: \"Oral bacteria encompass both gram-positive and gram-negative species exhibiting varied growth characteristics, including aerobic and anaerobic organisms.\" The composition of the polymicrobial community in oral biofilms and its association with periodontitis has been clarified, and we acknowledge this correction. The text has been revised to accurately state: \"The polymicrobial community in oral biofilms, comprising Streptococcus, Actinomyces, Lactobacillus, Veillonella, Neisseria, and Eubacterium, exists in homeostasis with the human host.\" Specific bacteria, including Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola, exhibit a strong association with periodontitis. Clarification regarding Streptococcus mutans (S. mutans): The characterization of S. mutans as \"normal flora\" has been refined to prevent misconceptions. The updated text specifies that S. mutans is a gram-positive facultative anaerobe typically located in the oral cavity. Under specific conditions, including inadequate oral hygiene, S. mutans may play a role in the formation of dental caries. Oral hygiene as a predisposing factor. The statement \"oral hygiene is a predisposing factor\" is indeed ambiguous and necessitates further clarification. The updated text clarifies: \"Inadequate oral hygiene fosters conditions that promote the proliferation of harmful bacteria, increasing the risk of oral diseases like caries and periodontitis.\" The revisions aim to address the raised concerns and enhance the clarity and quality of the manuscript." } ] }, { "id": "342753", "date": "30 Dec 2024", "name": "Zahreni Hamzah", "expertise": [ "Reviewer Expertise Biomedical Oralmaxillofacial Pathology", "Oral Biology", "Gerodontology" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article is very good and interesting for fellow dentists to know. Based on the literature used, it is proven that S. Mutans and Veillonella spp. have an interrelated role with each other in maintaining homeostasis in cases of dental caries. This article is very worthy for indexing. However, I as the reviewer stated that this article only needs a little improvement.\n\nThe revisions that need to be made are as follows: 1. There needs to be consistency in writing S. Mutans, for example: the writing of S. Mutans is written as S. Mutams. 2. There needs to be consistency in the writing of Veillonella, it should be written “Veillonella spp. Please check in this article.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes", "responses": [ { "c_id": "13119", "date": "23 Jan 2025", "name": "Hendrik Setia Budi", "role": "Author Response", "response": "The authors express gratitude to the reviewer for the favorable feedback and for emphasizing the significance of this study for the dental community. We acknowledge the recommendations for enhancement and have responded to them as outlined below: We have conducted a thorough review of the manuscript and rectified all inconsistencies in the writing of S. mutans. All instances now uniformly adhere to the correct format. S. mutans. Consistency in Writing Veillonella spp.: We have maintained uniformity in the representation of Veillonella spp. throughout the manuscript. All inconsistencies have been addressed. We anticipate that these revisions will fulfill your expectations and improve the manuscript's quality. I appreciate your insightful comments and suggestions." } ] }, { "id": "350938", "date": "08 Jan 2025", "name": "Fidya Fidya", "expertise": [ "Reviewer Expertise Oral Biology", "Anatomy", "Histology", "Cell biology" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study uses a systematic review to investigate the interaction between S. mutans and Veillonella spp. on caries development. The result revealed important aspects of the relationship between S. mutans and Veillonellae spp. in dental caries.\nOne significant finding is that Veillonellae spp. can affect the acid production capacity of S. mutan, potentially influencing its cariogenic potential. This systematic review was accorded to the guideline of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses provided to allow replication by others.\nThis review highlights the emerging evidence on the interaction between S. mutans and Veillonellae spp. in dental caries. The findings suggest that Veillonellae spp. can modulate the acid production and substrate competition of S. mutans, potentially influencing the cariogenic process. The conclusion supports the result presented in the review.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable", "responses": [ { "c_id": "13120", "date": "13 Jan 2025", "name": "Hendrik Setia Budi", "role": "Author Response", "response": "Thank you for the review and acknowledgement." } ] }, { "id": "350940", "date": "23 Jan 2025", "name": "Atik Kurniawati", "expertise": [ "Reviewer Expertise Oral Microbiology", "Oral Biology" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe urgency of this study is not yet clear. It is not mentioned that Veillonella sp. as a gram-negative anaerobic bacteria is mainly found in the gingival crevicular and tongue, which cannot use carbohydrates as an energy source. Instead, Veillonella sp. oxidizes lactic acid, which is the final metabolic product of bacteria that metabolize carbohydrates (including S. mutans), as a result the pathogenic potential of these bacteria in caries is reduced. So by manipulating part of this ecosystem, the pathogenic potential of bacteria is reduced or perhaps eliminated.\nMethods : Did it include exclusion criteria such as: 1) review article, 2) non-human study?\nIt is necessary to add a table of Conclusions on the interaction between S. mutans and Veillonellae sp. on caries, as positive or negative categories\nIt is necessary to discuss, from most of the reference results, whether they show the interaction of S. mutans and Veillonell sp. on caries as positive or negative. It is also necessary to explain the limitations of this review.\nCannot yet answer/conclude whether the interaction between S. mutans and Veillonellae sp on dental caries progression has a positive or negative impact\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Partly\n\nIs the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required.\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes", "responses": [] } ]	1	https://f1000research.com/articles/13-1080
https://f1000research.com/articles/13-957/v1	23 Aug 24	{ "type": "Case Study", "title": "Chronological approach to the characteristics of Ecuador’s debt with the IMF and the WB.", "authors": [ "Martha Lucía Romero Flores", "Marcelo Sánchez-Oro Sánchez", "Patricia Alexandra Chiriboga Zamora", "Ligia Ximena Tapia Hermida", "Patricia Alexandra Chiriboga Zamora", "Ligia Ximena Tapia Hermida" ], "abstract": "Where did Ecuador’s foreign debt originate and grow to alarming levels? The purpose of this article is to describe, from an analytical perspective based on the contributions of various authors, the origin of Ecuador’s external debt with international institutions such as the World Bank and the International Monetary Fund, as well as the support that these organizations provide for the development of the countries of the South, case Ecuador. To achieve this purpose, a documentary methodology was implemented that included an exhaustive review of studies focused on the specific variables subject to analysis, the PRISMA tool and Atlas.ti 23 were used. The results show that the creation of these financing agencies in their attempt to support the financial stability of developing countries has not been sufficiently effective in improving the welfare conditions of a good percentage of the population and has generated an imbalance in the sustained development of the poorest countries. It is concluded that the capitalist system gives predominant priority to the economic growth of nations, thus relegating in its model the consideration of human development. This orientation does not contribute effectively to the improvement of crucial aspects such: education, health and the standard of living of the population.", "keywords": [ "External debt", "World Bank", "International Monetary Fund", "development" ], "content": "1. Introduction\n\nFinancial institutions play an essential role in fostering economic growth and development by strengthening investment and promoting advances in productive technology and trade within a given economic system. However, despite the existence of policies designed to improve a country’s domestic conditions, they sometimes fail to do so. Ecuador continues to depend on international financial institutions to balance its balance of payments and is therefore subject to their conditions, which has given rise to significant difficulties, especially in the political and economic spheres.\n\nSince its establishment as a republic, Ecuador has inherited a debt burden that has experienced alarming growth over time. Consequently, it is imperative to scrutinize the process of conception and granting of this financial support throughout its history, in order to clarify the underlying reasons why the policies implemented by the different governments have failed to consolidate the country’s economic development. It is also of utmost importance to carry out an exhaustive investigation with the objective of understanding the causes that have given rise to an unequal distribution of income in the various strata of Ecuadorian society, in spite of the abundant natural wealth of the nation.\n\nIt is essential to understand the political, economic and social conditions that have prevailed during the different governmental periods, as well as to evaluate the progress of key indicators such as poverty, inequality, health, employment, education and production, key factors in the measurement of human development.\n\nWith the documents studied, it is concluded that the policies implemented by these organizations have reduced the opportunities for growth towards development, it is considered that the financial organizations act in a restrictive manner, imposing on debtor countries the adoption of internal policies that harm the most vulnerable sectors, intensifying inequality and worsening poverty indexes. The current political and economic crisis in Ecuador, devastated by drug trafficking, corruption and crime, makes it highly vulnerable to a financial meltdown, with the consequent need for external financing and therefore absolute dependence on the conditions of its financiers.\n\n\n2. Methods\n\nDescriptive documentary research, using the PRISMA methodology (Preferred Reporting Items for Systematic reviews and Meta-Analyses), in which the actors who have carried out studies on the bibliographic bases of Science direct, Scopus, Pub med and Google scholar and the repository of the Central University of Ecuador were identified. In this way, the number of coincidences with respect to the variables under study was determined and then, through elimination, the articles that analyze the concepts of development, international financing organizations IMF and WB and the application of these organizations in Ecuador were determined. Illustration 1-2, based on Atlas’ti, shows the weight of the concepts discussed in the bibliographic databases consulted.\n\nThe systematic matrix was used to study the authors’ coincidences in previous works on the variables by analyzing the findings. Identified records:\n\nDatabases (n =3.998) Records marked as eligible (n=1.187) Records deleted for other reasons (n= 2.811). Records reviewed (n =60) Excluded records (n = 5). Reports sought for retrieval (n = 31) Unrecovered reports (n =5). Reports evaluated for eligibility (n =60). Studies included in the review (n = 55).\n\n\n3. Results\n\n3.1.1 Agricultural production\n\nThe beginning of Ecuador as a republic dates back to 1809, when it was part of Gran Colombia and fought for independence from the Spanish colony. At that time, it was necessary to strengthen its armament and increase the number of soldiers to face the hard battles. In 1818 the Colombian and Venezuelan commissioners sought resources in Londres to finance the legitimate battle and in 1821 they signed the first contract for about £.186,475 (pounds sterling). In 1822 the loan of 2 million pounds sterling was acquired, and in 1824, £. 4.750.000, amortizing £.124.050, receiving a total of £.6.625.950, values destined to the acquisition of war armament, which later were branded as an overpriced purchase and for which, in spite of the disagreements of the assembly, it was agreed to pay (Paz y Miño, 2021). The responsibility for the beginning of a debt that to this day has not allowed a positive balance lies in the poor conditions of purchase and the prospects of the negotiators. In 1830 Ecuador separated from the great Colombia, having inherited the co-responsibility of a debt distributed at the discretion of the managers of Colombia and Venezuela, with 21.5% corresponding to Ecuador, giving rise to a totally inequitable.\n\nAs expressed,\n\nAlfaro (1896) “Venezuela and New Granada settled their foreign debt in a reasonable and honest manner, but Ecuador did not. The history of these two countries is evidence of the unpatriotic and immoral behavior recorded in the annals of the Latin American republics” (pp. 2-3).\n\nThe debt recorded at £1,424,579.05 rose to £2,393,293 by December 31, 1853 with interest at 6% per annum. New loans had to be renegotiated to cover the interest and overdue bonds. In some cases, these renegotiation agreements involved the use of vacant land as a form of payment, becoming an obstacle to economic development from the outset (Liehr, 1989). During this republican stage, the country experienced a significant influence of military power and the church. The new republic was established on a poorly defined territorial order, with a network of interests, hegemony and domination at the national level, which led to the exclusion of the masses and the absence of a shared history among the indigenous and mestizos (Acosta, 2006). Ecuador’s economy was framed in foreign trade, with cocoa as one of its main export products, which generated significant income through foreign exchange that contributed to the trade balance. This sector positioned itself as one of the main players in the global market, contributing to the generation of employment, economic growth and diversification of income sources. For Guerrero (1980) “this production boom gave rise to two social classes: cocoa and non-cocoa landowners, and bankers and traders, who were the main agents of the circulation of cocoa” (p. 82-83), called by Guerrero as the agro-financial and commercial oligarchy that achieved the complete integration of the production process and circulation of cocoa income (production chain); each member was a landowner, exporter and banker. This oligarchy was the result of the appropriation of large tracts of peasant land and the subjugation of its workers (Chiriboga, 2013. p. 20-22), exploitation in which capital takes precedence over social aspects, resulting in underdevelopment. However, years later the situation was not the same; Spain being the main buyer of cocoa, this country limited the opening of the world market due to its refusal to recognize the independence of its colonies, which led to a decrease in exports, low prices and the abandonment of some plantations due to the decrease in income (Maiguashca, 2012. p. 71-72).\n\nAcosta (2006) the report describes at length Ecuador’s vulnerable economic condition as a result of the decoupling of cocoa production from the rest of the country’s economy, with surpluses going out as royalties on foreign investments, debt repayments and capital flight. In response to an economy in crisis, in 1843 the second Coin Law was issued giving way to the fractioning of the currency, twenty years later the Banco Particular de Guayaquil was authorized to issue currency and in 1895 the sucre entered into circulation as a measure to improve the economy. The problems of minting, banknote backing, depreciation, World War I and others increased the economic capacity of the agricultural and commercial bank until 1927 when the Central Bank (CB) was created. with the aim of ordering the monetary situation and controlling the stability of the exchange rate. The CB assumed this condition, although leaving aside other important economic aspects such as deflation (1928-1932) and inflation (1936-1937) (Oleas, 1995, p. 99). The central bank reduced its involvement in macroeconomic aggregates and fiscal policy issues.\n\nIn 1940, the international market was opened for Ecuador, bananas stood out as the main product, and in 1946 there was a moderate growth in exports without reaching the same proportion as cocoa. Once again, the surpluses generated were invested outside the country, allowing exporters and producers to obtain large profits. These revenues were used to renegotiate the foreign debt, which by 1950 had increased to US$68.3 million. During this period, external financing for Latin America was consolidated, strengthening the support of the World Bank, the Inter-American Development Bank and the International Development Agency (Acosta, 2006, p. 106). Competition in the Central American market increased, the spread of a plague affecting banana plantations allowed the expansion of international markets, consolidating Ecuador’s participation until 1955. Cocoa, bananas and rice continued to be the main agricultural export products (Reyna, 2021, p.16); however, dependence on a monoculture economy, oriented to the export of primary products and with limited diversification conditions, led the country to a vulnerable situation in the face of competition and the subjugation and price control of the world market, a situation that placed it in a peripheral position (Mero, Piedra & Galeano, 2017, p. 208).\n\n3.1.2 Oil as a powerful product to get out of the crisis\n\nConditions such as political instability, constant changes of president, international competition, little national production, caused economic dependence on traditional export products that plunged into serious crises. It was necessary to consolidate production in other sectors in order to increase the State’s income, which led to an increase in indebtedness and dependence on international policies. In 1850, the first oil exploitation began in the coastal zone without favorable results and with a rather limited production that did not cover the internal demand, since production was less than the needs. In 1972, the exploitation process began in the eastern region of Ecuador. This period was marked by the colonization of land in the Amazon and the implementation of a development model with capitalist characteristics, driven mainly by the oil industry and the emergence of agro-industrial plantations (Baca et al., 1997, p. 97). Oil extraction became a major activity, attracting investments and generating significant income for the country. At the same time, the expansion of agro-industrial plantations was encouraged, focusing on large-scale crops such as bananas, cocoa, oil palm, among others. This development model had a significant impact on the economy and the natural landscape of the Amazon region. For Rodríguez Lara oil revenues would help the problems of the marginalized people, who struggle in misery, ignorance and lack of health care (Oleas, 1995). In effect, the exploitation and commercialization of oil would be the guarantee for the state’s income, whose main objective was to invest in social projects that would reduce the difficult conditions of the majority of the population. The state participated in a percentage of 63% of the total net income per barrel, although when taxes and royalties were added, 66% corresponded to the state, “this was the time in which it acted wisely and in accordance with the principles of the nation in defense of the interests of the state, the resources served for the common good and not for private interests” (Gordillo, 2004, p. 51). Ecuador, like some Latin American nations, was immersed in unfavorable conditions, the rise in oil prices improved public sector revenues, but at the same time there was a growing expansion of public spending, on the other hand, financing from international banks and imports increased. In order for the economy to continue expanding without inflation, it was necessary to depend on foreign debt (CEPAL, 1985).\n\nEcuador’s foreign debt has increased from US$ 24.5 million in 1950 to US$ 324.6 million in 1972, US$ 3,530.2 million in 1980, US$ 12,052.0 million in 1990, US$ 11,335.4 million in 2000 and US$ 46,974.3 million in October 2021 (Banco Central del Ecuador, 2022).\n\nThe existing inequality between the countries of the North and those of the South and their characterization as developing countries has a long history. After World War II, the economic and financial catastrophe left Latin American countries at a disadvantage compared to the rest of the world, with the consequent stagnation of production, which prevented them from maintaining growth and development. The Gross Domestic Product (GDP) in Latin American countries generated from their production was not enough to meet the internal investment needs in the social field, especially in education, health and production variables, being necessary to resort to international support through financial institutions that generally determine the conditions for each country, and that in most cases affect the population with lower incomes, widening the inequality gap and increasing poverty.\n\nThe major international financiers: International Monetary Fund (IMF) and World Bank (WB), support all countries that require capital injection, their main objective is to provide economic assistance to countries that need and require external aid to achieve local stability, promote industrial development or initiate a process of socioeconomic reconstruction. Within its lending capacity, it supervises the economic policies of borrowers, offers technical assistance, analyzes the condition of each country and the economic outlook. Its policies are usually accompanied by a series of corrective measures, with the assurance that these policies are appropriate (Cadenas, 2021), and implemented to ensure their payment.\n\nSome economic analysts consider these organizations as double-edged weapons, stressing the care that must be taken for safe negotiations, as in 2010, 2013, 2014, 2015 and 2017 were the years where the greatest controversies occurred almost at the same time in Chile, Argentina, Uruguay and Paraguay, countries where the economic measures imposed by the governments as a guarantee for access to a loan from the IMF ended in protests and multiple disagreements by the citizens. The last three decades represent a process of financial reforms that have led to uncertainty and constant volatility, as well as slow growth, crises and stabilization policies. Monetarist economic policies have diminished the purchasing power of families and companies, there has been a destructuring of currency spaces, and there have been many attempts at monetary union (Girón & Correa, 2008, p. 9).\n\nAccording to the latest report of the International Development Bank (IDB) the total debt of Latin America and the Caribbean has reached 117%, governments will have to allocate between 46 and 55% of their GDP for public debt obligations depending on the conditions of each country, for the multilateral development banks provide long-term loans at competitive rates and financial instruments to cover risks (Powell & Valencia, 2023).\n\nEcuador, with an economic condition leveraged on the primary production of cocoa, coffee and bananas; and since 1972 the oil that supported its economic growth in the early years of its, and which led to considerable improvements in education and health, however, its pace has been considerably slower, and in 1982 in several components, such as poverty, social inequality and employment, there has been a trend towards stagnation or deterioration (Larrea, 2006, p. 63).\n\nLike the rest of the Latin American countries, Ecuador has historically resorted to financial entities to meet its income deficit, with the consequent economic policies that have affected the entire population. In 2010, in governments considered to be leftist, this submission was rejected because they considered that they paralyzed development and subjected countries to their collateral conditions; it was not a fight for poverty but a rejection of the exploitation of the capitalist model (Harnecker, 2010); However, in 2019, in view of the economic measure ordered by the government of President Lenin Moreno, which consisted of the withdrawal of fuel subsidies, the reaction of social groups led to a general strike as a result of the “Paquetazo”. To while in Chile, days of riots and protests began due to the increase in the price of public transport fares and the consequent need for financing.\n\nThis dependence on the external sector made the country vulnerable to the events of international markets; exports represent approximately 20% of the Gross Domestic Product (GDP) and the imports vary between 15% and 20% of GDP, the degree of openness of Ecuador’s economy, seen from the participation in foreign trade is relatively high compared to other non-oil countries (BCE, 2022).\n\nOn the other hand, data from the Central Bank of Ecuador (BCE) indicate that public external debt was $41,495.6 million in 2019 (16.1% more than in 2018), representing 38.6% of GDP (5.4% more than in 2018); it also had an average year-on-year variation rate of 11.4% between 1950 and 2019. This debt covered 79% of total external debt in 2019 and registered a figure of $42,383.5 million through November 2020. In recent years, after the COVID 19 crisis, Ecuador obtained $514.1 million from the World Bank to support its economic reactivation, this financing contributed to the design of mechanisms for the expansion of social protection programs and the strengthening of cash transfer systems for the most vulnerable families. The Ministry of Economy and Finance has approved that the International Fund for Agricultural Development (FIDA) to finance $23.4 million for the Sustainable and Appropriate Development in Rural Territories project to be executed by the Ministry of Agriculture (Ministrio de Economía y Finanzas, 2020), by 2022 the external debt closes at $63.732 million.\n\nAnother important aspect to consider is the technological condition of the countries, because although before globalization it was difficult to know the scientific progress in the northern countries, today that situation should change, the transfer of knowledge and technological progress through the results of research can reach in real time to all countries of the world, and should be used so that all follow the same line and the philosophy of the United Nations “that no one is left behind” is fulfilled, however, is another component that in Latin America and Ecuador is not met, the knowledge arrives at least 30 years later.\n\n3.2.1 Some macroeconomic indicators\n\nThe credit condition that the country maintains with external organizations involves attention through economic policies for the payment of such credits; according to the law, no more than 40% of the GDP can be destined to external payments. The following table presents some macroeconomic indicators (Table 1).\n\nThe term development has evolved over time, being conceptualized in different ways by different authors. Although it has traditionally been associated with economic growth, this perspective is limited. Amartya Sen proposes a broader vision, where development implies not only economic progress, but also political and social progress, focusing on enabling individuals to live with dignity and freedom (Sen, 1998) During the 1990s, especially in Latin America, the different development models were criticized, the effectiveness of adjustment measures was questioned, and a structuralist approach to address economic and social inequalities was proposed (Mujica Chirinos & Rincón, 2010), these inequalities were absorbed by international cooperation, engaging the external community in the search for integrative solutions, especially in countries with high international economic dependence and poorly functioning economies, as evidenced by the growing external debt and social neglect (Duarte & González, 2014).\n\nThe cooperation of the larger in technology and innovation, towards the weaker allows the coexistence of two different worlds, but this cooperation should be focused on a real will for growth and development of the countries of the south but not out of remorse (Pérez, 2015).\n\nIn this action, the measurement of development solely through GDP is criticized and it is advocated to consider multidimensional indicators that include aspects such as quality of life, human development, natural resources and environmental sustainability, in which the joint participation of the state, market and society in key areas such as education, poverty reduction and environmental protection, linked to sustainable development with equal opportunities, prevails (Bidaurratzaga, Bosca, & Sánchez, 2021), to change the reality of the regions towards economic growth, but in a socially fairer way (SánchezOro-Sánchez, 2006, p. 193), The contribution of support agencies should differentiate each state and apply policies according to its internal reality in terms of history, institutions and culture, since the application of the same policies in different territories is incorrect (Adelman, 2002).\n\nThe immediate purpose of the creation of the World Bank and the IMF was to promote economic development and full employment. The Figure 1 represens the times the concept is mentioned in the works analyzed for this article. After World War II, these institutions focused on restoring the monetary system and rebuilding damaged economies, however, the influence of private money limited their financing capacity and has led the IMF to impose adjustment measures on borrowing countries in times of crisis (Arias & Vera 2002) and today the IMF’s ability to address financial problems and the inadequate representation of developing countries is questioned, since, the amount of loan that a member can request is not determined by its quota but by the improvement in 80-20 results, a rule that does not reflect the true demand for credit causing inefficiencies (Miyakoshi, 2014).\n\nThe key challenge for the IMF and WB is to maintain inclusive growth and adapt to the new global economic order (Sánchez, 2014), with negotiation and distribution costs low and assumed by the IMF (Miyakoshi, 2014).\n\nThe World Bank (WB), initially the International Bank for Reconstruction and Development (IBRD) created to support the reconstruction of Europe and the financial stability of developing countries, has evolved in its lending mechanisms from an economic approach to a more social and sustainable one, from being just a bank to becoming a development agency facing crises and difficulties that have evidenced the failure of the initial hopes for the development of the economies of the region. Its new vision is aimed at “creating a world free of poverty on a livable planet”, actions are summarized in new variables such as energy, technology, food security, innovation, opening of trade flows, greater support to developing economies, especially those that maintain an average debt-to-GDP ratio of around 75%, with weak credit ratings in which borrowing costs are nine times higher than for better-rated economies. The latest proposals are aimed at joint actions between the IDB and the World Bank to make development effective (Banco Mundial, 2023).\n\nBut, the promises of improving the welfare of the poorest have not been completely fulfilled, generating imbalances in the economic growth of developing countries (Alacevich, 2010) (p.149). Several authors criticize the actions of these financing agencies, as they undermine labor rights and the standard of living of workers through policies that include downsizing, privatization of state enterprises, insufficient wages, wage inequality and social security violations, which benefit corporate interests to the detriment of the labor force (Lloyd & Weissman, 2002) (Arias & Vera, 2002).\n\nThe World Bank Group with more than 70 years of history, has adapted its policies in the international economy, impacting Latin America and promoting competitive and globalized market economies, prioritizing global capital over human rights (Mendes, 2018). On the other hand, the IMF intervenes in economic crises assuming that the problems are similar (Casas, 2017), its lending policies, have consequences such as the lack of an established approach, subordination of the WB to the IMF, interaction with large private banks and the influence of the United States in these institutions, conditions that have led to an increase in the power of economic and financial sectors, reduction in the importance of the domestic market and a limited contribution to social (Lichtensztejn, 2012).\n\nThese institutions have contributed to increasing inequality and poverty in the world, especially in Africa, with disastrous results in the 70’s and 80’s. Drajem (2001), Dembele (2005), Stubbs and Kentikelenis (2017) criticize the influence of these international financial institutions, by imposing austerity measures on countries with high levels of public debt, affecting human rights. Countries that did not follow IMF and WB recommendations during times of economic growth are considered to have been more successful in escaping poverty than those that did.\n\nAttempts to redesign IMF policies to mitigate impacts on vulnerable populations have been insufficient, for Daoud, Herlitz, & Subramanian (2022), IMF policies have been criticized for not taking sufficient responsibility for the negative effects of austerity measures, increasing poverty in vulnerable countries.\n\nFaced with these negative situations, the authors agree that these organizations should reform their institutional framework, so that poor countries participate in decision-making and achieve development objectives (Alacevich, 2010, p. 149). Uncertainty should be considered and those affected should be listened to in order to design effective policies that promote freedom and autonomy (Casas, 2017). Propose reforms in public policies of self-sufficiency to help countries in economic crisis (Daoud, Herlitz, & Subramanian, 2022), protect the health and standard of living of the population, develop equity metrics in applied studies and promote an economy focused on sustainable human development. A reorientation in these institutions is urgent to protect rights in education, health and work (Stubbs & Kentikelenis, 2017).\n\nThe document prepared for the Latin American and Caribbean Regional Consultation on Financing for Development highlights the importance of a paradigm shift towards a sustainable development approach that considers social and environmental criteria, in addition to economic ones. It emphasizes the need to combine public financing with private resources to maximize development impact. The countries of the region, especially middle-income countries, should seek alternatives such as the mobilization of internal resources to achieve inclusive and sustainable development. It is crucial that they assume greater responsibility for their development and seek a favorable external environment that reduces asymmetries in the financial system, international trade and participation in technology and innovation; it is also important to consider opportunities for innovation, technology and knowledge transfer from developed countries (CEPAL, 2015).\n\nExpert analyses of the relationship between Ecuador and the IMF offer a multifaceted vision of the country’s economic and social dynamics. The Figure 2 represents the negative traits (red), possible improvements (yellow), positive factors (green); the following are the criteria of some authors:\n\nFernández and Santillana (2019) examine the letter of intent signed by Ecuador in 2019, highlighting the shift in the IMF’s discourse towards a focus on combating inequality and poverty, underlining the importance of the IMF’s constant monitoring to strengthen fiscal institutions and promote women’s participation in the labor market as generators of their own income. According to the latest report, 3,100 women-led small businesses receive financial support from the World Bank (Figure 2) to strengthen women’s participation in the business sector (Banco Mundial, 2023).\n\nContrasting this perspective, Weisbrot y Araúz (2019) criticize the IMF program and its effects on growth in Ecuador, pointing out that the proposed reforms may result in greater economic instability, lower GDP growth and an increase in unemployment and poverty. They highlight the accumulation of international reserves as a measure that, while increasing financial stability, does not necessarily translate into social benefits for the population.\n\nIn turn, García Shugulí (2020) examines the economic policies imposed by the IMF in the 1990s, arguing that these have contributed to increased poverty and migration, as well as decreased state investment in key areas such as education and health, this historical overview shows how the IMF’s structural adjustment policies have had negative repercussions on the Ecuadorian economy and society over time.\n\nFrom a more contemporary perspective, Quise Llivipuma (2021) highlights the increase in public debt and the decrease in international reserves in Ecuador in recent years, pointing out the need for reforms to improve competitiveness in international markets, however, the conditions imposed by the IMF, such as the increase in VAT and fuel prices, pose challenges for the economic and social recovery of the country. This impact of the tax reforms imposed in the 2017-2021 period, which were implemented as measures to increase revenues and strengthen the economy were hampered by the pandemic and did not generate the expected results (Garzón Falcón, 2022). Jepson (2022) also adds to these criteria with a complementary analysis of the Ecuador-IMF relationship, highlighting how China influence and political changes have disrupted domestic economic policies, negatively affecting the economy and income distribution (Table 2).\n\n\n4. Discussion\n\nSince the creation of the IMF and WB as financial organizations to overcome the post-war crisis, there have been several interventions in different countries, from a viewpoint of support to equalize their balance of payments and promote an international financial order, the contribution with the participation of the least favored countries has been quite limited in strengthening their development (Arias y Vera, 2002), without equal representation (Sánchez, 2014); The pandemic situation, the internal political crisis, and other macroeconomic factors cause poor debt management and increase macroeconomic imbalances (Neaime y Gaysset, 2022).\n\nThe analysis of the authors’ criteria mostly coincides in pointing out that this financial support for Ecuador has generated greater indebtedness and dependence on the policies of these organizations throughout history, increasing the degree of inequality and exacerbating poverty, which especially affects children, women and the elderly (Daoud, Herlitz y Subramanian, 2022). In recent years, the WB has become a development agency to support countries in crisis, therefore, according to the criteria of the analyzed authors, it is necessary to focus on sustainable projects that are framed in a sustained growth of income and support the achievement of rights, especially in education as a factor enabling the development of human capital (Wang & Zheng, 2024, p. 19).\n\n\n5. Conclusions\n\nThe historical condition of indebtedness of Ecuador since it was part of the Gran Colombia has been increasing over the years, several investigations from a historical approach determine the productive wealth of the country, as well as the commercial positioning of different products in international markets that, according to conditions such as the cyclical behavior of the economy, the emergence of competing products and the wrong decisions of the rulers did not allow since the early years of the Republic to settle that debt and in recent years has grown to exaggerated levels.\n\nThe studies examined in relation to development maintain that the demand for growth, prosperity and progress in various regions are fundamental to generate greater income in a country. These demands are predominantly evaluated from an economic perspective using indicators such as GDP, trade balance, monetary reserve, among others. However, in a capitalist system, terms such as improved living conditions, poverty reduction, education and health are often not given the same importance.\n\nIn relation to the support of international financial organizations for development in the context of Ecuador, the authors analyzed agree in the perception that the policies implemented by these organizations have reduced the opportunities for growth towards development, it is considered that these institutions act in a restrictive manner, imposing on debtor countries the adoption of internal policies that harm the most vulnerable sectors, which intensifies inequality and exacerbates poverty rates. Ecuador is currently facing the worst political and economic crisis in its history, a country devastated by drug trafficking, corruption and organized crime, which makes it highly vulnerable to a financial meltdown, the consequent need for external financing and therefore absolute dependence on the conditions of its financiers; in the medium term it will exacerbate inequality and poverty.\n\n\nEthics and consent\n\nEthical approval and consent not required.", "appendix": "Data availability\n\nNo data are associated with this article.\n\nZenodo: Chronological approach to the characteristics of Ecuador’s debt with the imf and the wb. https://doi.org/10.5281/zenodo.13131334 (Romero et al., 2024).\n\nThe project contains the following files:\n\n• Figure 1\n\n• Figure 2\n\n• Table 1\n\n• Table 2\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAcosta A: Breve historia económica del Ecuador. 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Guayaquil: CIDE Centro de Investigación y Desarrollo del Ecuador; 2017; 208.\n\nMinistrio de Economía y Finanzas: FIDA aprueba Usd 23,4 millones para el desarrollo rural del Ecuador.18 de 12 de 2020. Reference Source\n\nMiyakoshi T: Es favorable la respuesta pragmática a las cuotas y los límites de crédito del Fondo Monetario Internacional? Appl. Econ. 2014; 46>33: 40–75.\n\nMujica Chirinos N, Rincón S: El concepto de desarrollo: posiciones teóricas más relevantes. Revista Venezolana de Gerencia. 2010; 15(50): 294–320. Recuperado en 07 de marzo de 2023. Reference Source\n\nNeaime S, Gaysset I: Macroeconomic and monetary policy responses in selected highly indebted MENA countries post Covid 19: A structural VAR approach. Res. Int. Bus. Financ. 2022; 61: 101616–101674. Publisher Full Text\n\nOleas J: La política económica del Banco Central del Ecuador cilcos recesivo y expansivo de política monetaria y control del tipo de cambio: 1927-1937. Quito: FLACSO; 1995.\n\nPaz y Miño J: La deuda externa de la Gran Colombia-Histoira y presente. Máxico, México: PUCE; 07 de Juniio de 2021.\n\nPérez J: Introducción al concepto de desarrollo.09 de 01 de 2015. Reference Source\n\nPowell A, Valencia O: Lidiar con la deuda. menos riesgo para más crecimiento en América Latina y el Caribe. BID; 2023.\n\nQuise Llivipuma S: Estudio del impacto económico generado por los “acuerdos de crédito” del Fondo Monetario Internacional (FMI) en las Pequeñas y Medianas Empresas (PYMES) en el Ecuador. Quito: Repositorio digital Unversidad Central del Ecuador; 2021.\n\nRapkin D, Strand J: Developing country representation and governance of the International Monetary Fund. World Dev. 2005; 33: 1993–2011. Publisher Full Text\n\nReyna J: El comercio exterior del Ecuador 1890-1950. Universidad de Barcelona; 2021; vol. 16. .\n\nRomero Flores ML, SánchezOro-Sánchez M, Chiriboga Zamora PA, et al.: Chronological approach to the characteristics of Ecuador’s debt with the IMF and the WB. [Data set]. Zenodo. 2024. Publisher Full Text\n\nRowden R: International Monetary Fund sacrifices higher growth, employment, spending, and public investment in health systems in order to keep inflation unnecessarily low. Int. J. Health Serv. 2010; 40(2): 333–338. PubMed Abstract \| Publisher Full Text\n\nSánchez E: La perspectiva y estrategia multilateral: Los países en desarrollo en el Fondo Monetario Internacional. Revista de Economía ICE. Información Comercial Española. 2014; 800(5): 1–196.\n\nSánchezOro-Sánchez M: Extremadura: política regional y dependencia (1986-1999). Reis. 2006; 181–197.\n\nSen A: Las teorías del desarrollo a prinicpios del siglo XXI.1 de 07 de 1998. Reference Source\n\nStubbs T, Kentikelenis A: International financial institutions and human rights: implications for public health. Aust. Health Rev. 2017; 38(1): 1–17. Publisher Full Text\n\nWang S, Zheng L: The Impacts of the Poverty Alleviation Relocation Program (PARP) on Households’ Education Investment: Evidence from a Quasi-Experiment in Rural China. Sustainability. 2024; 16:19. Publisher Full Text\n\nWeisbrot M, Araúz A: “Obstáculos al crecimiento”: El programa del FMI en Ecuador.17 de 07 de 2019. Reference Source" }	[ { "id": "320035", "date": "10 Oct 2024", "name": "Ramón García Marín", "expertise": [ "Reviewer Expertise Human Geography", "Economic Geography" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nEcuador's foreign debt has been a constant concern throughout the country's history, ever since it gained independence in the early 19th century. Bad loans and poor negotiations increased the foreign debt, which was in many cases the result of corruption, as very important resources were diverted for private purposes. The basic needs of the Ecuadorian population, such as health, education, housing and other infrastructure necessary for its development, have been neglected. This research, from my point of view, is original, timely and necessary. The paper clearly contextualizes the problem and justifies the choice of the topic of analysis. The research questions, objectives and hypotheses are clear and well defined. Even though it is brief, there is a good and clear description of the research design (Analysis Methodology). Regarding the Results, the authors present the relevant information; they are well organized and supported with graphs and tables. The conclusions offer an overview of the main findings and a well-posed general assessment is presented. Regarding writing, style and format, the writing is fluid, clear, concise and understandable. The grammar and spelling are correct. There are no errors. There are clear transitions between chapters, subsections and paragraphs. And the citation format in the text and bibliography is applied correctly throughout the document. Therefore, and to conclude, I believe that the indexing of this research is appropriate.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Yes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes\n\nIs the case presented with sufficient detail to be useful for teaching or other practitioners? Yes", "responses": [ { "c_id": "12616", "date": "14 Oct 2024", "name": "Martha Lucía Romero Flores", "role": "Author Response", "response": "Dear Doctor I would like to thank you for your approval of the article: Chronological approach to the characteristics of Ecuador's debt with the IMF and the WB, which reveals from a historical approach, the situation of risk that Ecuador lived and that in the present time has transformed its external debt into eternal and exponential debt. This article will serve as a support for researchers in the economic and social field." } ] }, { "id": "333697", "date": "31 Dec 2024", "name": "Halder Yandry Loor Zambrano", "expertise": [ "Reviewer Expertise Finance", "business plan", "project management", "management" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe case study is extremely interesting and presents relevant data and the PRISMA methodology is appropriate for this type of work.\nHowever, I consider that they should update the study at the level of agricultural and oil production and some macroeconomic indicators of Ecuador, which may well be provided by the Central Bank of Ecuador, since we are in the year 2024.\nLikewise, although the criteria of the different authors cited in this document mostly coincide in pointing out that financial support for Ecuador has generated greater indebtedness and dependence on the policies of these organizations throughout history, I consider that they should also be included.\nin this case study, especially in the discussion section, to later refer to in the conclusions (to complete the analysis), those criteria that do not share this argument, given that, being multilateral credit organizations, they must ensure because that financial resource that they grant via loans to countries that request them, return to their coffers. It must be remembered that these institutions do not oblige any country to request this type of financial requirements and they are not responsible for the fact that certain rulers in power, in some countries and in the case of Ecuador specifically, have allocated the funds for an excessive increase in bureaucracy. waste of financial resources, corruption, among other evils (endemic in some South American countries), forgetting the origin of this type of funds, which must be returned according to the established deadlines and conditions.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Yes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly\n\nIs the case presented with sufficient detail to be useful for teaching or other practitioners? Partly", "responses": [ { "c_id": "13105", "date": "11 Jan 2025", "name": "Martha Lucía Romero Flores", "role": "Author Response", "response": "Dear Reviewer Thank you for your comments, which have been accepted and adjusted based on the recommendations and inserted in the text. I remain attentive to the indications for the respective correction. Kind regards" } ] } ]	1	https://f1000research.com/articles/13-957
https://f1000research.com/articles/13-722/v2	23 Dec 24	{ "type": "Research Article", "title": "Legal aspects and government policy in increasing the role of MSMEs in the Halal ecosystem", "authors": [ "Yusup Hidayat", "Aris Machmud", "Sonny Zulhuda", "Suartini Suartini", "Yusup Hidayat", "Sonny Zulhuda", "Suartini Suartini" ], "abstract": "Background Indonesia currently could not make it to the top ten global halal due to some external and internal factors, although it is the largest Muslim country. In the external sector, the competition map is getting tougher, while internally, there are handicaps in the form of weak public awareness of competition. As a country with the largest Muslim population in the world, Indonesia can become one of the largest markets in the world. As indicated in the Global Islamic Economic Report (GIER), Indonesia is one of the top ten countries that control the Islamic economic market, yet it fails to dominate its Islamic market. Accordingly, the government needs to play a stronger role through regulatory policies to encourage the development of the Islamic economic ecosystem in Indonesia (halal value chain). The purpose of this study is to find out and analyse the existence of Micro, small, and medium enterprises (MSMEs) in Indonesia in the world’s market for Halal products and Services.\n\nMethods The researchers have conducted a form of normative juridical research with the analytical descriptive method, namely by collecting, describing, analysing, and presenting what is (das sein) and what ought to be (das sollen).\n\nResults Support from the government and stakeholders has not been optimal in improving welfare - capital access, management, and halal certification, so the existence of the global halal ecosystem has not yet impacted MSMEs’ ability to compete competitively.\n\nConclusions The conclusion of this study shows that the quadruple helix innovation system is capable of guaranteeing the development of MSMEs in a manner to achieves a high level of competitiveness - efficiency, and effectiveness of the products and services produced.", "keywords": [ "Business Ecosystem", "Halal Product", "MSMEs", "Quadruple Helix" ], "content": "Introduction\n\nIndonesia has the potential to become a world market for halal goods and services. Its failure as the largest Muslim country in the world needs attention from stakeholders. This research shows why Indonesia should be the world’s biggest halal product market.\n\nIndonesia currently could not make it to the top ten global halal due to some external and internal factors, although it is the largest Muslim country. In the external sector, the competition map is getting tougher, while internally, there are handicaps in the form of weak public awareness of competition, such as; Indonesians’ lack awareness of halal standardization, and an inadequate understanding of the law. However, apart from halal products - food, cosmetics, and medicines - Indonesia has begun to stand out in the fields of Islamic finance, halal tourism, and Muslim fashion in the world (Permana, 2019).\n\nIndonesia has enormous unused potential in the ecosystem of halal products and services in the world by involving all stakeholders to synergize with each other to increase the capacity and capability of Micro, small, and medium enterprises (MSMEs) to be competitive with imported products. MSMEs are only a bearing for development, the existence of MSMEs is still a complement to economic and legal politics in sustainable economic development. Despite the influence of economic globalization, the state’s commitment to the attainment of constitutional goals remains questionable (Azis, 2018).\n\nMSMEs are the foundation of the national economy in developing countries, where their contribution is up to sixty percent of the national income (GDP). Meanwhile, large industries only contribute forty percent to the GDP (Suparji, 2020).\n\nThe global competitiveness of MSMEs and their contribution to national economic growth could be developed even further. They have been contributing for more than sixty percent of the GDP, absorbing up to ninety-seven percent of the workforce and fourteen percent of total national exports. This is due to the number of MSMEs that have reached more than fifty-seven million businesses, hence there is a need to enhance their capacity and capability. Switching the business ecosystem to a green economy poses a particular challenge for MSMEs in their effort to remain competitive. Therefore, the constraints they are facing need to be addressed immediately, enabling them to continue growing and become a mainstay in the national economy. Access to financing, lack of credit guarantees, production efficiency, and effectiveness remain serious obstacles for MSMEs to compete on a global level. Thus, solutions are needed to be sought through government regulation and policies (Suparji, 2020).\n\nSuch a condition is bound to harm the business world in general, especially if MSMEs’ existence is only considered as a complement to economic development. There is bound to be an increase in unemployment if the MSMEs’ competitiveness remains weak, which will make them act as mere spectators of the large potential of the global halal ecosystem (Suparji, 2021).\n\nThe weakness of Suparji’s research is that it tends to place greater emphasis on legal reform that is adaptive to all changes in the business environment to support green economic ecosystems and MSME business development through government facilities and policies. Globalization and free markets bring intense competition, whereby only products with competitive advantages can survive in the business world, including MSMEs.\n\nFor this reason, the government needs to support the existence of this largest business sector, namely MSMEs, by supporting the creation of a conducive ecosystem. Such a halal-based economy should be materialized through a policy of preference for domestic products because Indonesia is a country that has the largest Muslim market share in the world with more than two hundred million people (Asep Firmansyah, 2022).\n\nLimited capital is a common-place problem in MSMEs. It is evident that financial literacy, both sharia and conventional, has only reached seventy-six percent. This means, the potential to transform and digitize finance for MSMEs in increasing their production capacity as well as to improve the quality of their products. One of the difficulties of MSME actors in obtaining capital for MSME development is that capital owners do not yet have a prominent level of confidence in lending to MSME business actors (Asep Firmansyah, 2022).\n\nThey still lack confidence in the success of MSME businesses. They also have to increase production capacity and quality, in addition to their managerial capabilities. It is specifically related to financial administration to facilitate financial inclusion and the use of information technology in increasing business opportunities and expanding market share (Asep Firmansyah, 2022).\n\nThe contribution of MSME business units to Indonesia’s economic growth has been highly significant as they contribute almost ninety-nine percent of all business units. Therefore, there is a high chance that MSMEs will become major players in Indonesia’s and the world’s halal product ecosystem. Accordingly, the government needs to empower MSMEs by collaborating in expanding market access through various digital marketplace platforms and digitizing their finances (Hartomo, 2020).\n\nThe halal ecosystem has a huge potential that can be developed by MSME businesses. There is a high demand for halal products in the global level and the world Muslim market share offers a very lucrative potential for business actors including MSMEs - both in developing and developed countries. For such a reason, a new orientation is needed in shaping the world halal market through the transformation of the halal industry (Benuf & Azhar, 2020; Ali, 2021).\n\nThe progress of MSMEs has not been maximized due to limited access to capital and credit guarantees as well as the budget for obtaining halal product certificates (Nugraheni, 2020).\n\nBased on the background above, the authors see that regulations alone are not sufficient to solve the above-stated MSME problems. The question is; how to make Indonesia’s MSMEs soar high in the world’s market for Halal products and Services?\n\n\nMethods\n\nThe Authors have conducted a form of normative juridical research with an analytical approach based on statutory rules to solve problems that exist within positive law also referred to as doctrinal legal research. In normative law methodology, this can be done through the search for principles, rules, and legal systematics, both codified as well as in the form of legislation (Benuf & Azhar, 2020; Ali, 2021). Experts say that normative juridical research is a legal study that originates from positive or dogmatic legal norms - where the law as a system of norms and rules originates from legal products, both from regulators and court decisions as well as opinions of other experts to produce arguments, theories or a new concept as a prescription in solving the problem under investigation (Ali, 2021).\n\nBambang Waluyo argues that normative juridical research is a document study using legal sources in the form of regulations and decrees and also using library sources to analyse and resolve legal issues. This study aims to get an objective description of a situation in a complete and detailed manner regarding a collection of arrangements regarding Islamic finance and MSMEs (Kholid, 2018).\n\nThis form of research is intended to be a statute approach research, namely research that aims to track and analyze based on material in laws and regulations and analyze between das sollen and das sein -between what ought to have happened and what has happened (Efendi and Ibrahim, 2016).\n\nThe analytical method used in this research is prescriptive analysis. Collection of legal materials in the form of literature studies through journal, literature books, statutory regulations such as the Monopolistic Practices and Unfair Business Competition law, Sharia Financial, Halal products are the responsibility of the government through the Halal Product Guarantee Agency (BPJPH) has functions based on presidential regulations, as well as data collection, through electronic media related to the problem (Hafidz et al., 2018).\n\nThe criteria for financial inclusion is the community’s ability to access the formal financial system. The low level of financial inclusion is because there are barriers and access to formal finance (loan sharks). Inclusive finance can answer these reasons by providing many benefits for the community, regulators, government, and the private sector. Financial exclusion is the level of society that access the formal financial system at low and sustainable costs. Communities classified as having low financial inclusion are people with disabilities, low-income communities, and communities in disadvantaged, frontier, and outermost areas. Apart from that, workers without legal identity and small companies are un-bankable. Therefore, government policy should adopt the nine principles stated in the 2010 Toronto Summit on Innovative Financial Inclusion – leadership, diversity, innovation, protection, empowerment, cooperation, knowledge, proportionality, and frameworks (BI, 2018).\n\nThis research was conducted in 2023 and has been presented in international seminars, strategies for finding legal sources from various sources, either through published or published websites, and relevant journals in 2018-2023. The analytical method used is a descriptive and prescriptive analysis based on sources and secondary laws that are collected, sorted, and interpreted to answer the problem formulation (Indrawan & Nahartyo, 2020).\n\n\nResults\n\nIndonesia is currently still the largest consumer in the world in the world’s ecosystem of halal products and services. Indonesia has the potential to be on top based on indicators and instruments that support this - large potential consumers of halal products and services, availability of certification bodies, and recognized fatwa institutions (Syamsu, 2023).\n\nIn addition to the foregoing, product quality assurance is supported by regulations (President Republic of Indonesia Law of the Republic of Indonesia Number 33 Year 2014 on Halal Product Assurance, 2014), policies, and also qualified halal auditors so that Indonesia can play a more active role in the global halal export market. Indonesia’s weakness is undeniable that the limited non-production budget for the processing of halal certification can potentially lead to a high-cost economy. This plays a part in reducing the level of competitiveness (Syamsu, 2023).\n\nOrosz in Suparji states that MSMEs can make a more optimal contribution by increasing access to capital and assistance to increase effectiveness and efficiency in production so that they have a level of global competitiveness in line with the conditions faced as a consequence of the free market (Suparji, 2021).\n\nThe obstacles that are often faced by MSMEs are the lack of financial inclusion and literacy; the protection of MSMEs requires a different approach vis-à-vis the existing regulations. Thus, there is a need for an adaptive legal reform granting them equal treatment with large and established businesses. The existing fiscal and monetary policies do not support the existence of MSMEs - there are no subsidies and the implementation of a financing system (equated with large businesses) (Azis, 2018).\n\nBased on the foregoing it can be concluded that the achievement of the purposes of the 1945 Constitution through the development of people’s businesses and MSMEs has experienced ups and downs since the era of independence, as a result of which there are still groups of people who are classified as underprivileged (Azis, 2018).\n\nFacilities need to be provided by the state specifically to MSMEs - without compromising the essence of maintaining halal integrity. The provision of a simple halal product guarantees registration form and the imposition of a processing fee adjusted to the business conditions and sales turnover of each of these MSMEs so that through halal certificates and other documents they can expand their market access – going from local to global (Ahyar, 2020).\n\nPartnerships between large entrepreneurs and MSMEs can create prosperity for stakeholders and they can also contribute to the national economic growth through the fulfillment of commitments and business ethics. However, an unequal bargaining position frequently occurs as a result of setting detrimental partnership agreement clauses (Tanjung, 2022).\n\nFor such reasons, the role of the government and corporate companies - through CSR - is needed to provide protection and progress for MSMEs. It needs to be based on sociocultural aspects and mutually beneficial partnerships among stakeholders - whereby MSME products are absorbed by corporations making it easier to market them (Kelly et al., 2020).\n\nPartnership agreements need to be simple and understandable to both parties and applicable in complex circumstances. Policies in business competition in Indonesia are aimed at encouraging the equal distribution of business opportunities, legal certainty, and ease of access to markets, capital, and technology for MSMEs following the mandate of the Monopolistic Practices and Unfair Business Competition law (Kelly et al., 2020).\n\nThe halal ecosystem is supported by the seriousness of the government through regulations of halal products. Halal products are the responsibility of the government through the Halal Product Guarantee Agency (BPJPH) which has functions based on presidential regulations. said body has the following authorities (President Republic of Indonesia Law of the Republic of Indonesia Number 33 Year 2014 on Halal Product Assurance, 2014) see (Government Regulation in Lieu of Law No. 2 Year 2022 (“Perppu No. 2”), 2022):\n\na. Formulating and establishing policies related to the halal nature of a product;\n\nb. Establish SOPs, norms, and criteria related to the halal nature of a product;\n\nc. Issue halal certificates that have received halal fatwas from MUI (Indonesian Ulemas’ Council) and revoke certificates for products from within and outside the country;\n\nd. Registering halal product certificates from within and outside the country.\n\nThe determination of halal products begins with a review and research process by LPPOM (Institute for the Assessment of Cosmetic Drugs and Food) by considering the halal nature of a product, both goods and services, from consumer goods to kitchen utensils and clothing - all under the Islamic law. Business actors who have obtained Halal certificates are required to declare and disclose both on product packaging which is easily visible and difficult to be damaged or removed.\n\nHowever, Indonesia has the potential to become a world market for halal goods and services. Its failure as the largest Muslim country in the world needs attention from stakeholders. This research shows why Indonesia should be the world’s biggest halal product market. Indonesia currently could not make it to the top ten global halal due to some external and internal factors, although it is the largest Muslim country.\n\nIn the external sector, the competition map is getting tougher, while internally, there are handicaps in the form of weak public awareness of competition, such as; Indonesians’ lack awareness of halal standardization, and an inadequate understanding of the law. However, apart from halal products - food, cosmetics, and medicines - Indonesia has begun to stand out in the fields of Islamic finance, halal tourism, and Muslim fashion in the world (Permana, 2019).\n\nIndonesia has enormous unused potential in the ecosystem of halal products and services in the world by involving all stakeholders to synergize with each other to increase the capacity and capability of MSMEs to be competitive with imported products.\n\nPartnerships between large entrepreneurs and MSMEs can create prosperity for stakeholders and they can also contribute to the national economic growth through fulfilment of commitments and business ethics; however, an unequal bargaining position frequently occurs as a result of setting detrimental partnership agreement clauses (Tanjung, 2022).\n\nFor such reason, the role of the government and corporate companies - through CSR - is needed to provide protection and progress for MSMEs. It needs to be based on socio-cultural aspects and mutually beneficial partnerships among stakeholders - whereby MSME products are absorbed by corporations making it easier to market them (Mantili, 2020).\n\nPartnership agreements need to be simple and understandable to both parties and applicable in complex circumstances. Policies in business competition in Indonesia are aimed at encouraging the equal distribution of business opportunities, legal certainty, and ease of access to markets, capital, and technology for MSMEs by the mandate of the Monopolistic Practices and Unfair Business Competition law (Mantili, 2020).\n\nAn agreement is binding on the parties who make it, all clauses are agreed upon by the parties and the parties are responsible for enforcing the partnership agreement (Kelly et al., 2020).\n\nThere are many companies in the market, both large businesses and SMEs that allow for economies of scale to occur through partnerships with one another. However, these partnerships do not guarantee a business ecosystem that is free from competition between them because of the subjective desire of the parties to create and abuse market power - cartel or other illegal behaviour that has the potential for criminal prosecution. For such reason, the state can intervene to prevent unhealthy business actions from occurring, especially for MSMEs which constitute the largest number of business units that can absorb labour.\n\nTherefore, the capacity and capabilities of MSMEs need to be protected to enable them to be competitive. One form of capacity building is forming partnerships with large business actors. However, such partnerships are frequently more profitable for large businesses due to their greater bargaining power, which ultimately results in unfair business competition through unreasonable unilateral pricing. Such abuse of bargaining power can potentially lead to reduced competition due to obstacles in the ease of doing business and fair business, it is at this point that the state through its policies and regulations provides legal protection (Stiglitz, 2021).\n\nSudaryanto and Wijayanti stated that MSMEs need internationalization to be able to explore market access opportunities abroad through partnerships so that they can be competitive amid globalization and high competition, and thus have the ability to face global challenges. Such internalization takes the form of increasing product and service innovation, developing human resources and technology, and expanding marketing areas (Hadi & Setyawati, 2020).\n\nIt needs to be noted that partnerships bring legal consequences to the parties agreeing. Agus Budiarto and Ridwan Khairandy state that companies are legal subjects, including companies that are bound by civil law by the provisions of Book III of the Indonesian Civil Code (Prabowo, M Shidqon and Umami, 2018).\n\nCorones in Michael Schaper suggests that competition policy is needed to ensure the creation of a perfect competition market without any restriction and for this reason competition law is needed to ensure that business actors carry out business in good faith and refrain from unhealthy business conduct. At the same time, the competition law is in the form of regulations that are related to certain forms of competition.\n\nHowever, it also includes other measures including limiting the role of the state in market intervention, unfair trade practices - a ban on anti-competitive agreements; prohibition of abuse of dominant market position; prohibition of anti-competitive mergers and acquisitions - as it would distort perfect market competition (Michael Schaper, 2021).\n\nMSMEs are entities that are vulnerable to being affected by behaviour that deviates from fair trade - abuse of bargaining power, cartels, and abuse of dominance - as happened in the Philippines and Fiji - through exclusive transaction arrangements. ASEAN has agreed to apply general competition laws similar to the prohibition of anti-competitive agreements (including cartels), abuse of dominant position, and anti-competitive mergers and acquisitions (Michael Schaper, 2021):\n\na) Cartels and other anti-competitive agreements. Cartel is considered the most serious violation of competition law and it generally carries the most severe penalties (fine and, in some jurisdictions, possibly imprisonment). A cartel is an agreement in which competitors in the same market agree to fix prices, share markets, bid rigs, or limit production or supply. In general, other anti-competitive agreements that have the effect of distorting competition in the market (unbalancing the playing field) are also prohibited.\n\nb) Abuse of dominant position. Businesses that hold dominant market positions must not exploit their positions to the detriment of their customers or exclude competitors from the market. All ASEAN competition laws contain prohibitions of this type. Proving these types of violations can be very difficult for competition agencies, especially those with less experience.\n\nc) Anti-competitive amalgamation. Mergers that result in significantly reduced competition in the market after the merger takes effect, may be prohibited by the competition authorities. The policy aims to ensure that competition remains in the market after the merger so that consumers still have a choice.\n\nIndonesia is currently still the largest consumer in the world in the world’s ecosystem of halal products and services. Indonesia has the potential to be a winner based on indicators and instruments that support this - large potential consumers of halal products and services, availability of certification bodies, and recognized fatwa institutions. In addition to the foregoing, product quality assurance is supported by regulations (President Republic of Indonesia Law of the Republic of Indonesia Number 33 Year 2014 on Halal Product Assurance, 2014), policies and also qualified halal auditors so that Indonesia can play a more active role in the global halal export market. Indonesia’s weakness is undeniable in that the limited non-production budget for the processing of halal certification can potentially lead to a high-cost economy thereby reducing the level of competitiveness (Syamsu, 2023).\n\nCummings, Cross & Cummings, Davenport & Prusak state that development must refer to Sustainable Development (SDGs) adopted at the 2015 UN General Assembly session (United Nations, 2015). In this context, the collaboration of stakeholders with community members plays a highly significant role in finding innovative solutions through knowledge sharing to achieve effective use of resources through social networks and related local communities (Hakeem et al., 2023).\n\nEconomic-based knowledge has become available as a result of globalization in sustainable development through innovation and knowledge transfer as well as collaboration among all stakeholders (Triple Helix (TH) Model). However, Milner et. al, Kimatu believes that TH is still ineffective due to the lack of support from civil society for it to become the Quadruple Helix (QH) model as the fourth pillar towards achieving sustainable development. There is an urgent need for civil society involvement in such a helix model because it places greater focus on the micro perspective so that dynamic relationships, synergy, collaboration, coordinated environment, and value creation activities accelerate problem-solving due to the maximization of effective resource exploration (Hakeem et al., 2023).\n\nLikewise, global Halal products and services involving elements of government, entrepreneurs (investors), academics, and also the community (producers and consumers) form a circle involving mutually linked elements aimed at realizing Sustainable Development Goals, ensuring that people are free from hunger, stunting, poverty rates are reduced, especially in countries with Muslim populations and globally (Krisna et al., 2023; Sukoso et al., 2020).\n\nThe government is the foundation for all policies and becomes a political power in the discovery of these policies and regulations. (Yolanda, 2021) Multi-stakeholder collaboration in the quadruple Helix element can potentially enhance the development of MSMEs with more added value (Windhyastiti et al., 2022).\n\nH Etzkowitz & Leydesdorff, Carayannis et al state that in the system model an environmental ecosystem is needed. Therefore, the effectiveness of this quality system achieves sustainable development due to embedding social environmental factors in QHI is not only an aspect that becomes an ecological area for QH actors to work together and interact with each other but more than that the environment can influence the formation of innovation in a sustainable manner in the QHI model, it can be seen that the social environment represents, frames, and simultaneously influences the cooperation and interaction of the five helices ( Figure 1) (Wahdiniwaty et al., 2022).\n\nSource: This figure/table has been reproduced with permission from Wahdiniwaty et al. (2022).\n\nEnvironmental factors are disruptive as innate and global external influences so they require adaptive behavior and social interaction from the helix to create balance and harmony (Wahdiniwaty et al., 2022).\n\nTobing and Adrian state that the transformation and digitization of Islamic finance facilitate the flow of trade transactions in the business world, with a reach beyond inter-jurisdictional boundaries. It is through the use of technology that transactions can be carried out in a free space and time thus the digitization of payments can improve the global economy. However, the role of transformation and digitalization must involve the quadruple helix - the government or public authorities, industry, educational institutions or institutions, and the community as users. The low level of Islamic financial literacy, namely only 8.93 percent of the national average, indicates that most Indonesian people do not understand the characteristics of formal financial institution products and services. This is evident from the level of public ownership of Islamic financial accounts and Islamic products which is still relatively very small. The level of Islamic financial literacy can be measured using four indicators, including the following (Fawaid & Utama, 2022):\n\n(1) Basic financial knowledge (prohibition of usury, Gharar, and prohibition of maysir).\n\n(2) Loans/credit (mudharabah financing, musyarakah financing, murabahah financing, salam financing, istishna financing, ijarah financing, and qardh financing).\n\n(3) Investment/savings (types of investment and types of savings recommended in Islamic finance).\n\n(4) Insurance, (sharia/takaful insurance). With the development of the digital world, increasing Islamic financial literacy can be carried out through the transformation and digitization of Islamic finance.\n\nBased on OJK (Financial Services Authority) data - SNLIK 2022 results - financial inclusion has increased significantly from 76.19 percent in 2019 to 85.10 in 2022 thus showing that the gap between literacy and inclusion levels has been decreasing, namely from 38.16 percent in 2022 to 35.42 percent. Based on the survey, data on the financial literacy index and also financial inclusion shows that as of 2022 financial literacy increased by thirty-eight-point zero-three percent compared to 2019, while the financial inclusion index in 2022 increased by thirty-eight-point sixteen percent from 2019, as shown in Table 1 (Keuangan, 2022).\n\nSource: OJK (2022).\n\nBased on this data, in 2019, nationally it was concluded that Islamic financial literacy was still relatively low. From 2016 to 2019, there was only an increase of 0.83%, namely to 8.93%. Unlike the case with conventional financial literacy, from 2016 to 2019 there was an increase of 8.22%, namely to 37.72%. The development of Sharia financial inclusion and literacy per three years from 2016 to 2022 shows in Figure 2 below (OJK, 2016, 2022a, 2022b).\n\nSource: From Press release Indonesia FSA (OJK, 2016, 2022a, 2022b).\n\nIncreasing Islamic financial literacy is fundamental for the development of Islamic finance. This makes it interesting to study more in-depth, hence the authors are interested in examining this in an analytical descriptive study. This is done to explain the various efforts and strategies carried out by the four elements, namely the government or public authorities, industry, educational institutions or institutions, and the community as users. Based on SNLIK 2022, it shows that the level of sharia financial literacy has increased from 8.93% in 2019 to 9.14%, while the level of financial inclusion has also increased from 9.10% in 2019 to 12.12% in 2022. Graphical representation of Financial Sharia and Usury Literacy of the year 2019 is shown in Figure 3 and Graphical representation of Financial literacy data in 2022 can be seen in Figure 4 below (OJK, 2022b).\n\nSource: From Press release Indonesia FSA (OJK, 2022b).\n\nSource: From Press release Indonesia FSA (OJK, 2022b).\n\nThe government’s seriousness in enhancing the transformation and digitization of MSMEs was emphasized by President Joko Widodo who stated that through collaboration between stakeholders, it is possible to improve and accelerate the process of transformation and digitization in the Islamic financial sector to provide added value to MSMEs in Indonesia.\n\nThe lack of skilled personnel in the Islamic financial services sector is also due to cross cross-placement of labour, whereby the banking sector is mostly filled with non-Islamic finance graduates. The development of financial technology (Fintech) is yet to be utilized properly (Sukoso et al., 2020).\n\nIslamic financial digital literacy is an important indicator of success or failure regarding the understanding of Islamic financial products by the wider community. The lower the literacy index value, the lower the level of public understanding of Islamic financial literacy (Fawaid & Utama, 2022).\n\nThe government can encourage the use of digitalization of Islamic finance through socialization to the public, both through online and offline services, as well as commercial advertisements both print and television, or by conducting FGDs with interested parties. Improved products and services, enhanced human resources, and a more competitive profit-sharing ratio are required to increase financing for MSMEs and can compete with conventional banking (Fawaid & Utama, 2022).\n\nHalal product ecosystems function through supply chains that absorb the legal approach of supply and demand as well as enablers or supports. Meanwhile, from the supply side, it is necessary to have an industrial sector that offers quality halal products and is needed by the community, namely halal goods and services. At the same time, from the demand side, there is a great number of consumers/people who need halal products, whereas on the supply side, the high interest in halal products encourages all countries, both Muslim and non-Muslim, to offer premium halal products to form a perfectly competitive market through the provision of infrastructure, supply distribution and support for research and development of halal products (for product competitiveness) – through product, service, and process innovation support (Brier & Jayanti, 2020).\n\nThe halal industrial ecosystem requires a supply chain system to ensure the sustainability of quality and efficient halal products, namely products that are presented by the law of demand and supply, without a high-cost (Brier & Jayanti, 2020).\n\nThe demographics of the world’s Muslim population in 2060 are estimated to reach the level of two point nine billion people. This offers a potential for increasing the world’s Islamic economy with a growth rate of consumption of halal products of five-point two percent per year or a value of two point two billion US dollars per year, which is a huge potential (Brier & Jayanti, 2020).\n\nIt is a great challenge for Indonesia to become a global player in the world Sharia business. With the world’s largest Muslim community, it also has a productive population of nearly 68% of its total population; in 2019/2020 Indonesia ranked fifth in the world after Malaysia, UAE, Bahrain, and Saudi Arabia – previously ranked in the top ten (Brier & Jayanti, 2020).\n\nThe halal industry sectors that can be developed and improved by business actors, both large industries as well as MSMEs, namely the food and beverage industry, the halal tourism industry, the beauty and cosmetics industry, the fashion industry and the financial and pharmaceutical services industry.\n\nThese figures indicate that the awareness and need for halal products in Indonesian society continues to increase – particularly for food and beverage, pharmaceutical, and cosmetic products - although it is still supported by imported products. It gives a signal that the time has come for the domestic halal industry to take this opportunity to become a host in the world of global halal products. Unfortunately, the government has also been rather serious about encouraging the growth of sharia business in Indonesia through regulation. In the halal product ecosystem, we can break down the sectors of goods and services that can be transacted in the Sharia business world both locally and globally, as shown in Figure 5 (Ahyar, 2020).\n\nSource: This figure/table has been reproduced with permission from Ahyar (2020).\n\nThe Global Islamic Economic Report for 2019-2020 reports that on a global scale, Indonesia is not included in the top 10 countries with the best halal food performance in the world. For such a reason, it is necessary to have enforcement from business actors and other stakeholders to ensure that we can become a centre for products and also a global Sharia economic market (Sukoso et al., 2020).\n\nOne of the roles of the government in developing the halal industry is through strategic policies to utilize the potential of the halal industry, which supports the productivity of MSMEs in meeting international demand for halal products as well as encouraging the public to use domestic halal products. Regulatory support is no less important in supporting the development of the Indonesian halal industry. This is reflected in the seriousness of the Indonesian government in issuing regulations related to halal certification, namely Government Regulation (PP) Number 39 of 2021. The strategy adopted by the government is as follows (Ahmed, 2023):\n\na. Halal Product Policy Development;\n\nb. Infrastructure Expansion;\n\nc. Halal Product Guarantee System;\n\nd. Fiscal and Non-Fiscal Incentives – Monetary, Financing;\n\ne. International Collaboration for Halal Ingredients;\n\nf. Increasing Market Access;\n\ng. National Halal Certification;\n\nh. Mutual Recognition Agreement (MRA) with other countries;\n\ni. Festival to Promote Literacy Initiatives.\n\nThe role of the education sector is supported by the National Science and Technology Law. It is to make Indonesia a ’knowledge economy’ that will drive economic growth through innovation and access to information. There is awareness that this requires collaboration among stakeholders - government, academia, the private sector, and civil society.\n\nWith the above strategy, Indonesia has the potential to increase spending by the Indonesian people on Indonesian halal goods and services by around fifteen percent of the total population with an estimated income of more than two hundred and eighty-one billion dollars in 2025 and make Indonesia the largest consumer in the world, by contributing eleven-point thirty-four percent of global halal spending (Ahmed, 2023).\n\nKartasasmita states that the strong growth of the Sharia economy and the halal industry has resulted from several factors; a large Muslim population, growing awareness of Islamic values related to halal products, and a national strategy targeting the development of halal products and services. Bank Indonesia projects that the domestic halal value chain sectors which include agriculture, halal food and beverages, Muslim fashion, and Muslim-friendly tourism will grow by four point five-to-five-point three percent in 2023, contributing more than twenty-five percent to the national economy (Ahmed, 2023).\n\nLocal halal businesses supported by their communities will be able to compete, absorb a lot of labour and contribute to a sustainable economy. Community empowerment through the creation of community-supported job opportunities will increase people’s income which in the long run will have an impact on national economic development and can potentially bring about stability in the community industries (Ahmed, 2023).\n\nThe role of academics in developing halal products is through the creation of innovations that will be socialized and implemented by the community so that they can develop product diversification and halal product certification services. Networking and collaboration between the two pillars of the Quadruple Helix is the sharing of this knowledge that is essential to promote halal business effectively, educate people about the importance of halal compliance, and build connections with the Halal ecosystem, namely individuals, organizations, and industries (Ahmed, 2023).\n\nIncreasing awareness of the halal business will encourage the development of the halal industry as a whole. Local halal businesses - in this case, MSMEs - can play an important role in supporting and promoting halal businesses and empowering their communities through the application of halal principles (Ahmed, 2023).\n\n\nDiscussion\n\nThe message in the Qur’an Surah Al Baqarah Verse 168 requires that something Halal, and Thoyib is an order from Allah SWT as a form of self-serving to be free from sin as well as the personal right of Muslims that must be respected. As a guarantee of quality with zero tolerance for unclean materials or substances into halal materials, whether intentionally or not – contaminated with haram (forbidden) materials (Syamsu, 2023).\n\nHalal products contain spiritual and safety (quality) aspects that require them to be free from the main elements of the ingredients or the results of contamination of prohibited materials so that they are suitable for consumption by Muslim and non-Muslim consumers globally. The increasing trend of global halal products and services has been creating great potential in the national economy over the years, with an economic potential of nearly three trillion dollars (Syamsu, 2023).\n\nThe potential for the halal industry is very promising because the ecosystem can become a prima donna in the world economic sector. The development of halal products and lifestyles is experiencing an increasing investor interest in building and developing the Sharia industrial sector in Indonesia as well as with Indonesia having the largest Muslim market share in the world as well as government support in encouraging the Indonesian halal industry to become a champion in the global halal industry (Ahyar, 2020).\n\nThe position of Indonesian MSMEs is comparable to those in India. In addition to access to formal finance, MSMEs in India have management boundaries and the complexity of MSME procedures due to the banking adequacy ratio based on Basel III (Nikam, 2019).\n\nSuch challenges call for a government policy to overcome the challenges. Such policies included fiscal as well as non-fiscal policies. Indonesia has implemented fiscal policies for MSMEs based on Government Regulation (PP) No. 23 of 2018, applying a 0.5 percent tax for turnover of no more than IDR4.8 billion per year (Kemenkeu, 2022).\n\nIn addition to that, the government can potentially offer convenience through non-financial policies, namely by facilitating the process of halal certification for MSMEs. Generally, MSMEs only have a budget for production – all of the foregoing to enable MSMEs to be more productive and competitive in the halal industrial ecosystem. Likewise, in India, the government also encourages the empowerment of start-ups and MSMEs through the benefit of fiscal zero percent for MSMEs (Nikam, 2019).\n\n\nConclusions\n\nThe results of this study indicate that the quadruple helix innovation system can help to ensure that the legal system has strong binding power while providing a multiplier effect on the national economy. The quadruple helix quality system creates cohesiveness of the government through fiscal and non-fiscal incentives, as well as policies and regulations that support the productivity of MSMEs in halal goods and services. In the academic sector, with support from the National Science and Technology Law, which can be expected to encourage economic growth through innovation and access to information. Collaboration in the quadruple helix between government, academia, industry, and community makes it possible for MSMEs to develop and have global competitiveness in the Ecosystem of Halal Products and Services. The halal ecosystem requires a halal social environment that must be adaptive so that stakeholders can at all times be agile towards any changes that occur.\n\nThis study examines the impact of regulations and also the involvement of parties in the development of MSMEs in competition for halal products, to increase their role. Indonesia is in control of market share in the product ecosystem of halal goods and services. Research is not immune from imperfections. Therefore, it is necessary to study other factors that hinder Indonesia’s position in controlling the world’s halal products.", "appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nAhmed HM: How Can Gen Z Muslims Shake the Global Halal Industry. The Halal Times. 2023, April 12; 1. Accessed May 18, 2023.\n\nAhyar MK: Halal Industry and Islamic Banking: A Study of Halal Ecosystem Regulation in Indonesia. Journal of Finance and Islamic Banking. 2020; 2(2): 165–182. Publisher Full Text\n\nAli Z: Metode Penelitian Hukum. Sinar Grafika. Mataram University Press; 2021. Reference Source\n\nAsep Firmansyah RS: Ministry optimistic of halal ecosystem driving the national economy. ANTARA News. 2022, February 23. 1 Diakses 02 Maret 2023.\n\nAzis MH d M: Pembangunan Ekonomi & Pemberdayaan Masyaakat Strategi Pembangunan Manusia dalam Perspektif Ekonomi Lokal (Edisi Kedu). CV. Nur Lina dan Pustaka Taman Ilmu.2018.\n\nBenuf K, Azhar M: Metodologi Penelitian Hukum sebagai Instrumen Mengurai Permasalahan Hukum Kontemporer. Gema Keadilan. 2020; 7(1): 20–33. Publisher Full Text\n\nBI: Keuangan Inklusif. Bank Indonesia Website. 2018; pp. 1. Accessed April 27, 2024. Reference Source\n\nBrier J, Jayanti LD: Strategi Nasional Pengembangan Industri Halal Indonesia. Komite Nasional keuangan Syariah; 2020; Vol. 21(Issue 1). Reference Source\n\nEfendi J, Ibrahim J:Metode Penelitian Hukum: Normatif dan Empiris (Pertama):Prenadamedia Group;2016.\n\nFawaid MW, Utama YY: Digital Literacy of Sharia Finance in Indonesia With a Quadruple Helix Approach. 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Com. 2020, October 20. 1 Di akses 26 Februari 2021. Reference Source\n\nIndrawan F, Nahartyo E: Analisis Penilaian Kinerja Aktivitas Tanggung Jawab Sosial dengan Metode Pengukuran Kinerja Prism dalam Perspektif Flobal Reporting Initiative (GRI) (Kasus pasa Unit Program Kemitraan dan Bina Lingkungan (PKBL) Suatu BUMN Pelabuhan). ABIS: Accounting and Business Information Systems Journal. 2020; 7(4). Publisher Full Text\n\nKelly D, Holmes A, Hayward R: Partnership Law. Business Law. 2020; 4: 341–366. Publisher Full Text\n\nKemenkeu: Ayo Kenali Pajak bagi pelaku UMKM. Kemenkeu.Go.Id. 2022. Reference Source\n\nKholid M: Prinsip-Prinsip Hukum Ekonomi Syariah Dalam Undang-Undang Perbankan Syariah. Asy-Syari’ah. 2018; 20(2): 145–162. Publisher Full Text\n\nKrisna R, Yusuf M, Putra E: Analysis of the halal ecosystem and halal literacy on the development of Islamic economic halal regulation. Proceeding of International Conference on Business and Economics. 2023; 1(1): 318–336.\n\nMantili R: Model Of Partnership Agreement Between Medium Small Businesses (Smes) And Big Businesses In Realizing Joint Welfare. Sociological Jurisprudence Journal. 2020; 3(1): 28–33. Publisher Full Text\n\nMichael Schaper RB: The Role of Competition Policy in Strengthening the Business Environment for MSMEs in the ASEAN Region.2021 February; pp. 1–45.\n\nNikam RJ: Bespoke Crowdfunding Regulation: A Boost Up to Startups and SMEs in India. Hasanuddin Law Review. 2019; 5(1): 55–76. Publisher Full Text\n\nNugraheni N: Crowdfunding-based fiduciary warrant in providing capital loans for small and medium enterprises. Hasanuddin Law Review. 2020; 6(3): 224–231. Publisher Full Text\n\nOJK: Survei Nasional Literasi dan Inklusi Keuangan 2016. Survei Nasional Literasi Dan Inklusi Keuangan 2019. 2016; 282.\n\nOJK: Siaran Pers Survei Nasional Literasi Dan Inklusi Keuangan Tahun 2022. Otoritas Jasa Keuangan. 2022a November; 10–12.\n\nOJK: Press Release: The 2022 National Financial Literacy and Inclution Survey Number: Sp/82/dhms/ojk/xi/2022. Ojk: Go.Id; 2022b. Reference Source\n\nKeuangan OJ: Hasil Survey Nasional Literasi dan Inklusi Keuangan Tahun 2022.2022.\n\nPermana A: Tantangan Dan Peluang Industri Halal Di Indonesia Dan Dunia. Institut Teknologi Bandung. 2019, March 18; 1. Accessed May 18, 2023.\n\nPrabowo MS, Umami YZ: the Existence of a Company in the Society and Its Legality in Indonesian Law. Journal of Private and Commercial Law. 2018; 2(1): 33–46. Publisher Full Text\n\nPresident Republic of Indonesia Law of the Republic of Indonesia Number 33 Year 2014 on Halal Product Assurance, Pub. L. No. Official Gazette of the Republic of Indonesia Year 2014 Number 295. 2014. Reference Source\n\nStiglitz JE: The Welfare State in the USSR. State and Social Welfare, The. 2021; 205–227. Publisher Full Text\n\nSukoso W, Kusnadi A, Sucipto J: Ekosistem Industri Halal. Departemen Ekonomi dan Keuangan Syariah-Bank Indonesia Pusat Studi Halal Thoyyib-Universitas Brawijaya; 2020.\n\nSuparji: Implementation of Intellectual Property Right to Strengthen Small and Medium-Sized Enterprise Business Capacity in Global Competition. Academic Journal of Interdiciplinary Studies. 2020; 9(6): 139–147. Publisher Full Text\n\nSuparji.: Investment climate for MSMEs towards a green economy. International Journal of Research in Business & Social Science. 2021; 10(6): 153–158. Publisher Full Text\n\nSyamsu K: Produk Halal Indonesia: Mampukah Kekuatan Domestik Memenangkan Persaingan Global?. Pusat Kajian Sains Halal -IPB2023, April 27. Accessed May 18, 2023. Reference Source\n\nTanjung KTP: Penguasaan dan Posisi Taward dalam Perjanjian Kemitraan: Sebuah Diskursus tentang “Penguasaan” dalam Perjanjian Kemitraan. Jurnal Persaingan Usaha. 2022; 2(2): 91–99. Publisher Full Text\n\nWahdiniwaty R, Firmansyah D, Dede SA, et al.: The Concept of Quadruple Helix Collaboration and Quintuple Helix Innovation as Solutions for Post Covid 19 Economic Recovery. MIX: JURNAL ILMIAH MANAJEMEN. 2022; 12(3): 418. Publisher Full Text\n\nWindhyastiti I, Khouroh U, Aristanto E: The Role of Quadruple Helix in Supporting Sustainability of Culinary Business. 7th International Conference of Graduate School Oon Sustainability. 2022; 2009; 10–14." }	[ { "id": "354847", "date": "08 Jan 2025", "name": "Muhammad Anwar Fathoni", "expertise": [ "Reviewer Expertise Islamic economics", "Islamic consumer behavior", "halal industry" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nComments and General Review\nClarity and Focus of Writing: The article covers essential aspects of MSMEs' roles in the halal ecosystem, including legal, governmental policy, and the Quadruple Helix system. However, some sections feel repetitive, particularly regarding challenges and potential MSMEs face in the halal ecosystem. The structure could be improved for better flow, especially in the results and discussion sections, which tend to merge without clear boundaries. Methodology: The normative juridical research approach is appropriate for exploring regulations and policies. However, there is room to elaborate on how the data was analyzed within the research context. The heavy reliance on secondary sources leaves the study lacking primary data, such as interviews or surveys, which could strengthen the arguments. Results and Discussion: The findings clearly highlight MSME challenges, such as access to capital, financial literacy, and halal certification. However, the discussion on solutions, such as the implementation of the Quadruple Helix, lacks depth and practical application. Further elaboration is needed on how the government, academics, industry, and society can collaborate in practical terms to improve MSME competitiveness. References: The references are comprehensive and relevant. However, some parts rely on secondary sources that are general and not specifically tailored to Indonesia's context. The article could benefit from including more recent empirical studies to support the arguments.\n\nTechnical Comments Language and Grammar: The language used is formal and academic, but some sentences are overly long and complex, making it challenging for readers to grasp the main points. There is repetitive use of terms like \"halal ecosystem,\" which could be simplified or diversified.\nSuggestions for Improvement\nSharpen Focus: Reduce repetitive content in sections like the background and discussion. Focus on key points that support the research objectives. Detail Solutions: Provide more in-depth elaboration on the implementation of the Quadruple Helix system and how each element can concretely contribute to MSME development in the halal ecosystem. Conclusion: Strengthen the conclusion with more practical recommendations for stakeholders, especially the government and MSME actors.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "13129", "date": "13 Jan 2025", "name": "Aris Machmud", "role": "Author Response", "response": "Dear Muhammad Anwar Fathoni Thank you for the review and recommendations. Here are the responses to the review results: 1. Clarity and Focus of Research: In this study, we have improved it by dividing it into sub-themes, and we have improved the suggestions and improvements in the revised article. 2. Methodology: in normative legal research, there is no data, except for the method used is empirical juridical, which uses two approaches quantitatively and qualitatively. However, the existing data is only a tool for answering problems. The normative juridical method is different from other social research. The availability of data is the main source of social research. Normative juridical research emphasizes the approach of statutory regulations with primary and secondary legal sources obtained through literature studies. 3. Results and discussion: the involvement of each helix - government, academics, society, and the industrial world - has been explained in the revised article. 4. References: relevant and comprehensive references, the use of a multidisciplinary or interdisciplinary approach can be considered in further research. Best Regard Aris Machmud" } ] }, { "id": "354842", "date": "08 Jan 2025", "name": "Mohamed Syazwan Ab Talib", "expertise": [ "Reviewer Expertise Halal business management" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper provides insights into the role of MSMEs in Indonesia’s halal ecosystem and growth potential. However, it has some notable weaknesses: 1. Methodological Limitations: The study relies exclusively on normative juridical research, which may limit its ability to address practical implications and provide empirical evidence. The absence of primary data (e.g., surveys and interviews) weakens the robustness of the findings and restricts its relevance for stakeholders. 2. Ambiguity in Key Arguments: While the quadruple helix model is emphasized as a solution, the discussion lacks specificity in detailing how each stakeholder—government, academia, industry, and community—can practically collaborate. The paper does not critically assess the feasibility of implementing this model in Indonesia’s socio-economic context. 3. Overgeneralization: The conclusions drawn about the potential of MSMEs are overly optimistic without addressing critical challenges such as inadequate access to financing, the lack of skilled personnel, and the limited impact of existing policies. The absence of a detailed SWOT analysis undermines the paper’s strategic contributions. 4. Insufficient Novelty: Many ideas discussed, such as the importance of financial inclusion and halal certification, are well-established in existing literature. The paper lacks innovative or groundbreaking perspectives to make it stand out in this field. 5. Data Gaps: While the paper mentions statistics (e.g., MSMEs' contributions to GDP), it does not substantiate these with comprehensive or recent data. Additionally, empirical validation or case studies do not support the claim that the quadruple helix system can enhance MSME competitiveness.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13128", "date": "13 Jan 2025", "name": "Aris Machmud", "role": "Author Response", "response": "Dear Mohamed Syazwan Ab Talib Thank you for the review and recommendations. We will then send a revised article. The responses related to the review results: 1. In legal research. The method often used is normative juridical with a statutory regulatory approach. However, it can used nomos and empiricism to become empirical normative juridical. In our research, the methodology used is normative juridical, the use of a multidisciplinary or interdisciplinary approach can be considered in further research. 2. The role of inter-helix in the development of MSMEs a. The role of the government in government policies and regulations in supporting MSMEs is a study of whether the norm is in favor of the development of MSMEs, such as tax regulations where the government provides relief in the form of a one percent tax for MSMEs with a maximum turnover of 4.8 billion per year is enough to help MSMEs. Then President Prabowo's program to relax MSME debt and the regulations of the Ministry of Cooperatives and MSMEs encouraged the development of MSMEs in addition to government policies to collaborate between relevant institutions. b. Academic helix. Its role in developing teaching, research, and community services can provide input to MSMEs to increase their capacity and capabilities in terms of marketing and management innovation so that they can increase their business level so that they can be bankable and gain access to financing from formal financial institutions that can provide capital facilities - because one of the obstacles to unbankable is the limitations in management, one of which is marketing and financial management including the preparation of MSME financial reports and assistance with financial and tax audits. c. The helix of the industrial world is through mutually beneficial assistance and collaboration - in terms of accommodating and marketing MSME products. d. The role of the community or society. The community in the halal product ecosystem produced by MSMEs is making goods produced by MSMEs a choice in meeting their life needs because their role is very crucial in supporting the development of MSMEs in Indonesia. That the role of each helix will be in vain if there is no close relationship and mutual support together. 3. Regarding overgeneralization. In the case of MSMEs, there are several constraints in terms of capacity and capability so that the involvement of the four helixes (Quadruple helix) is a solution and not a fantasy and relying on pessimistic conditions that occur, many efforts have been made by various stakeholders to bridge the gap in MSMEs. 4. The novelty in this study is that the quadruple helix system can be a solution to increasing the capacity and capability of MSMEs in the global halal industry. 5. Data gap. We realize that normative legal research does not recognize data but relies more on primary and secondary legal sources to answer existing problems, but in social research, data sources are primary Best Regard Aris Machmud" } ] } ]	2	https://f1000research.com/articles/13-722
https://f1000research.com/articles/14-120/v1	22 Jan 25	{ "type": "Systematic Review", "title": "A Social Constructionist Influenced Scoping Review of Addictions, Deviance and Crime: Biopsychosocial Perspectives for the Emerging Forensic Mental Health Nursing and Healthcare Services of the Middle East", "authors": [ "Richard Mottershead", "Muhammad Arsyad Subu", "Mustafa Habeb", "Nafi Alonaizi", "Wegdan Bani-Issa", "Jacqueline Maria Dias", "Fatma Refaat Ahmed", "Mini Sara Abraham", "Sadeq AL-Fayyadh", "Ruwaya Khalfan Saif Almesafri", "Ali Alhaiti", "Khalid Awad Al-kubaisi", "Conrad Murendo", "Mohammed Al-Jabri", "John Hall", "Ghada Shahrour", "Chloe Harrison", "Muhammad Arsyad Subu", "Mustafa Habeb", "Nafi Alonaizi", "Wegdan Bani-Issa", "Jacqueline Maria Dias", "Fatma Refaat Ahmed", "Mini Sara Abraham", "Sadeq AL-Fayyadh", "Ruwaya Khalfan Saif Almesafri", "Ali Alhaiti", "Khalid Awad Al-kubaisi", "Conrad Murendo", "Mohammed Al-Jabri", "John Hall", "Ghada Shahrour", "Chloe Harrison" ], "abstract": "Background Nurses and healthcare professionals employed in correctional and forensic mental health settings encounter unique challenges in the care of their patients due to custodial and restrictive environments. Regions within the Middle East, such as the United Arab Emirates and the Kingdom of Saudi Arabia, have recently experienced exponential economic and healthcare infrastructure development. Mental health has been prioritized for development by recent legislation and practice that incorporate the development of specialist forensic psychiatry services that mediate the need for specialized nurses and allied healthcare staff. Traditionally, forensic care has been provided by general services. The need to progress specialist forensic services with a focus on multidisciplinary staff that seeks to develop safer communities, enhance care, and support the criminal justice system.\n\nMethods This review article aims to provide a foundation for the nuances of forensic staff through social constructionism. We adopted the framework of Arksey and O’Malley (2005). The use of a scoping review provides a better understanding of the compatibility, content, and outcomes to position the reader to the theoretical construct that society can be seen as existing in both objective and subjective reality.\n\nDiscussion This paper argues for the preparedness of thought understood through social constructionism and demonstrates that it is envisaged that any frequently repeated action becomes cast into a pattern that can be reproduced without much effort. The interconnectedness between the themes of addiction, deviance, and crime allows for a holistic overview and improved understanding for care providers and this was achieved through bio-psychosocial model.\n\nConclusion Through the emergence of these complex forms of knowledge, deviance within the lives of patients can be better understood by the emerging professions employed in the emerging forensic healthcare services within the Middle East. These individuals are carefully and dutifully navigating the cultural complexities of mental illness, addictions, and associated deviant behavior.", "keywords": [ "Forensic mental health", "scoping review", "social construction", "deviance", "addiction", "crime", "biopsychosocial", "Middle East" ], "content": "Introduction\n\nThe relationship between mental health and crime has been prioritized by the WHO (2020) as a necessity to safeguard the mental health of offenders. As a theoretical and conceptual starting point, Crotty’s (1998) research stipulates that the experience of society as a subjective reality is achieved through a primary and secondary process of socialization. By adopting this approach, this study explores addiction and deviance as encountered by patients needing forensic mental health care within the Middle East region. Burr (2003) stipulated that an individual’s identity stems not from inside the person but from the social realm in which they inhabit. In this method, the study will seek to extend the findings of Berger and Luckmann’s (1991) work on socialization in that the processes are enacted upon patients through significant others such as nurses who mediate the objective reality of society, rendering it meaningful; in this way, it is internalized by the individuals (patients). Atkinson (1998) advocates that understanding an individual’s life story can create meaning, which is crucially important for generic healthcare staff who may work in forensic settings within the region. The nation is multicultural, and has a diverse range of languages. Burr (2003) highlighted that language can hold inherent challenges for social constructionism in the accurate transmission of an individual’s thoughts and feelings, but its strength lies in the interpretation of thought in constructing concepts. This paper will demonstrate the importance of developing knowledge about forensic staff, and pertinent issues and concepts that can preempt the development needs of this service within the Middle Eastern region. The authors attempted to provide a means by which knowledge can be explored and realized by nurses and healthcare staff by structuring the way the world is experienced by patients they encounter within forensic settings and how they may then reflect on deviance and addiction. The study extrapolates the ethos of the biopsychosocial model (Engel, 1977) to explore the phenomena of addictions, substance misuse issues, deviance, and criminality in order to create a holistic understanding. In contrast to the medical model, the bio-psychosocial model of health care (Engel, 1977) focuses on the patients as ‘experts’ of their own conditions and in the management of their lifestyles (Carel, 2008). This is particularly important for nurses in forensic settings in the Middle East, who, because of cultural and religious backgrounds, may have little or no understanding of the nuanced lived experiences of patients with criminality and substance misuse needs. Furthermore, it is important to formulate a plan of care for these individuals to support their rehabilitation, recovery, and custodial discharge.\n\n\nMethods\n\nThis study undertakes a scoping review of the relevant literature that allows for an exploration of mental health and crime that seeks to support the emergence of forensic mental health as a necessity to safeguard the mental health of offenders and to prioritize the needs of the multidisciplinary teams entrusted to progress forensic mental health in the Middle East.\n\nArksey and O’Malley (2005) advocate the use of scoping reviews. These authors advocate the use of a scoping review to highlight the need to address broader topics where many different study designs might be applicable and whether there is a challenge in identifying a clear question. Additionally, Arksey and O’Malley (2005) explain that, whereas literature and systematic reviews are predominantly concerned with providing answers to questions from a relatively narrow range of quality-assessed studies, scoping reviews are less inclined to seek to address a specific research question or, consequently, to assess the quality of included studies.\n\nThis research strategy of adopting a scoping review, rather than a systematic review, allowed the authors to adopt an evidence-based approach when sourcing relevant studies that allowed for a philosophical exploration with recommendations. Arksey and O’Malley (2005) advocate that an inclusive approach should be adopted. This allowed the authors to review qualitative, quantitative, and randomized control trials within the scoping review. However, it became apparent that there was a challenge in sourcing a breadth of material from the Middle East, so grey literature, theory, or perspectives that may behave relevance to the understanding of the selected topic were applied. Table 1 provides the tabular format for the study’s adherence to this framework.\n\nThe co-authors were selected as they are embedded within relevant clinical and educational positions within the region or have specialised professional backgrounds that can add insight into this study’s explorative approach. The authors wished to create an understanding for addictions, deviance, and crime with the inclusion of both historical and contemporary literature. This was formulated as the use of the biopsychosocial model to focus on the findings of the scoping review. This allowed the authors to nurture perspectives and triangulate relevance to the cultural nuances of addiction, crime, and subsequent needs of forensic mental health within the Middle East and North Africa (MENA) region. Therefore, the authors needed to extrapolate and justify a continuation and strengthening of the new paradigm shift to offer evidence for the need to develop forensic healthcare services and strategies within the region.\n\nTypes of sources\n\nThis scoping review considered quantitative, qualitative, and mixed-method study designs for inclusion. Documents published from the inception of the database to the present were included. If search parameters were allowed, literature and studies from 1850 to the present were included to allow for the inclusion of seminal literature. Sources were eligible only if the full text was available (e.g., documents available only as abstracts were excluded). Only sources available in English were considered for inclusion because of the limited literature on forensic mental health in the region.\n\nFollowing the search, all retrieved sources were entered into the reference management software EndNote v.8 (Clarivate Analytics, PA, USA), and duplicate references were removed. Two reviewers independently reviewed the titles and abstracts of all the citations against the inclusion criteria to determine the relevance of the study. If the relevance of a study is unclear in the abstract, then the full article will be reviewed. The full articles of the selected studies will be reviewed independently against the inclusion criteria by two reviewers. The reasons for exclusion of full-text papers that do not meet the inclusion criteria will be recorded and reported in the scoping review. Any disagreements between the reviewers at each stage of the selection process will be resolved through discussion or by a third reviewer.\n\nThis research strategy adopted the scoping review by Arksey and O’Malley (2005). This scoping review model supports an inclusive approach that allows for both sourced literature and insights from the authors. This allowed the authors to review qualitative, quantitative, and randomized control trials within the scoping review and assess their relevance to the cultural and societal needs of the region. This was of benefit, as there was a challenge in sourcing seminal work on forensic mental health within the region, and contextualizing the subject matter with reference to the historical text on addictions, crime, and deviance was the approach adopted to create an understanding of the nursing and healthcare workforce.\n\nThe author’s rationale for conducting a scoping review was to provide a methodology for determining the state of the evidence on the selected topic, which is especially useful when issues require clarification before further empirical studies can be undertaken. Therefore, the purpose of this study is to adopt Arskey and O’Malley’s scoping review methodology to explore addiction and deviance through a holistic overview of the biopsychosocial approach.\n\n1. What is the extent and nature of published literature that will assist in a biopsychosocial overview of addiction and deviance that will empower a dialogue of the emerging forensic mental health services of the Middle East.\n\nThis review paper was conducted to aid in the ongoing dialogue for policy makers to consider when seeking to enhance forensic client-centered frameworks and to examine the training needs of an emerging specialized service focusing on the juxtaposing interplay between mental health and criminology.\n\n\nMethodological frameworks: Creating a perspective\n\nConstructionism in this study refers to two forms of understanding: the meaning-making activity of the individual mind, and the collective generation and transmission of meaning in society, as described by Crotty (1998). Crotty’s interpretation was chosen, as he claims that meanings are constructed by human beings as they participate in the world they are interpreting (Crotty 1998). This approach to social constructionism is based on the studies of Berger and Luckmann (1966), in which all knowledge is socially constructed, including our knowledge of what is real. The landmark contribution to social constructionism by Berger and Luckmann was recognized through their work within The Social Construction of Reality (Crotty 1998). This epistemological approach was first attached to the work of Immanuel Kant (Crotty 1998) and this understanding of social constructionism was utilized by notable sociologists of the Chicago Tradition, such as Mead (1934). The authors adopt Crotty’s approach, evident in his earlier work, as it explains that social constructionism creates an awareness that humans (patients) in some respects construct the reality they perceive (1998). This is important to this study, which seeks to create an understanding of the lived experiences of patients within forensic services and how they may interpret their world and, consequently, how their nurses can create meaning about that reality. Therefore, a constructionist approach asserts that concepts are constructed rather than discovered and argues that they correspond to a reality within society (Hammersley, 1992). Berger and Luckmann (1991) highlight the subtle realism that reality is socially defined but that this reality relates to the subjective experience of individuals’ interactions with ordinary life and how they make meaning of the world rather than to the objective reality of the natural world. This is of crucial importance for the emerging health and social care forensic workforce in the Middle East to explore perceptions of the offending behavior of patients. Articulating this concern, Steedman (2000) believes that the very nature of being human and our attempts to come to an understanding of what this means provide the essence of our need to pursue knowledge, as opposed to scientific inquiry. This paper adopts social constructionism into its exploration, as there is a need for nurses and healthcare staff within the forensic settings within the identified region to understand deviance and addictions and how their patients define their reality and how they perceive it. Therefore, this article is concerned with the nature and construction of knowledge on the issue of addiction, its relationship with deviance, and how this emerging knowledge can have significance for forensic services in the MENA region.\n\nSteedman (2000) emphasized that social constructionism is not concerned with ontological questions or questions of causation. This study argues that both forms of understanding are relevant and necessary for nurses and healthcare staff, as their patients’ experiences can be seen as constructions of an individual nature and constructions that have arisen from engrained political, cultural, and societal influences that have impacted their lives and influenced maladaptive behavior. Consequently, it creates addiction and the presence of deviance and crime as either a causality or a subsequent feature within the lives of patients. Lincoln (2005) argues that constructionism focuses on the fact that humans are social beings who interact with two realities: a physical and temporal reality and an enacted and constructed reality. In reference to forensic patients identified as addicts and deviants, these definitions suggest that their experiences can be understood on at least two levels by their nurses and the multidisciplinary team. Firstly, at the physical and temporal level of reality, the ‘addict’ is an ontological reality that impacts significantly on the patients experience of society (Klotz, 2004). In relation to Lincoln’s (2005) first reality, Lantman-De Valk, Metsemakers, Haveman, and Crebolder (2000) indicated that an awareness of their lives can be constructed by gaining knowledge of how they are shaped by their substance misuse experiences, which sets them apart or identifies them as different from the rest of a society in which these practices are not accepted or tolerated by the population. Lincoln (2005) explains that these factors (addiction and substance misuse) in a patient’s life may prove challenging to explain solely in a socially, culturally, and politically constructed term. Therefore, Lincoln’s (2005) second reality is relevant to this study as it explores the enacted and constructed level of reality that patients within forensic settings experience and become part of a social categorization system that is based on dichotomies of identity, before their addiction, and importantly for recovery and discharge, after their illicit substance misuse. This is supported by Gallagher (2002), who articulates the point that constructions are socially, culturally, and politically embedded, and can change in different contexts and at a given historical moment. This will be evidenced and explored further within the discussion section on causality and the relationship between addiction, deviance, and crime. Crotty (1998) urges caution in that constructionism should be used to reify people (patients) as objects by their offending behavior, as would be the case in the lives of patients. Instead, nurses and healthcare staff may need to consider that reality may exist beyond the way that an individual (addict) makes sense of the ways that they actually are. In creating an awareness of this through Lincoln’s (2005) belief that constructionism can create a focus on the two realities that the patient (addict) within the study provides an insight into these realities. This is an important feature to be explored in the subsequent sections.\n\nCrotty (1998) stipulates that the experience of society as a subjective reality is achieved through a primary and secondary process of socialization. By adopting this approach, this paper explores the identity of addicts and deviants as constructed by society. Burr (2003) stipulated that an individual’s identity stems not from inside the person but from the social realm in which they inhabit. This is important for this study, which examines societal perceptions of the addict engaged in deviance and crime and how understanding can be created through this methodological process for multidisciplinary professions within the Middle East.\n\nIn this approach, the study will seek to extend the findings of Berger and Luckmann’s (1991) work on socialization in that the processes are enacted upon the patients through significant others who mediate the objective reality of society, rendering it meaningful and in this way internalized by patients with addictions and substance misuse issues. According to Plummer (2001), this point is stressed in that the observers (nurses and wider healthcare practitioners) provide guidance; it is the patient’s voice that determines the frame of reference for their story and the interactions between the individual and social world. For a culturally diverse multidisciplinary workforce, there is a need to conceptualize the relationship and understanding between criminality, deviance, and addiction through a conceptually understood model to improve their skill set and understanding of forensic care needs within the MENA region.\n\n\nDiscussion – Biopsychosocial Approach: Understanding Criminality, Deviance and Addictions\n\nTo perpetuate understanding, this paper continues with a deliberation on why individuals appear to be drawn into a criminal act with the presence of addictions and substance misuse as causality. The authors will explore the causes of criminal behavior and relate these to the literature on offending and the relationship with addictions and substance misuse. Within the available literature, the causes of criminal behavior are systematically divided into biological, psychological, cognitive, socio-economic, and political explanations. In addition to these fields, the authors believed that there was a need to integrate criminogenic factors into a holistic overview prior to exploring the relationship between addiction, deviance, and crime from the theory and practice relevant to the care of patients within forensic services.\n\nConklin (1995) proposed that offenders differ from non-offenders at a physiological and anatomical level, and therefore attribute crime to individual traits and factors. Indeed, this is relevant to patients with a pre-existing tendency towards criminal activity prior to addiction, and substance misuse becomes a feature within their lives. There are a number of early theories, such as Lombroso’s theory of atavism (1911) and Conklin’s (1995) theory of somatotypes, that held that criminals were of a substandard breed, far removed from law-abiding members of the public because of hereditary or genetic defective composition inclusive of a propensity towards addictions and substance misuse behaviors.\n\nThere has been some progression from these early theories and an inclination to not just categorize individuals as inherently substandard but rather to look for intraindividual causes of criminal behavior and addictions. Barlow and Durand (2005) reviewed research on family, twin, and adoption studies and suggested that there was a genetic influence on criminal behavior, but that the combination of gene-environmental interaction was more plausible, as genetic factors only influenced crime causation in the presence of certain environmental influences such as addiction and substance misuse. Barlow and Durand (2005) theorized that individuals showing abnormally low levels (under-arousal hypothesis) of cortical arousal might cause individuals to engage in stimulation-seeking behaviors such as gambling or substance misuse in order to reduce perceived boredom. Bird (2007) explains that many individuals who engage in inappropriate behavior, which leads them to contact the judicial system, appear to have a natural inclination towards risk-taking behavior. Barlow and Durand (2005) proposed the fearlessness hypothesis, which holds that individuals diagnosed with personality disorders often have difficulty associating certain cues or signs with impending punishment or danger, thereby preventing them from developing an adequate capacity for impulse control. This can be a feature within the profile of patients being cared for within forensic services with addictions and substance misuse issues.\n\nFurthermore, Conklin (1995) highlighted the fact that within the research offenders appear to have lower levels of monoamine oxidase, which in turn has been linked to extreme impulsivity, sensation seeking, childhood hyperactivity, poor academic performance, and high rates of alcohol and substance misuse, all of which are linked to criminality. Within the female offending population, a study by Conklin (1995) found that the criminal activity was more likely to occur during the four days before and four days during the menstruation cycle. Nurses’ and healthcare practitioners’ awareness of these biological factors will assist in enhancing care provision and support holistic care when examined in collaboration with psychological and cognitive causes.\n\nDrake et al. (2010) highlight that psychological explanations have to some extent replaced biological explanations of criminality during and after the 20th century. They believe that the current overview of those engaged in deviant behavior associated with substance misuse as being psychologically unbalanced has brought about the present philosophical shift in rehabilitation through the use of talking therapies. Brookman et al. (2010) discuss this progression towards psychological explanations linked to the emergence of the psychoanalytical perspective, that is, that individuals are regarded as antisocial by nature and therefore in need of socialization to avoid further addiction and substance misuse behavior. From a psychoanalytical perspective, Becker (1963) believes that deviance and unlawful behavior, such as the use of illegal substances, can be viewed as a result of faulty or inadequate socialization, which could be solved through psychological treatment rather than direct involvement of the judicial system, which could be viewed as an agent of social control, albeit provided to ensure the immediate safety of society.\n\nIn the past, psychological causes of deviance and criminal behavior were believed to be located intra-individually in the form of defective development, low intelligence, and psychopathology and were therefore seen as unrelated to the individual’s environment. Researchers such as Hudson (1996) and Steinberg (2001) noted that the psychological effects of interindividual factors such as themes noted within this study of unemployment, poverty, one-parent family, sexual abuse, child hood abuse and neglect, childhood violence, and dysfunctional family relations were possible causes of criminogenic factors associated with substance issues within life stories. Hernstein and Murray (1994) suggested that this change in the view of the possible reasons for psychological causes of crime has led to the development of mental deficiency theory.\n\nThe mental deficiency theory identifies offenders as having a generally lower intelligence quotient and, as a result, they are unable to appreciate the reasons for the existence of the law and the consequences of their actions, or are unable or unwilling to control their actions (Conklin, 1995). Similarly, this theory has drawn criticism by Cullen (1994), who found that the effects of intelligence on deviance and crime were insignificant and further criticized the mental deficiency theory for completely ignoring white-collar crime. However, Hirschi’s control theory (Hirschi, 2002) supports the belief that psychological factors cannot be viewed as isolated from interpersonal factors. Hirschi’s control theory supports evidence that suggests that individuals who engage in illicit use of alcohol and drugs lack intimate attachments, aspirations, and moral beliefs that connect law-abiding individuals to a conventional way of life (2002).\n\nSpecifically relevant to this research is the suggestion by Conklin (1995) that involvement in addictions and substance misuse can create a social stigma that weakens social bonds. This is highly relevant within the Middle East, where criminal activity, addiction, and substance misuse will have stigma and associated shame for perpetrators. In addition, Hirchi’s control theory (Conklin, 1995) maintains that maladaptive peer relationships in childhood are linked to later deviance, and this study suggests links to the use of substances leading to criminality.\n\nResearchers have not yet demonstrated conclusive evidence linking personality characteristics to criminal behavior, despite the fact that a great number of studies have initially shown tenuous links to various traits (Conklin, 1995). Tittle (1985) maintains that various conditions, such as coming from a single parent family, having a diagnosis of a personality disorder, and being susceptible to peer pressure, may result in interpersonal insecurity, which may predispose an individual to deviant and criminal activity. Conklin (1995) explains that there has long been an identified link between criminal behavior and traits such as a low frustration threshold, high levels of aggression, and an inability to delay gratification. Research undertaken by Barlow and Durand (2005) adds that impulsivity, defiance, resentment, absence of feelings of remorse or guilt, indifference to the concerns of others, inability to establish and maintain close interpersonal traits, and inability to learn from experience are the typical traits of psychopathic personality disorder. Furthermore, Barlow and Durand (2005) claimed that many individuals with a personality disorder are at significantly elevated levels of risk for criminal behaviors, such as associations with drug use. These researchers suggest that the difference between individuals diagnosed with personality disorder who become criminals and those who do not is intelligence. Carson et al. (1998) highlight research on differences in the quality of socialization in non-offenders, first offenders, and repeat offenders, finding that repeat offenders are the most poorly socialized. Related to this issue is Rubington and Weinberg’s (2015) proposition that the development of a deviant personality is influenced by the response of others to the alleged deviant act. The authors of this article theorize that depending on the identity of the persons responding, approval and disapproval of the act may either facilitate or inhibit the development of the deviant personality as a function of inclusion in or exclusion from a substance user or group associated with addiction. The authors urge awareness that stigma and shame emanating from a deviant or criminal behavior associated with illegal substances could provide a “family,” with a community based on shared beliefs, experiences, and support socializing albeit that the actions maybe deviant in nature and against the rules imposed by society. This factor means that detecting and diverting individuals with addiction and substance misuse behaviors away from judicial and forensic services could become problematic. One solution could be patients undertaking corrective actions through restorative actions found within peer support that utilizes shared experiences. Campbell and Leaver (2003) state that peer support between individuals can help them be more empowered against the distractions caused by stress and coping with substance abuse. This was similar to a feature within the lead authors’ earlier research on the benefits of peer support with those of a shared identity and life experiences (Mottershead, 2022; Mottershead & Ghisoni, 2021; Mottershead & Alonaizi, 2021, 2023; Mottershead et al. 2023).\n\nIn the 1970s, Yochelson and Samenow (1976) identified criminal thought patterns that were supposedly responsible for criminal behavior, and this research was similar to the work undertaken by Walters and White (1988), who claimed that faulty and irrational thinking characterizes lifestyle criminals. Barlow and Durand (2005) believed that individuals with mental disorders such as substance misuse or addiction could process reward and punishment differently from individuals without this diagnosis in that they are less likely to be deterred from a goal due to the lack of reward or the likelihood of punishment. These researchers believed that by utilizing Gray’s model of brain functioning, it was possible to stipulate that individuals with a mental deficiency could have genetically inherited weak behavior inhibition systems and overactive reward systems (Barlow and Durand, 2005). This explanation, if assimilated by the emerging forensic workforce, aids in explaining why individuals become engaged in addiction and substance misuse, leading to criminality.\n\nIn exploring social structures as a cause of criminal behavior, Merton (1968) created his theory of anomie, which suggested that normlessness occurs when social structures prevent individuals from reaching culturally approved goals through institutionalized means; consequently, the individual may resort to violations of the law to reach their goals, which society they consider desirable.\n\nAgnew (1995) developed a general strain theory that holds that there are various sources of strain that cause crime. Agnew proposed the actual or anticipated failure to achieve positively valued goals, actual or anticipated removal of positively valued stimuli, and actual or anticipated presentation of negative stimuli. Therefore, this may be seen as three measures of strain that may cause criminal behavior depending on the magnitude, recency, duration, and clustering of stressful events. Agnew (1995) believed that the impact of strain is influenced by individual adaptability, as well as factors such as temperament, intelligence, interpersonal skills, self-efficacy, association with delinquent peers, and conventional social support. Agnew’s (1995) theory is of specific value to understanding the relatedness of addictions, deviance, and crime as it provides an opportunity to explore the factors underlying addict perpetrator crime. It is hypothesized that the strains of ‘actual or anticipated removal of positively valued stimuli’ (e.g., social standing) and ‘actual or anticipated presentation of negative stimuli’ (e.g., addicts and drug users). This strain experienced by patients in forensic services may precipitate a link between crimes committed by those with addiction and substance misuse needs.\n\nCarson et al. (1998) state that historically, societies that experience periods of extensive unemployment have observed an increase in crime. Conklin (1995) believed that there was a complex connection between unemployment and crime, as some crimes could only occur as a result of opportunities found while in employment, whereas others occur because of being unemployed. The current global downturn may contribute to crimes committed due to addiction and substance misuse and may be an indicator of risk assessments that clinical practitioners may observe within forensic services. This feature mirrors research undertaken by Conklin (1995), who explains that steady employment tends to give people a stake in society in which they do not wish to jeopardize by committing crimes. Conklin (1995) theorized that relative deprivation is an important issue in the causation of crime. As Conklin (1995) states, resentment of poverty is more common among the poor in wealthy nations than among people in poor nations. Therefore, it is the perception of an unfair distribution of wealth rather than a person’s actual level of poverty that can violate the law.\n\nThis early work by Glaser (1956) provides further insight in explaining that although an individual may initially violate a law by chance or out of ignorance, the social labelling, devaluing, and stigmatization of the individual may cause the deviant aspects of the individual’s behavior to be overemphasized. Nurses and healthcare workers within the Middle East’s forensic services need to be aware of this overemphasis, as it may cause changes in the patient’s self-concept, leading to feelings of unworthiness and hostility towards others in society. A consequence of the labelling may be the attributing factor that observed continued criminal behavior for the addict/substance misuser, associated with a subculture of labelled individuals, and a limitation of opportunities for success through the perceived short-term misplaced benefits of crime. Based on the work of Werdmolder (1997), it is possible to ascertain that for those patients that healthcare workers in the Middle East may encounter, feelings of rejection may be an indication that they have less ties to conventional institutions and that this marginalization could lead to increasingly inadequate socialization as the label of addicts and substance abusers become engrained within their self-image.\n\n\nConclusion\n\nThe study’s research question was reached through the adoption of a scoping review and constructionist epistemology to create an understanding of addictions and substance misusers’ experiences and relationships with deviance and crime. The authors argue that a general theory on the relatedness of deviance, crime, addiction, and substance misuse is problematic, as there is considerable variation in both human behavior and the environment to expect one theory to be applicable in all instances and across multiple cultures. However, the authors also contend that it is indeed possible to construct a general theory on the causation of this interrelatedness for the training of nurses and healthcare practitioners, as different phenomena relating to the relationship may be included within a theoretical commonality, so that what appears to be different causes may be expressions of a common casual relatable theme. This study articulates that the relationship between deviance, crime, and addiction should not be simplified into mere casual observations. Rather, the development of a conceptual framework for the rehabilitation of this offender group with significant health needs should be based on the formulated theory for the betterment of patients receiving care. The societal needs underlying criminal behavior related to addictions must also be fully understood to ensure that they are met in rehabilitation and, ultimately, prevention. The study explored the theoretical causality of deviance and crime as it relates to addictions, taking inspiration from the biopsychosocial model (Engel, 1977) which considered all the factors that contribute to illness, rather than giving primacy to biological factors alone, which will enhance the healthcare workforce’s ability to understand the patients’ experiences of disrupted well-being, as it relates to addictions. These findings assist in developing a further understanding of challenging subgroups within the region. If patients (offenders) with addiction and substance misuse needs are respected as even partially competent agents of their own lives when they afford adequate access to information and resources, it becomes possible to provide a framework in which they can consider their personal and social reasons for acting unlawfully and assist in finding ways to overcome their forensic healthcare needs and eventually contribute positively to society.\n\n\nAuthors contribution\n\nRM Conceptualisation, all authors writing, editing.", "appendix": "Data availability statement\n\nNo data is associated with this article.\n\n\nAcknowledgements\n\nThe research team wishes to acknowledge the forensic multidisciplinary teams working at pathfinders within this developing service, and to raise awareness of their positive contributions to providing care and recovery within these services.\n\n\nReferences\n\nAgnew R: Crime and public policy: putting theory to work. Boulder: Westview; 1995; 43–70.\n\nArksey H, O’Malley L: Scoping Studies: Towards a Methodological Framework. Int. J. Soc. Res. Methodol. 2005; 8(1): 19–32. Publisher Full Text\n\nAtkinson RG: The Life Story Interview: Qualitative Research Methods. Thousand Oaks, California: Sage Publication; 1998.\n\nBarlow DH, Durand VM: Abnormal Psychology: An Integrated Approach. 4th ed.Southbank: Victoria; 2005.\n\nBecker H: Outsiders: Studies in the Sociology of Deviance. New York: Macmillian; 1963.\n\nBerger P, Luckmann T: The social construction of reality: a treatise in the sociology of knowledge. New York: Doubleday & Co; 1966.\n\nBerger P, Luckmann T: The social construction of reality. London: Penguin Books; 1991.\n\nBird S: Compulsory Drugs Testing in the British Army: Assessing the data. RUSI J. 2007; 152(6): 54–59. 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Connecticut: Dushkin/McGraw-Hill; 1994.\n\nDrake D, Muncie J, Westmarland L: Criminal Justice: Local and Global. London: Willan Publishing; 2010.\n\nEngel GL: The need for a new medical model: A challenge for biomedicine. Science. 1977; 196(4286): 129–136. PubMed Abstract \| Publisher Full Text\n\nGallagher E: Adult clients with mental health issues: rethinking our assumptions. J. Fam. Ther. 2002; 23(4): 202–210.\n\nGlaser D: Criminalality theories and behaviour image. Am. J. Sociol. 1956; 61: 433–444.\n\nHammersley M: What’s Wrong with Ethnography? London: Routledge; 1992.\n\nHernstein RJ, Murray C: The bell curve: The reshaping of American life by difference in intelligence. New York: The Free Press; 1994.\n\nHirschi T: Causes of delinquency. New Brunswick, N.J.: Transaction Publishers; 2002.\n\nHudson BA: Understanding Justice: An introduction to ideas, perspectives and controversies in modern penal theory. Buckinghamshire: Open University; 1996.\n\nKlotz J: Sociocultural study of disability: moving beyond labelling and social constructionist perspectives. Br. J. Disabil. 2004; 32(2): 93–104. Publisher Full Text\n\nLantman-De Valk H, Metsemakers J, Haveman M, et al.: Health problems in people with disabilities in general practice: a comparative study. Fam. Pract. 2000; 17(5): 405–407. PubMed Abstract \| Publisher Full Text\n\nLombroso C: Crime, its causes and remedies. Brown Publishers; 1911.\n\nLincoln Y: Constructivism as a theoretical and interpretive stance. Introduction to the philosophies of research and criticism in education and the social sciences. New Jersey: Pearson Merrill Prentice Hall; 2005; 60–65.\n\nMead H: Mind, Self and Society. Chicago: University of Chicago Press; 1934.\n\nMerton RK: Social Theory and Social Structure. New York: Free Press; 1968.\n\nMottershead R: The social prescribing of psychosocial interventions in the treatment of addictions and substance use disorders with military veterans: a reclamation of identity and belonging. F1000Res. 2022; 11: 944. [version 2; peer review: 2 approved]. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMottershead RM, Dias JB, Issa W, et al.: Life Story Research: Methods, Theory and Analysis in Exploring Addictions and Substance Misuse with Military Veterans Exposed to. J. Drug Alcohol Res. 2023; 12: 1.\n\nMottershead R, Ghisoni M: Horticultural therapy, nutrition and post-traumatic stress disorder in post-military veterans: developing non-pharmaceutical interventions to complement existing therapeutic approaches. F1000Res. 2021; 10: 885. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMottershead R, Alonaizi N: A narrative inquiry into the resettlement of armed forces personnel in the Arabian Gulf: a model for successful transition and positive mental well-being. F1000Res. 2021 Dec 16; 10: 1290. Publisher Full Text\n\nMottershead R, Alonaizi N: Empowering social prescribing and peer support: A proposed therapeutic alliance against addictions and substance misuse within the middle east. J. Drug Alcohol Res. 2023; 11. Publisher Full Text\n\nPlummer K: Documents of Life 2: An invitation to a Critical Humanism. Sage Publication; 2001.\n\nRubington E, Weinberg M: Deviance: The interactionist perspective. Routledge; 2015.\n\nSteedman P: On the relations between seeing, interpreting and knowing, research and reflexivity. London: Sage; 2000; 53–62.\n\nSteinberg J: Crime wave: The underworld and its foes. Johannesburg: Witwatersand University; 2001.\n\nTittle CR: The assumption that general theories are not possible. Connecticut: Dushkin/McGraw-Hill; 1985.\n\nWalters GD, White TW: Crime, popular mythology, and personal responsibility. Fed. Probat. 1988; 52: 18.\n\nWerdmolder H: A generation adrift: an ethnology of a criminal Moroccan gang in the Netherlands. The Hague: Kluner Law International; 1997.\n\nWho.int: Mental Health and Prisons.2020 [cited 20th May 2024]. Reference Source\n\nYochelson S, Samenow SE: The criminal personality Vol 1: A profile for change. N.Y. Jason Aronson; 1976." }	[ { "id": "361963", "date": "05 Feb 2025", "name": "Keith Ford", "expertise": [ "Reviewer Expertise Mental health nursing." ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a thorough and comprehensive study addressing a very important and pertinent area of mental health.\nThe scoping was sufficient and addresses the research question well. The methodology is clearly stated and is replicable for future studies if required and the conclusion draws the together findings nicely.\nOverall an important contribution to the body of knowledge.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes", "responses": [] } ]	1	https://f1000research.com/articles/14-120
https://f1000research.com/articles/13-1442/v1	28 Nov 24	{ "type": "Research Article", "title": "Impact of chlorine dioxide and chlorhexidine mouthwashes on friction and surface roughness of orthodontic stainless steel wires: an in-vitro comparative study", "authors": [ "Shivani Apte", "Divya S", "Arun S Urala", "Shivani Apte", "Arun S Urala" ], "abstract": "Objectives Good oral hygiene measures are important for successful orthodontic treatment. They involve various types of mouthwashes which have been reported to cause alteration of mechanical properties of archwires. This study aimed to evaluate the effects of a new kind of chlorine-dioxide-containing mouthwash on the mechanical properties and surface morphology of stainless steel orthodontic archwires against the already prevalent chlorhexidine mouthwash in the market.\n\nMethod Group A – Chlorhexidine mouthwash 0.2% (study), Group B – Chlorine Dioxide mouthwash (study), and Group C – Artificial Saliva (control). 42 specimens of 5 cm long 19x25 inch SS archwires were immersed in each group equally. Post immersion, the frictional force was analyzed in the universal testing machine for each group using custom-made acrylic jigs for 10 specimens. The remaining 4 specimens from each group were sent for surface morphology evaluation using an atomic force microscope.\n\nResults Friction resistance evaluation for the archwires revealed a mean friction of 0.011 ± 0.0056 in Group A, 0.015 ± 0.0052 in Group B, and 0.010 ± 0.0067 in Group C. Results suggested that the static friction of Group C (control group) was found to be the least when compared with the experimental groups, although not producing statistically significant values. Surface roughness of archwires compared at a 10μm range revealed a mean roughness of 19.38 ± 0.82 in Group A, 25.39 ± 7.01 in Group B, and 16.65 ± 3.07 in Group C which shows there wasn’t any statistically significant difference in the mean roughness midst the three sets.\n\nConclusion Chlorine dioxide and Chlorhexidine mouthwashes caused an increase in the frictional resistance of the archwires when compared to the control group. This increase was statistically insignificant. When measured at a range of 10μm the mean surface roughness did not statistically differ across the control and the experimental groups.", "keywords": [ "Mouthwash", "In-Vitro study", "Orthodontics", "Archwires", "Frictional resistance", "Surface characteristics" ], "content": "Introduction\n\nOrthodontic treatment is the use of dental archwires and attachments to move teeth. Because the appliances can be found in the mouth and subjected to changed biological circumstances, orthodontic patients are more susceptible to gingivitis and enamel decalcification; thus, mouthwash application in addition to brushing is crucial to avoid these possible consequences.\n\nMouthwashes contain active agents that have been used as an adjunct to maintaining oral hygiene in patients undergoing fixed orthodontic therapy. As a result, Orthodontists should be aware of the impact of mouthwashes containing various active agents on the physical properties of various alloys to propose a suitable mouthwash to patients throughout the treatment period and use the arch wire accordingly. Researchers have struggled to develop an oral rinse that is as potent as Chlorhexidine (CHX) while having fewer side effects. Commercially accessible is a mouthwash comprising Chlorine Dioxide (ClO2). The active ingredient is sodium chlorite in a state of stabilized chlorine dioxide. Currently, oral rinses comprising ClO2 are utilized.1\n\nClO2 is thought to be a good choice for usage in children since it is not oncogenic or allergic and has no influence on the taste experience. Furthermore, research has revealed that it is not as harmful to people as CHX. As a result, whereas CHX is commonly regarded as the gold standard, ClO2 is equally beneficial for biofilm reduction.\n\nPrevious research has shown ClO2 and chlorite anion to be effective bactericidal agents against majority of periodontogenic bacteria.2,3 In orthodontic patients, it has shown to be useful in reducing gingivitis and halitosis, and plaque otherwise.4,5\n\nThe biomechanical forces produced by orthodontic archwires, through brackets to cause tooth movement, are vital in clinical practice. Light, continuous forces are considered ideal for tooth movement in a regulated manner within physiologic limits, thus avoiding hyalinization, resorption, and patient discomfort. The most popular arch wire materials used today vary mainly between Stainless-steel (SS), Beta-titanium (TMA) also Nickel-Titanium (Ni-Ti) alloys.\n\nThere are constant competitive alterations in the market for newer arch wire materials and configurations to perfect the biomechanical and clinical needs necessitating the orthodontist’s need for knowledge and understanding about the same to foresee desirable treatment outcomes.\n\nStainless steel wires have remained popular since their introduction to orthodontics because of their suitable properties. It forms the stiffer arch wire that helps to bring about the key tooth movements including space closure, etc.6\n\nDespite their positive benefits, mouthwashes have the potential to alter the mechanical and surface characteristics of archwires and brackets, as well as enhance microhardness and friction.7 Corrosion can significantly alter the surface properties of metals, and elevated friction during sliding within the bracket and wire can occur because of the wire’s greater surface roughness, resulting in improper distribution of load in the orthodontic appliance and, as a result, dropped efficacy of guided movement of the teeth across the archwire.\n\nAccording to the existing literature, studies on the effect of Chlorine Dioxide mouthwash on surface characteristics of stainless steel orthodontic archwires haven’t been conducted, therefore the purpose of this study will be towards evaluating effects of this mouthwash on the properties of stainless steel (SS) wires to formulate a mechanically useful archwire and mouthwash combination to be used during orthodontic treatment as well as to form a basis for comparison with Chlorhexidine.\n\n\nMethods\n\nThe research’s permission was acquired from the Ethics committee of Kasturba Medical College and Kasturba Hospital (IEC2: 50/2022) on 12/05/2022.\n\n\n\n1. Orthodontic archwires - 19 × 25 inch Stainless steel orthodontic archwires (G&H company, Libral traders)\n\n2. Pre-adjusted Edgewise brackets - MBT prescription with a slot dimension of 0.022 inch (Forestadent)\n\n3. Customized acrylic jig (25 cm × 7 cm)\n\n4. Stainless steel ligature wire\n\n5. Artificial saliva (Department of Biochemistry, Kasturba Medical College, Manipal)\n\n6. Chlorine Dioxide Mouthwash – 500 ml\n\n7. Chlorhexidine Mouthwash (0.2%) – 500 ml\n\n8. Borosil® petri dishes for keeping the wires immersed\n\n9. Universal testing machine with load weight (10 N) – Dental Materials, Manipal\n\n10. Atomic Force Microscope – Innovation Centre, MIT\n\n\nMethod\n\n\n\n• Experimental mouthwashes i.e. Chlorine Dioxide mouthwash (ClO2) and Chlorhexidine mouthwash (CHX) were procured. 126 upper stainless-steel metal brackets with 0.022-inch slot sizes were selected. 0.019 × 0.025 inch straight rectangular stainless-steel arch-wires of a sample size of 42 were used ( Figure 1).\n\n• The wires were cut, and experimental units were immersed in 0.2% Chlorhexidine mouthwash (Group A) and Chlorine Dioxide mouthwash (Group B) respectively, for 30 seconds twice daily for 3 months. During the time interval of each immersion apart from the mouthwash immersion, the experimental units were immersed in artificial saliva ( Figure 2).\n\n• The control units were immersed in artificial saliva (Group C), obtained from the Department of Biochemistry for 3 months.8,9 14 specimens of wires were immersed in an individual 20-ml Borosil petri dish per group in 3 groups ( Figure 2). After a period of 3 months, the experimental and control specimens were removed from their respective solutions and rinsed with distilled water for evaluation.\n\n\n\n• Frictional force was measured using a Universal Testing Machine.\n\n• 10 Samples from each group were tested. A customized jig was designed for grasping wires during testing. The brackets were bonded on the jigs and ligation between the bracket and wire was with a stainless-steel ligature wire during frictional force evaluation which was standardized with 11 turns per bracket ( Figure 3).\n\n• A load cell was calibrated between 0 and 10 N, and the archwire was drawn through the bracket at a crosshead speed of 10 mm/min over a 5-mm section of the arch-wire ( Figure 4).\n\n• After every test, the bracket-wire grouping was removed, and a new assembly was.placed. The recorded data was statistically analyzed to determine significant differences between the one type of archwire immersed in two test environments ( Figure 4).\n\n\n\n• The remaining 4 samples from each group of specimens were cleaned with 95% ethanol before Atomic Force Microscope (AFM) observations.\n\n• The surface topography and roughness (Ra) of the stainless steel (SS) arch-wires after immersion in the Chlorhexidine, Chlorine dioxide, and artificial saliva were evaluated using an AFM10 ( Figure 5).\n\n• Each wire sample that was selected was cut to a length of 1 cm using a distal end cutter. At a scanning rate of 10 Hz, scanning was done while in the air. Four specimens per group were used to quantify surface roughness, and each specimen produced a total of three measurements over a 10 × 10-μm region ( Figures 6, 7, 8). The software provided with the AFM was used to evaluate the wire’s external surface.\n\n• The Ra, Rq, and Rmax values were obtained using the software.\n\n• The recorded data of surface roughness after the immersion test were statistically measured.\n\nData was analysed using the statistical.package SPSS 26.0 (SPSS Inc., Chicago, IL) and the level of significance was set at p<0.05. To evaluate the mean and standard deviation of each group, descriptive statistics were used. The normality of the data was assessed using the Shapiro-Wilkinson test. One way ANOVA was used in inferential statistics to determine the difference within the group (3 groups) followed by Bonferroni Post-hoc Test. Pearson Correlation Test was used for correlation analysis. Data was presented using tables and bar and plot graphs.\n\n\nResults\n\nTable 1 and Figure 9 provide the results of a one-way analysis of variance (ANOVA) conducted to compare the frictional force among three groups (Groups A, B, and C) corresponding to different immersion solutions i.e. Chlorhexidine, Chlorine Dioxide, and artificial saliva respectively. Regarding ‘FRICTIONAL FORCE’ Inter-group analysis by ONE WAY ANOVA did not report a significant difference (p > 0.05).\n\n* p < 0.05 is statistically significant (Shapiro Wilkinson test, p > 0.05).\n\nTable 2 presents the results of post hoc pairwise comparisons using the Bonferroni correction method for multiple comparisons. These comparisons are conducted to determine whether there are significant differences in mean frictional force between each pair of groups (A, B, and C) after conducting a one-way ANOVA.\n\nThese results suggest that there are no significant differences in mean frictional force between any pair of groups (A, B, and C) based on the Bonferroni-corrected post hoc pairwise comparisons. The p-values for all comparisons are greater than the chosen significance level (>0.05), indicating that the observed differences are not statistically significant.\n\nSurface roughness was analyzed for the arch-wires at 3 separate regions with a range of 0-10μm and an average of three values was taken to examine the data. A one-way ANOVA was then done to analyze if the mean roughness was the same across all the groups. There was no significant difference concerning mean surface roughness among the three study groups (p = 0.056). Table 3 and Figure 10 depict the effects mouthwashes and artificial saliva had on the surface roughness of arch-wires compared at a 10 μm range.\n\nPost hoc tests for multiple comparisons were done using the Bonferroni correction method ( Table 4). There is no statistically significant difference between any of the pair group comparisons in terms of surface roughness (p > 0.05).\n\n\nDiscussion\n\nIn orthodontic therapy, dental archwires and attachments are used for moving teeth. Stainless steel (SS) is often used in orthodontic treatment due to its superior resistance to corrosion and protective oxide coating on its surface. Because the appliances are in the mouth and exposed to changing biological conditions, orthodontic patients are more susceptible to gingivitis and enamel decalcification. To prevent these potential dangers, mouthwash should be used in conjunction with brushing. Chromium oxide serves as the protective layer for stainless steel wires. However, this protective layer is prone to mechanical and chemical rupture as measured by frictional force and surface characteristics following immersion in various solutions.11\n\nChlorine dioxide mouthwash is a type of oral rinse that uses chlorine dioxide as its active ingredient. It is known for its ability to help reduce bad breath, as it is effective at neutralizing volatile sulfur compounds that are often responsible for halitosis. The use of chlorine dioxide in mouthwash is seen as beneficial due to its oxidizing properties, which can disrupt the cell walls of microorganisms, leading to their destruction. When considering its effects on dental materials, like stainless steel archwires commonly used in orthodontics, it’s important to evaluate whether the oxidative nature of chlorine dioxide could cause corrosion or any other negative impact on the materials’ integrity or function. The study of these interactions is valuable for orthodontic care and can inform recommendations for oral hygiene practices in individuals undergoing orthodontic treatment.\n\nIn general, stainless steel is resistant to many types of chemical exposures, but certain substances could cause problems such as surface pitting, discoloration, or even corrosion. Given the oxidizing nature of chlorine dioxide, there is a possibility that prolonged exposure or high concentrations could have some impact on the surface of stainless-steel archwires.\n\nPrevious research has not looked at the influence of chlorine dioxide-containing protective agents on the surface.roughness of stainless-steel archwires or the frictional resistance between orthodontic metal brackets and archwires. In this research, we intended to determine how chlorine dioxide-containing mouthwash affected the frictional force and surface roughness of stainless-steel orthodontic archwires, given the assumption that these properties would not alter much. This would aid in the development of safe methods for those wearing braces who want to use chlorine dioxide mouthwash in their oral hygiene routine.\n\nThe present study assessed static friction since the sliding motion of teeth down an archwire is not uninterrupted but occurs in a sequence of brief leaps or jumps. Thus, static friction is more critical thank inetic friction since that must be overcome every time there is movement of teeth.2\n\nConcerning friction, a greater amount of it for the chlorine dioxide group in comparison with the Chlorhexidine group was seen, but not significantly (p < 0.05). In a different investigation conducted by Alwafe et al.,12 wires placed in a fluoride-containing mouth rinse had the greatest mean coefficient of friction and roughness of the surface, after herbal mouthwash, and the lowest value for artificial saliva. Several studies have investigated the influence of fluoridated mouth rinses on surface texture7,9,12 and the wear of orthodontic archwires and brackets. Although, the impact of chlorine dioxide-comprising mouthwash in this area hasn’t been well studied. In a prior in-vitro investigation,10 the influence of chlorhexidine on the surface characteristics as well as the friction between orthodontic wires and brackets was assessed. The findings demonstrated that surface roughness of archwires and the frictional force in between two varieties of orthodontic wires made of stainless-steel and NiTi alloy metals and stainless-steel brackets were not substantially impacted by a 1.5-hour immersion in mouthwashes containing 0.2% chlorhexidine. However, in contrast to the Persica mouthwash, another investigation over the surface.morphology of orthodontic archwires determined that mouthwashes containing 0.12% chlorhexidine and 0.12% peroxide had a greater pitted appearance on stainless-steel and NiTi wires, respectively.13 Given that chlorhexidine molecules are known to form bonds with the oral mucous membrane and teeth, outcomes of any in vitro investigation may differ from those of an in vivo study. Laboratory studies that execute the sliding mechanism amid a lack of moisture may also overstate the resistance to friction as saliva acts as a lubricant.\n\nThe study’s overall findings indicate that, although not statistically important, the frictional force and roughness of stainless-steel wires immersed in chlorine dioxide were higher; additionally, SS wires immersed in chlorhexidine did not exhibit significantly different surface behavior from that of the artificial saliva category. The surface information in our results was in line with those of Bundy K14 and Rondelli G,15 which demonstrated the high corrosion resistance of orthodontic wires in a variety of solutions such as Ringer, artificial saliva, and NaCl had a high corrosion resistance.16 From the perspective of film breakdown, titanium alloys used in these solutions have a stronger resistance to corrosion than stainless steel alloys. Although not significantly different from one another, wires submerged in ClO2 were found to have the most surface flaws in this investigation.\n\nDartar Oztan et al. evaluated the level of stainless-steel deterioration in mouthwashes containing EDTA, chlorhexidine (0.2%), and NaCl (5.25%). The findings indicated that there was a degree of corrosion in the stainless steel files, particularly pitting corrosion with the chlorhexidine solution.17 Dental rinses with chlorhexidine as an ingredient may be recommended as harmless preventive measures, according to research by Hosseinzadeh Nik et al.10\n\nAccording to the present investigation, it was determined that the stainless-steel wires immersed in mouthwash containing chlorine dioxide had the highest levels of friction and surface roughness, albeit not significantly. It also found that stainless steel wires are detrimentally affected by chlorhexidine.\n\nThe methodology cannot perfectly replicate the actual clinical setting, as with any in vitro study. It’s also important to remember that the resistive frictional forces found in our study differed significantly from those that were exerted during orthodontic movement. The duration of exposure in our investigation was rather short, and the experimental setting might not accurately represent the complex oral environment. A further constraint of this research is that it has not examined other varieties of orthodontic archwires, like Ni-Ti and beta-titanium wires, so it isn’t possible to generalize its findings to them. Future research should aim to expand upon these findings by conducting in vivo studies to evaluate the effects of Chlorine dioxide-containing mouthwash on orthodontic materials in a more clinically relevant setting. Additionally, investigations into the effects of other mouthwash formulations and their potential interactions with orthodontic materials would provide valuable insights into optimizing patient care.\n\n\nConclusion\n\nIn conclusion, our study suggests the following:\n\n1. Chlorine dioxide-containing mouthwash does not significantly affect the frictional force and surface roughness of stainless steel orthodontic archwires under the conditions tested.\n\n2. Chlorine dioxide may be a viable adjunct to orthodontic treatment. However, further research, particularly in vivo studies, is necessary to validate these findings and ascertain the long-term effects of Chlorine dioxide on orthodontic materials.\n\n\nClinical significance\n\nEvaluating the effects of this mouthwash on the properties of stainless steel (SS) wires will help researchers formulate a mechanically useful archwire and mouthwash combination to be used during orthodontic treatment as well as to establish a future base for comparison of Chlorine Dioxide mouthwash with gold standard Chlorhexidine mouthwash.\n\n\nEthical approval\n\nBefore commencing the study, clearance was sought from the Kasturba Medical College and Kasturba Hospital Institutional Ethics Committee, Manipal, Karnataka – IEC2: 50/2022 on 12/05/2022.\n\n\nInformed consent\n\nNot applicable as it is an in vitro study.", "appendix": "Data availability statement\n\nFigshare: Impact of chlorine dioxide and chlorhexidine mouthwashes on friction and surface roughness of orthodontic stainless steel wires: an in vitro comparative study. Doi: https://doi.org/10.6084/m9.figshare.27646026.v118\n\nThis project contains following underlying data:\n\n1. Excel.xlsx\n\n2. Word document.docx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nNone.\n\n\nReferences\n\nGornitsky M, Paradis I, Landaverde G, et al.: A clinical and microbiological evaluation of denture cleansers for geriatric patients in long-term care institutions. J. Can. Dent. Assoc. 2002 Jan 1; 68(1): 39–45. PubMed Abstract\n\nFrank CA, Nikolai RJ: A comparative study of frictional resistances between orthodontic bracket and arch wire. Am. J. Orthod. 1980 Dec; 78(6): 593–609. PubMed Abstract \| Publisher Full Text\n\nAlavi S, Barooti S, Borzabadi-Farahani A: An in vitro assessment of the mechanical characteristics of nickel-titanium orthodontic wires in Fluoride solutions with different acidities. J. Orthod. Sci. 2015; 4(2): 52–56. PubMed Abstract \| Publisher Full Text\n\nBrantley WA, Augat WS, Myers CL, et al.: Bending deformation studies of orthodontic wires. J. Dent. Res. 1978 Apr; 57(4): 609–615. Publisher Full Text\n\nMathur S, Mathur T, Srivastava R, et al.: Chlorhexidine: The Gold Standard in Chemical Plaque Control. Natl. J. Physiol. Pharm. Pharmacol. 2011 Jan 1; 1.\n\nRenuka S, Muralidharan NP: Comparison in benefits of herbal mouthwashes with chlorhexidine mouthwash: A review. Asian J. Pharm. Clin. Res. 2017 Feb 1; 10(2): 3–7. Publisher Full Text\n\nYanisarapan T, Thunyakitpisal P, Chantarawaratit PO: Corrosion of metal orthodontic brackets and archwires caused by fluoride-containing products: Cytotoxicity, metal ion release and surface roughness. Orthodontic Waves. 2018 Jun 1; 77(2): 79–89. Publisher Full Text\n\nWalker MP, White RJ, Kula KS: Effect of fluoride prophylactic agents on the mechanical properties of nickel-titanium-based orthodontic wires. Am. J. Orthod. Dentofac. Orthop. 2005 Jun; 127(6): 662–669. Publisher Full Text\n\nNalbantgil D, Ulkur F, Kardas G, et al.: Evaluation of corrosion resistance and surface characteristics of orthodontic wires immersed in different mouthwashes. Biomed. Mater. Eng. 2016 Jan 1; 27(5): 539–549. PubMed Abstract \| Publisher Full Text\n\nHosseinzadeh Nik T, Hooshmand T, Farazdaghi H, et al.: Effect of chlorhexidine-containing prophylactic agent on the surface characterization and frictional resistance between orthodontic brackets and archwires: an in vitro study. Prog. Orthod. 2013 Nov 20; 14(1): 48. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHouse K, Sernetz F, Dymock D, et al.: Corrosion of orthodontic appliances--should we care? Am. J. Orthod. Dentofac. Orthop. 2008 Apr; 133(4): 584–592.\n\nAlwafe NA, Hammad SM, El-wassefy NA, et al.: Evaluation of the Effect of an Experimental Herbal versus Fluoridated Mouthwash on Frictional Resistance and Surface Roughness between Orthodontic Brackets and Two Types of Archwire: in vitro Study. J. Dent. Mater. Tech. 2019 Oct 1; 8(4).\n\nOmidkhoda M, Poosti M, Sahebnasagh Z, et al.: Original Research Effects of three different mouthwashes on the surface characteristics of nickel-titanium and Stainless steel archwires in orthodontics. JDMT. 2017 Jan 1; 6.\n\nBundy KJ, Vogelbaum MA, Desai VH: The influence of static stress on the corrosion behavior of 316L stainless steel in Ringer’s solution. J. Biomed. Mater. Res. 1986 Apr; 20(4): 493–505. PubMed Abstract \| Publisher Full Text\n\nRondelli G, Vicentini B: Evaluation by electrochemical tests of the passive film stability of equiatomic Ni-Ti alloy also in presence of stress-induced martensite. J. Biomed. Mater. Res. 2000 Jul; 51(1): 47–54. PubMed Abstract \| Publisher Full Text\n\nKaneko K, Yokoyama K, Moriyama K, et al.: Degradation in performance of orthodontic wires caused by hydrogen absorption during short-term immersion in 2.0% acidulated phosphate fluoride solution. Angle Orthod. 2004 Aug; 74(4): 487–495. PubMed Abstract\n\nDartar Öztan M, Akman AA, Zaimoglu L, et al.: Corrosion rates of stainless-steel files in different irrigating solutions. Int. Endod. J. 2002 Aug 1; 35(8): 655–659. PubMed Abstract \| Publisher Full Text\n\nDivya S, Urala AS: Impact of chlorine dioxide and chlorhexidine mouthwashes on friction and surface roughness of orthodontic stainless steel wires: an in vitro comparative study. Dataset. figshare. 2024. Publisher Full Text" }	[ { "id": "344507", "date": "02 Dec 2024", "name": "Ahmed Jasim", "expertise": [ "Reviewer Expertise Operative Dentistry", "Digital Dentistry", "Endodontics", "Dental Material" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall, the article is well-structured and clearly communicates the study's objectives, methods, results, and conclusions.\nSpecific Comments: Clarity of Objectives: The objectives are clearly stated and focused on the impact of two mouthwashes on the mechanical properties and surface morphology of orthodontic archwires. Methodology: The experimental design is well-described, including the division into three groups and the number of specimens per group. The use of a universal testing machine and atomic force microscopy is appropriate for the study. However, more details about brands of wires used and the specific conditions of the immersion (temperature, storage, replenishment of solutions, etc.) would enhance the reproducibility of the study. Results: The results are presented clearly, including the mean friction and surface roughness values for each group. The statistical significance of the differences between the groups is correctly reported. Conclusion: The conclusion accurately summarizes the main findings of the study. It would be helpful to discuss the possible clinical implications of the increased friction, such as potential effects on orthodontic treatment time. Additionally, considering the lack of statistical significance in the surface roughness differences, a more nuanced interpretation of the results could be provided. Suggestions for Improvement: Discussion of Limitations: The research could briefly acknowledge potential limitations of the study, such as the relatively small sample size or the specific brands of mouthwash used. Future Directions: Suggesting future research directions, such as investigating the long-term effects of mouthwash exposure or testing a wider range of mouthwash types, could add value to the research. By addressing these points, the research can be further strengthened and provide a more comprehensive overview of the study's findings and implications.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] }, { "id": "344500", "date": "11 Dec 2024", "name": "Rand Salih Al-Obaidi", "expertise": [ "Reviewer Expertise Preventive dentistry and cariology." ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear authors, I hope the following comments could help you to improve your manuscript.\n-What are the major differences between Chlorine Dioxide and Chlorhexidine concerning composition, mode of action, concentration..etc? -What is the concentration of Chlorine Dioxide used in this study? - How did you make the design of your study using CHX mouthwash for 3 months while it can’t be used for more than one month due to eminent side effects related to prolonged use? -I think all figures and tables need more clarification and explanation to make them more evident.\n-The article requires language revision and reformulation.\n-Concerning friction, a greater amount of it for the chlorine dioxide group in comparison with the Chlorhexidine group was seen, but not significantly (p < 0.05). How can the p < 0.05 and the statistical difference is not significant?? Please check.\n-What is the effect of morphology of arch wires on mouthwash selection? And did you inspect that in your study?\n-(According to the present investigation, ,) I think your findings disagree with your conclusion.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No", "responses": [] }, { "id": "344504", "date": "23 Dec 2024", "name": "Sarmad S. Salih Al Qassar", "expertise": [ "Reviewer Expertise I am working on the dental material research", "polymers and 3D analysis beside I have some research regarding friction." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI would like to express my sincere gratitude for considering me as a reviewer for the manuscript titled Impact of Chlorine Dioxide and Chlorhexidine Mouthwashes on Friction and Surface Roughness of Orthodontic Stainless Steel Wires: An In-Vitro Comparative Study. The topic is indeed quite fascinating, particularly the exploration of chlorine dioxide as a mouthwash and its effect on the friction of stainless steel wires. The manuscript thoroughly discusses the role of these mouthwashes in influencing both the surface roughness of the wire and the friction at the bracket-wire interface. While the manuscript is generally well-designed and well-written, I have identified a few areas that could be addressed to enhance its quality. In the Abstract section, I suggest that statistical terms be omitted from the conclusion, as they are more appropriate for the results section. In the Introduction, there are several lengthy sentences, and the number of references cited appears to be somewhat limited. I recommend revising these sentences for clarity and strengthening the reference list to provide more comprehensive context. The Methodology section would benefit from further details regarding the effects of thermocycling on friction. Additionally, it would be helpful for the authors to clarify how the sample size was calculated. I also suggest that the authors specify the testing conditions more clearly, particularly in regard to whether the results were obtained in dry or wet conditions. Furthermore, it would be beneficial to consider the ligation adjustment for all samples. Regarding statistical analysis, I would like to inquire about the utility of conducting a post hoc statistical test for the non-significant results from the ANOVA test. Moreover, the Results section seems to be missing the correlation results that were referenced in the Methodology section, and I believe these should be included for completeness. Finally, I recommend that the authors include more recent references to update the manuscript with the latest information on friction and surface roughness. For instance, the following studies might be valuable additions: [Ref 1] and [Ref 2]\nThank you once again for the opportunity to review this manuscript. I believe that by addressing these points, the authors will be able to further strengthen their work. Sincerely,\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13070", "date": "21 Jan 2025", "name": "Divya S", "role": "Author Response", "response": "Dear Sir, We have added the references you have mentioned. Also, sample size justification and corrections have been made." } ] } ]	1	https://f1000research.com/articles/13-1442
https://f1000research.com/articles/13-780/v1	09 Jul 24	{ "type": "Research Article", "title": "Evaluating the dynamics of fee-free higher education in South Africa: a causal loop diagram approach ", "authors": [ "Tlotlo Ramasu", "Grace Kanakana-Katumba", "Grace Kanakana-Katumba" ], "abstract": "Background This research investigated the dynamics of fee-free higher education in South Africa, aiming to elucidate the complexities surrounding its implementation and impact. By employing a causal loop diagram approach, the study examined the interplay of socioeconomic, political, and institutional factors influencing the provision of fee-free higher education.\n\nMethod A participatory approach to developing the CLD was used. Through an extensive literature review, the research contextualised fee-free higher education enabling a preliminary CLD to be developed. Discussions were held to improve the preliminary model based on stakeholder and expert opinion. The model was then validated by stakeholders and experts.\n\nResults The CLD has explicitly mapped out the causal relationships which play a fundamental role in fee-free higher education in South Africa. Key findings revealed that fee-free higher education initiatives, such as managing funding constraints and administrative complexities, hold promise for fostering inclusivity and socioeconomic development but are hindered by bureaucratic policy establishments and inefficiencies. These challenges underscore the gap between policy formulation and implementation, highlighting the need for comprehensive reforms to streamline administrative processes and enhance financial sustainability within the higher education sector.\n\nConclusion This research thoroughly examined the dynamics of fee-free higher education in South Africa, highlighting both the challenges and opportunities in its implementation. The study emphasized the need for systemic reforms to improve accessibility and effectiveness, while also underscoring the potential of such initiatives to promote social mobility and economic empowerment, aligning with global goals like the SDGs and the African Agenda 2063.", "keywords": [ "Fee-free education", "Higher education", "Inclusive growth", "Education equity", "Socioeconomic progress", "Causal loop diagran" ], "content": "1. Introduction\n\nHigher education in South Africa is pivotal in shaping the nation’s socioeconomic sector and fostering individual and national development (Leibowitz & Bozalek, 2014). Spreen & Vally (2006) point out that since the end of apartheid in 1994, South Africa has been actively expanding access to tertiary education, aiming to address historical disparities and promote inclusivity. The country boasts a diverse higher education sector comprising universities, universities of technology, and comprehensive institutions (Lange, 2020), offering a wide array of programs spanning various disciplines to cater to the diverse needs of students and industries alike. However, as Yende & Mthombeni (2023) stated, financial barriers have long hindered access to higher education, particularly for disadvantaged communities. Historically, tuition, accommodation, and related expenses have presented a significant obstacle for many aspiring students, perpetuating socioeconomic inequalities and limiting the realisation of individual potential (Mutekwe, 2017). The significance of this study lies in its use of a methodology capable of analyzing the causality of relationships involved in the complex discourse on fee-free higher education through the development of a participatory causal loop diagram. This is aimed at assisting policymakers come to an informed decision on how the interrelationship between these variables will be affected by their decision on the subject of fee-free higher education.\n\nAs denoted by Kioupi & Voulvoulis (2019), education is a cornerstone for national progress. In the context of South Africa, characterised by its status as a developing nation, a pressing need exists for a skilled workforce (Vogel, 2015). The country grapples with staggering levels of income inequality, evidenced by a Gini coefficient of 0.67, the highest globally (Vogel, 2015). According to Barro (2013), education emerges as a potential avenue to mitigate the stark disparities between affluent and marginalised communities. Additionally, South Africa contends with a formidable unemployment rate of 31.9%, according to (Lauder & Mayhew, 2020). Many unemployed individuals lack the requisite skills for gainful employment, underscoring the pivotal role of education in enhancing their employability (Lauder & Mayhew, 2020).\n\nPost-apartheid South Africa’s educational policy has focused on equitable access to higher education to promote social mobility and economic development (Ayuk & Koma, 2019; Varghese et al., 2023). A significant initiative in this regard is fee-free higher education for eligible students, introduced following the #FeesMustFall protests in 2015, which highlighted the systemic failures in serving marginalized communities (Ntombana et al., 2023; Akala, 2023). President Jacob Zuma’s 2017 announcement of tuition-free education aimed to alleviate financial barriers and promote inclusivity (Spreen & Vally, 2006). The dynamics of this policy involve various stakeholders and aim to address historical disparities (Mokgotho et al., 2023).\n\nIn response to these challenges, the South African government has implemented various policies and initiatives to democratise access to higher education (Salmi & D’Addio, 2021). Following the study by Salmi & D’Addio (2021), one such initiative is the introduction of fee-free higher education for eligible students, which seeks to alleviate financial burdens and enhance inclusivity within the tertiary education sector. This research journal uses a causal loop diagram approach to evaluate the dynamics of fee-free higher education in South Africa. When factors influencing the implementation and impact of fee-free higher education are examined, this study aims to contribute to a deeper understanding of the complexities surrounding access to tertiary education in the country. Through an analysis of causal relationships and feedback loops, the study explored the underlying mechanisms shaping the efficacy and sustainability of fee-free higher education policies in South Africa.\n\nFee-free higher education policies operate within a complex socioeconomic and institutional context characterised by numerous interacting variables (Mlambo et al., 2018). Causal loop diagrams allow for the visualisation of these intricate relationships, enabling researchers to identify feedback loops and non-linear dynamics that may not be apparent through traditional analytical methods (Forrester, 2009). By mapping out causal relationships and feedback loops, causal loop diagrams facilitate a systemic understanding of fee-free higher education dynamics. This holistic perspective helps researchers uncover underlying patterns and mechanisms that drive policy implementation, impact, and outcomes, thereby informing more effective intervention strategies, as Abidin et al. (2017) highlighted.\n\nFurthermore, unlike quantitative modelling techniques, such as econometric or statistical models, causal loop diagrams prioritise qualitative analysis and conceptual mapping. This approach is well-suited to exploratory research endeavours seeking to elucidate the complexities of social systems and policy environments, where precise numerical data may be limited or uncertain, as emphasised by Haraldsson (2004). Causal loop diagrams offer a participatory research tool that can engage stakeholders in the research process, similar to the research methodology (Toole, 2005). Researchers can harness collective knowledge and perspectives by involving policymakers, educators, students, and other relevant actors in developing causal loop diagrams to create more robust and inclusive analyses of fee-free higher education dynamics. Causal loop diagrams have been used in several fields to assist decision-making process. For instance, tourism scholars are increasingly advocating for the use of complexity science to understand and manage tourism governance and policymaking. Complexity science is valued because its ability to handle the unpredictable and interconnected nature of tourism, unlike traditional methods that simplify and assume linear relationships. This approach aims to provide a more accurate and comprehensive analysis of the complexities involved in policymaking (Crabolu et al., 2023; Farsari, 2023; McDonald, 2009; I. Pappas, 2019). The application of causal loop diagrams has also been utilized to investigate policy resistance mechanisms in Southern Italy in a study that emphasizes the consequences of overlooking ambiguity in problem framing during decision-making processes. The scholars highlight that when decision-actors oversimplify the interaction space by disregarding the roles of other decision-actors or making erroneous assumptions about their mental models, it can impede the effective implementation of environmental policies (Giordano et al., 2017).\n\nResearch such as Ayuk & Koma (2019) has shown that South Africa’s post-apartheid educational policy has centred on equitable access to higher education. Recognising education’s crucial role in fostering social mobility and economic development, the government has implemented various measures to broaden access to tertiary education, particularly for historically marginalised communities (Varghese et al., 2023). One of the most significant initiatives in this regard is the introduction of fee-free higher education for eligible students (Akala, 2023). In 2015, widespread student protests erupted across South Africa under the hashtag #FeesMustFall (Ntombana et al., 2023). These protests were triggered by the University of the Witwatersrand’s proposal to raise tuition fees for the 2016 academic year. Subsequently, following the research by Jacobs et al. (2019), similar demonstrations spread to all government-funded universities, marking a crucial moment in the country’s higher education sector. These protests catalysed a call for free higher education, driven by the recognition of the systemic failure of the South African education system to adequately serve historically marginalised and oppressed communities (Ntombana et al., 2023). On December 16, 2017, according to the report by Wangenge-Ouma (2012), President Jacob Zuma made a surprising announcement, declaring the introduction of tuition-free education at the higher education level. Enacted in response to widespread protests and demands for accessible tertiary education, the policy aims to alleviate financial barriers and promote inclusivity within the higher education sector (Spreen & Vally, 2006).\n\nAkala (2023) emphasised that socioeconomic, political, and institutional factors shape the dynamics surrounding fee-free higher education in South Africa. These factors, as highlighted by Mokgotho et al. (2023), involve various stakeholders such as student representatives, The Presidency of South Africa, the Department of Higher Education and Training (DHET), the National Treasury, the Heher Commission of Inquiry into the Feasibility of making Higher Education and Training Fee-free in South Africa (Heher Commission), media outlets, and researchers. Consequently, the policymaking terrain for fee-free higher education is characterised by diverse actors with differing perspectives and interests (Mokgotho et al., 2023). At its core, this initiative aims to rectify historical disparities in educational access and promote a more equitable society.\n\nThe policy framework governing fee-free higher education in South Africa is multifaceted (Masutha & Motala, 2023), with the National Student Financial Aid Scheme (NSFAS) playing a central role in providing financial assistance to eligible students (Jacobs et al., 2019). NSFAS aims to alleviate the financial burden of tertiary education by covering tuition fees, accommodation, and living expenses for qualifying students (Ntombana et al., 2023). Additionally, (Mokgotho et al., 2023) stressed that legislative measures have been enacted to ensure equitable access to higher education, including laws prohibiting discrimination and promoting inclusivity.\n\nStudies conducted by the Council on Higher Education (CHE) and the Department of Higher Education and Training (DHET) offer valuable insights into the institutional mechanisms and implementation strategies of fee-free higher education (Masutha & Motala, 2023). These studies examine the operational aspects of NSFAS, such as eligibility criteria, application processes, disbursement mechanisms, and monitoring procedures (Mokgotho et al., 2023). Moreover, they assess the effectiveness of outreach and awareness campaigns to inform prospective students about available financial aid opportunities. Despite the intentions behind these policies and initiatives, Wangenge-Ouma (2012) highlights various challenges that hinder their effective implementation. Bureaucratic inefficiencies within NSFAS and other administrative bodies often result in delays in processing applications and disbursing funds (Sayed & Motala, 2012), leading to student frustration and disillusionment. Furthermore, Kishun (2007) emphasised that funding constraints pose a significant barrier to expanding access to fee-free higher education, as the demand for financial aid often exceeds available resources. This issue is exacerbated by competing budgetary priorities and economic uncertainties (Dutywa, 2022).\n\nFurthermore, administrative complexities also contribute to the challenges of implementing fee-free higher education (Yende & Mthombeni, 2023). The intricate requirements and documentation needed to qualify for financial aid can be daunting for students, as denoted by Wangenge-Ouma (2012), particularly those from marginalised communities with limited access to information and support services (Ahmed & Sayed, 2009). Additionally, the decentralised nature of higher education institutions in South Africa introduces variability in implementing fee-free education policies, leading to inconsistencies and disparities in access and support (Sayed & Soudien, 2005).\n\nMokgotho et al. (2023) research shows that addressing these challenges requires a coordinated effort from policymakers, educational institutions, and relevant stakeholders. Streamlining administrative processes (Yende & Mthombeni, 2023), increasing funding allocations (Dutywa, 2022), and enhancing communication and support services (Yende & Mthombeni, 2023) are essential steps towards improving the implementation of fee-free higher education. Moreover, ongoing evaluation and monitoring of policy outcomes are crucial for identifying areas of improvement and ensuring that the goals of equitable access and social inclusion are realised (Salmi & D’Addio, 2021).\n\nHigher education serves as a vital avenue for both personal advancement and economic development (Kioupi & Voulvoulis, 2019), playing an essential role in enhancing individual knowledge and bolstering the nation’s economy by supplying the workforce with skilled professionals (Ndaba, 2023). A higher education qualification fosters independence and sustainability in one’s life. It contributes to the overall growth and prosperity of a developing country like South Africa, where higher education represents a significant investment in human capital (Mlambo et al., 2018).\n\nIn light of South Africa’s triple challenges of unemployment, poverty, and inequality, investing in higher education is a strategic approach to address these pressing social issues while stimulating economic growth (Jordaan, Van Heerden, & Jordaan, 2014). As a result, education policymakers should prioritise improving access to higher education and ensuring that the educational system equips the South African workforce with the necessary skills and competencies demanded by the contemporary job market (Jordaan, Van Heerden, & Jordaan, 2014).\n\nWhile fee-free higher education represents a significant step towards promoting educational equity, its implementation has encountered several challenges (Wangenge-Ouma, 2012). Implementing fee-free higher education has raised concerns about the long-term sustainability of funding mechanisms (Kishun, 2007). According to Sayed & Motala (2012), while the policy aims to alleviate student financial burdens, the strain on public finances is considerable. With competing budgetary priorities and limited resources (Sayed & Soudien, 2005), sustaining fee-free higher education programs over the long term presents a significant challenge. Moreover, economic conditions and government revenue fluctuations further exacerbate funding availability uncertainties (Mokgotho et al., 2023). Following the study by Ayuk & Koma (2019), addressing this challenge requires innovative financing models, including public-private partnerships and alternative revenue streams, to ensure the continued viability of fee-free higher education initiatives without compromising the quality of education or other essential services. Several studies (see e.g, Ayuk & Koma, 2019; Varghese et al. 2023; Jacobs et al. 2019 and Marire, 2017) have highlighted the role of investing in quality education and concerns of quality in the implementation of of fee-free higher education.\n\nLastly, this research emphasises the transformative potential of fee-free higher education in South Africa. When there is a provision for equitable access to quality education, these initiatives can break the cycle of poverty and drive socioeconomic progress. Moreover, the alignment of fee-free higher education with global development agendas such as the Sustainable Development Goals (SDGs) and the African Agenda 2063 underscores its significance in advancing inclusive growth and fostering social cohesion. The implications of this research extend beyond academia, offering valuable insights for policymakers, educators, and stakeholders seeking to address educational inequalities and promote equitable access to higher education in South Africa and beyond.\n\nFree education has been highly debated in South Africa. However, technical grounds that supports decision-making in this regard has been less explored.\n\n\n2. Methods\n\nThe research methodology employed in this study utilises system dynamics, specifically causal loop diagrams (CLDs), to analyse the dynamics of fee-free higher education in South Africa. Initially developed by Forrester (2009), system dynamics offers a framework to comprehend the structure and behaviour of complex systems. This methodology has found application across various domains, including project management (Toole, 2005), education (Faham et al., 2017), strategic planning (Goyol & Dala, 2013), and capacity planning (Vlachos et al., 2007). CLDs, conceptualised by Forrester (2009) depict the interconnections and feedback loops within a system. These diagrams elucidate a system’s structure and feedback mechanisms, facilitating the understanding of how behaviours manifest and enabling the development of strategies to address or mitigate them (Abidin et al., 2017). Additionally, CLDs help ascertain the extent of interconnectivity between the focal system and other related systems, providing insights into the broader context of the issue under investigation (Abidin et al., 2017).\n\nThe key components of the diagram, as outlined by Haraldsson (2004), include:\n\na. Variables: Relevant elements for describing the system.\n\nb. Oriented arcs: Indicate causal relationships, with the + and - signs denoting positive or negative effects.\n\nc. Positive loops (denoted as R): Represent self-reinforcing loops, where an initial disturbance leads to further change, indicating an unstable equilibrium.\n\nd. Negative loops (denoted as B): Represent self-correcting or balancing loops, where the system seeks to return to equilibrium after a disturbance.\n\nThese elements collectively form the Causal Loop Diagram (CLD), which visually illustrates causal relationships and significant feedback loops among variables within the system (Vlachos et al., 2007). CLDs have been constructed using two primary approaches: participatory processes or the collection of textual data through traditional qualitative methods such as interviews and document analysis. The participatory approach involves stakeholders in the analysis, facilitating a shared understanding of system complexity (Eker et al., 2018). On the other hand, the textual data collection approach maintains high validity by utilizing multiple sources, which is particularly beneficial when participatory methods are impractical (Eker & Zimmermann, 2016; Kim & Andersen, 2012; Yearworth & White, 2013). This paper illustrates the application of the participatory data collection method to understand the complexities in higher education public funding.\n\nParticipatory System Dynamics Modelling (SDM) approaches considers the complex, non-linear interactions among various elements that influence fee-free higher education, and integrates scientific and stakeholder knowledge. The effectiveness of this approach has been demonstrated in several recent studies (Zomorodian et al., 2018; Santoro et al., 2019; Pagano et al., 2019; Coletta et al., 2024). Among the different participatory SDM methods, this work uses Causal Loop Diagrams (CLDs) to support collective system understanding and modeling (Mirchi et al., 2012; Inam et al., 2015; Giordano et al., 2017; Perrone et al., 2020). CLDs help describe the complex interconnections and feedback loops affecting system dynamics, allowing for the identification of key mechanisms that produce expected co-benefits and generate trade-offs among stakeholders. CLDs were chosen for their ability to map and visualize interactions among different system components, making them accessible to non-experts and facilitating discussions among stakeholders and local experts (Inam et al., 2015; Coletta et al, 2024).\n\nThe construction of a CLD to analyse the dynamics of fee-free higher education in South Africa is the primary objective of this research, detailed further in the subsequent section. For this study Vensim Personal Learning Edition (PLE) software was used to develop the CLD. However, there are other softwares available such as Microsoft Visio, Anylogic and Visual Paradigm.\n\nFee-free higher education policies operate within a complex socioeconomic and institutional context characterised by numerous interacting variables (Mlambo et al., 2018). Causal loop diagrams allow for the visualisation of these intricate relationships, enabling researchers to identify feedback loops and non-linear dynamics that may not be apparent through traditional analytical methods (Forrester, 2009). By mapping out causal relationships and feedback loops, causal loop diagrams facilitate a systemic understanding of fee-free higher education dynamics. This holistic perspective helps researchers uncover underlying patterns and mechanisms that drive policy implementation, impact, and outcomes, thereby informing more effective intervention strategies, as Abidin et al. (2017) highlighted.\n\nFurthermore, unlike quantitative modelling techniques, such as econometric or statistical models, causal loop diagrams prioritise qualitative analysis and conceptual mapping. This approach is well-suited to exploratory research endeavours seeking to elucidate the complexities of social systems and policy environments, where precise numerical data may be limited or uncertain, as emphasised by Haraldsson (2004). Causal loop diagrams offer a participatory research tool that can engage stakeholders in the research process, similar to the research methodology (Toole, 2005). Researchers can harness collective knowledge and perspectives by involving policymakers, educators, students, and other relevant actors in developing causal loop diagrams to create more robust and inclusive analyses of fee-free higher education dynamics.\n\nThe context of this research revolves around the pursuit of equitable access to higher education in post-apartheid South Africa, where historical injustices and socioeconomic disparities have limited opportunities for historically marginalised communities. Despite efforts to broaden access through fee-free higher education initiatives, challenges persist, including questions about the sustainability of funding mechanisms, the quality of education, and the adequacy of support services for disadvantaged students. Addressing these challenges is imperative to ensure that fee-free higher education policies promote inclusivity and foster social mobility. Therefore, this research seeks to evaluate the dynamics of fee-free higher education in South Africa, exploring the interplay of socioeconomic, political, and institutional factors through the causal loop diagram.\n\nThis section demonstrates the step by step framework of the mothod which was adopted in developing the causal loop diagram based on the System Thinking principles. The causal loop was development was carried out in three phases as illustrated in Table 1.\n\n\n\n• Literature review on fee-free higher education\n\n• Gathering information about the study area, for example, from reports, existing models, etc.\n\n\n\n• Informal discussions with stakeholders and experts\n\n• Integration of scientific and stakeholder knowledge\n\nThe first phase was to conduct a literature review and develop a preliminary causal loop diagram based on the existing knowledge of the scenario as well as the concept. This process involved an in-depth review of published articles on CLDs to understand the intricate details of the various methods that could be followed in its development as well as studying published work on fee free higher education in South Africa to identify the key variables at play. Studies show that a CLD can be co-developed with the stakeholders directly (Inam et al., 2015; Perrone et al., 2020; Coletta et al., 2024), however, there is a significant role that independently exploring literature and developing a preliminary CLD plays in understanding the background of the dynamics of the problem. The preliminary CLD was developed to explicitly illustrate the current understanding of the relationships between the key players on the dynamics of fee-free higher education on the basis of the literature that was reviewed. The model was subsequently improved after the stakeholder and expert discussions were held.\n\nThe second phase of developing the CLD was to involve stakeholder and expert for their input on the preliminary CLD which was developed in phase 1. This involved individual detailed informal discussions on the topic of fee-free higher education in South Africa with the aim to add value and contribute to knowledge to the CLD by addressing the system boundaries in relation to the subject, the causality (cause and effect) of the relationships, and improving the overall CLD (Inam et al., 2015; Kotir et al., 2016; Pluchinotta et al., 2021; Salvia et al., 2021; Coletta et al., 2024). The preliminary CLD was shared with the stakeholders and experts during the discussions to ensure that the discussions are concise, remain within the context of the subject and they add value. Figure 1 shows the preliminary CLD.\n\nThe third and last phase of this study entailed the validation of the CLD by stakeholders and experts. Scholars have cited that a CLD using the participatory method can be validated by involving stakeholders and experts during various phases of the modelling process (Mirchi et al., 2012; Coletta et al., 2024). A number of studies in different fields have as such used this to validate their work (see e.g. Bertone et al., 2019; Pagano et al., 2019; Sahin et al., 2016; Susnik et al., 2012). The another set of meetings with the stakeholders was arranged for the validation of the CLD. The variables were divided into thematic clusters and stakeholders were asked to validate relationships particularly where stakeholders expressed conflicting views in phase 2 and where there was not sufficient literature. Once the causal relationships were finalized, meetings with experts were arranged to validate the final CLD structure which incorporates both the stakeholders and experts, as well as the scientific knowledge.\n\n\n3. Causal loop diagram for fee-free higher education in South Africa\n\nThe concept of fee-free higher education is not merely an isolated policy decision; it represents a complex system influenced by a number of interacting factors, including economic, social, and political dynamics as illustrated in Figure 1. Understanding these interdependencies is crucial in the developing the CLD. This section presents and discusses the CLD which encapsulates the key variables and their interactions within the context of fee-free higher education in South Africa. It is important to note that the CLD is a description based on the current available knowledge which can be revised and updated. It is not singular and final view of the analysed system.\n\nThe causal loop diagram (CLD) below (Figure 2) aims to expound the dynamics of fee-free higher education in South Africa by examining socioeconomic factors influencing its implementation and impact. The diagram encompasses variables grouped under the socioeconomic category, including student enrolment, student success rate, unemployed individuals, graduates, employed individuals, employed population, gross domestic product (GDP), and economic development.\n\nThe CLD delineates various causal relationships among these variables with several reinforcing loops (R1, R3 & R4) and one balancing loop (B2). Foremost, student enrolment is positively related to the student success rate (see loop R4), indicating that higher enrolment rates may lead to improved student outcomes, supported by the study by Matsolo et al. (2016). This underscores the importance of ensuring access to education and the quality and support mechanisms necessary for student retention and achievement. Also, it resonates with the research emphasising the need for comprehensive student support services to enhance educational outcomes and maximise the benefits of fee-free higher education policies (Donald et al., 2018). This positive relationship extends to graduates, suggesting that increased student success rates can result in more graduates entering the workforce.\n\nFurthermore, graduates hold significant implications for unemployment and employment dynamics. Graduates have positive relationships with unemployed and employed individuals, implying that they can contribute to reducing unemployment or increasing employment. This highlights the potential of higher education in addressing labour market challenges and promoting socioeconomic inclusion, which aligns with the study by Vogel (2015). Conversely, the CLD also suggests that the impact of fee-free higher education on employment outcomes may vary, necessitating targeted interventions to ensure alignment between educational qualifications and labour market demands (Donald et al., 2018).\n\nIn addition, economic development emerges as a central factor influenced by multiple variables in the CLD. It has positive relationships with GDP and the employed population (see loops R1 & R3), indicating that economic growth fosters both increased economic output and higher employment levels. This shows the importance of education in driving economic development and creating opportunities for gainful employment, as supported by Melguizo et al. (2017). Similarly, this highlights the positive correlation between investment in higher education, human capital development, and economic prosperity (Lauder & Mayhew, 2020).\n\nLastly, the CLD also explains feedback loops within the system. Economic development forms a positive feedback loop with employed and unemployed individuals despite the negative relationship between unemployment and economic development (see loop B2). This suggests that sustained economic growth can lead to further employment and overall socioeconomic development (Matsolo et al., 2016), thereby creating a balance in the system. Similarly, GDP exhibits a positive feedback loop to economic development, emphasising the reinforcing nature of economic growth through various channels. Leveraging these feedback loops effectively requires holistic approaches that address systemic barriers to education and employment, thereby maximising the socioeconomic impact of fee-free higher education initiatives (Sneyers & De Witte, 2017).\n\nThe causal loop diagram (CLD) below (see Figure 3) provides a comprehensive framework for understanding the complex relationships among political variables influencing fee-free higher education in South Africa. The analysis dives into the variables of budget allocation to universities, higher education budget, national budget, and availability of funds, shedding light on their interplay and implications for educational access and quality.\n\nOne of the prominent findings from the CLD is the strong positive relationship between economic growth, as measured by GDP, and government spending, represented by the national budget (see loop R1). This relationship accentuates the pivotal role of economic prosperity in enabling governments to allocate more resources to critical sectors such as education, resonating with the research by Heintz and Pollin (2008). Studies have shown that countries with higher GDP per capita tend to invest more in education, reflecting the importance of economic development in supporting public spending on social services (Fowles, 2014). In the context of South Africa, this finding denotes the potential for sustained economic growth to bolster government support for fee-free higher education initiatives (Tregenna, 2015).\n\nIn addition, the CLD illuminates the linkages between the national and higher education budgets, emphasising the significance of political decisions in shaping funding priorities. Government budget allocations directly influence the financial resources available for higher education (Barro, 2013), impacting the affordability and accessibility of tertiary education for students. This finding also aligns with literature highlighting the critical role of government funding in supporting higher education institutions and ensuring equitable access to quality education (Van Der Berg et al., 2011).\n\nMoreover, the CLD explains the importance of adequate funding for higher education in facilitating the availability of funds for universities, aligning with the study by Oketch (2016). The positive relationship between the higher education budget and the availability of funds indicates that government investments in tertiary education directly impact the financial resources accessible to institutions. This suggests that robust government support is essential for ensuring the sustainability of fee-free higher education initiatives and enhancing the capacity of universities to accommodate students (Brewer & McEwan, 2010).\n\nAnother significant insight emerging from the CLD is the presence of a positive feedback loop between the national budget, student enrolment, and budget allocation to universities (see loops R4 & R7). This feedback loop suggests a reinforcing cycle wherein increased government spending on education leads to higher student enrolment, prompting further budget allocations to universities. This finding underscores the potential for proactive government investment in education to stimulate demand for higher education and drive expansion and improvement in the tertiary education sector (Faham et al., 2017). It also points to the need for strategic policy interventions to ensure sustained government support for fee-free higher education initiatives and promote inclusive and equitable tertiary education for all South Africans, as explained by Sayed & Motala (2012).\n\nThe causal loop diagram (CLD) below (see Figure 4) explores the institutional dynamics surrounding fee-free higher education in South Africa, offering a detailed examination of variables related to the capacity of institutions, infrastructure, and staff. These institutional factors play critical roles in shaping the accessibility, quality, and effectiveness of higher education initiatives, making them essential components for analysis and understanding.\n\nOne of the key insights from the CLD is the positive relationship between budget allocation to universities and the capacity of institutions (see loop R7). This relationship underlines the fundamental role of financial resources in bolstering institutional capacity, as supported by Tewari & Ilesanmi (2020). Adequate funding enables higher education institutions to invest in essential areas such as infrastructure development, faculty recruitment, and academic programs, thereby enhancing their capacity to accommodate students and deliver quality education (Van Der Berg et al., 2011).\n\nLikewise, the CLD points to the interconnectedness between infrastructure, staff, and the capacity of institutions. Investments in infrastructure, including buildings, laboratories, libraries, and technology, are crucial for creating conducive learning environments and supporting academic activities (Tewari & Ilesanmi, 2020). Similarly, the availability of qualified and motivated staff members, including professors, lecturers, and support personnel, is essential for delivering high-quality teaching, research, and student support services (Oketch, 2016).\n\nIn addition, the positive relationship between the capacity of institutions and student enrolment underlines the significance of institutional development in driving educational access and participation, resonating with Tewari and Ilesanmi (2020). Institutions with robust capacity are better equipped to accommodate larger cohorts of students, offer diverse programs, and provide adequate support services to ensure student success. By expanding institutional capacity, higher education institutions can play a pivotal role in addressing the growing demand for tertiary education and promoting inclusive access for historically marginalised and underrepresented groups (Sayed & Soudien, 2005). This feedback loop underscores the importance of ongoing investment and strategic planning to sustainably expand institutional capacity and meet the evolving needs of students and society (Faham et al., 2017).\n\nFigure 5 shows the final CLD. A list of the variables and their descriptions pertaining to this CLD are shown in Table 2 below.\n\nThe research findings on evaluating fee-free higher education in South Africa resonate strongly with several Sustainable Development Goals (SDGs) and the aspirations of the African Agenda 2063. The study emphasises the importance of equitable access to quality education, economic empowerment, and reducing socioeconomic disparities, all of which are central to the global development agenda.\n\nThe research’s alignment with Sustainable Development Goal 4 (SDG 4), Quality Education, underscores its potential in addressing global priorities for inclusive and quality education. SDG 4 is a beacon for fostering equitable access to education and promoting lifelong learning opportunities for people worldwide (Kioupi & Voulvoulis, 2019). By emphasising the importance of enhancing student success rates and increasing the number of graduates, the research aligns closely with the core objectives of SDG 4, which seek to ensure that education is accessible, equitable, and of high quality for all individuals, regardless of background or circumstance.\n\nThrough its focus on improving student success rates, the research addresses barriers to educational attainment and strives to create a more inclusive learning environment. By identifying and addressing factors that hinder academic achievement, such as financial constraints, inadequate support services, and systemic inequalities, the research aims to promote equal access to educational opportunities and ensure that every learner has the chance to thrive, concurring with the perceptions of Jordaan, Van Heerden, and Jordaan (2014). Furthermore, by advocating for increased graduates, the research expands access to higher education and vocational training, empowering individuals with the knowledge and skills needed to contribute meaningfully to society. This aligns with SDG 4’s overarching goal of building a more educated, skilled, and empowered global population capable of driving sustainable development and fostering social progress (Kioupi & Voulvoulis, 2019).\n\nSustainable Development Goal 8 (SDG 8): Decent Work and Economic Growth. SDG 8 emphasises the importance of promoting sustained, inclusive, and sustainable economic growth and fostering full and productive employment for all individuals (Frey, 2018). By equipping graduates with the skills, knowledge, and qualifications needed for employment, fee-free higher education initiatives play a crucial role in advancing the objectives of SDG 8. As graduates enter the workforce, they contribute to creating new job opportunities, innovation, and productivity enhancements, thereby driving economic growth and development, according to research by Barro (2013).\n\nMoreover, the positive correlation between graduates and employment stresses the critical role of education in facilitating labour market participation and reducing unemployment rates (Lauder & Mayhew, 2020). By investing in higher education and expanding access to quality educational opportunities, countries can cultivate a skilled and adaptable workforce capable of meeting the demands of evolving industries and technological advancements supported by Vogel (2015). This not only enhances individual employability and earning potential but also strengthens the overall resilience and competitiveness of the economy. In this way, fee-free higher education initiatives serve as catalysts for achieving the goals of SDG 8 by promoting inclusive economic growth, reducing inequalities, and ensuring that no one is left behind in the pursuit of decent work and sustainable livelihoods.\n\nSustainable Development Goal 10 (SDG 10): Reduced Inequalities. SDG 10 accentuates the importance of reducing inequalities within and among countries, including income, education, and access to opportunities (Kioupi & Voulvoulis, 2019). By addressing disparities in access to higher education, fee-free higher education initiatives play a crucial role in promoting social inclusion and levelling the playing field for individuals from marginalised communities, in line with the research by Motala et al. (2023). By removing financial barriers to education, these initiatives enable students from low-income backgrounds and historically marginalised groups to access higher education, thereby narrowing the gap between privileged and disadvantaged groups and fostering more significant social equity (Reddy, 2004).\n\nMoreover, the research findings highlight the potential of fee-free higher education initiatives to improve outcomes for historically marginalised groups, such as reducing dropout rates, increasing graduation rates, and enhancing employment opportunities, which also correlates with the study of Sneyers & De Witte (2017). By providing students from marginalised backgrounds with the resources and support needed to succeed in higher education, these initiatives contribute to breaking the cycle of intergenerational poverty and inequality (Brewer & McEwan, 2010). Furthermore, by promoting diversity and inclusivity within higher education institutions, fee-free higher education initiatives create opportunities for individuals from diverse backgrounds to thrive and contribute to society (Ndaba, 2023). In this way, free higher education initiatives align with the objectives of SDG 10 by addressing systemic inequalities and promoting a more equitable and inclusive society for all members.\n\nAfrican Agenda 2063: The research findings are closely aligned with the aspirations outlined in the African Agenda 2063, a strategic framework for the socioeconomic transformation of the African continent. One of the key pillars of the African Agenda 2063 is human capital development, which emphasises the importance of investing in education, skills development, and lifelong learning to unlock the potential of Africa’s youth population (Addaney, 2018). By investing in fee-free higher education initiatives, South Africa can contribute significantly to advancing this objective by equipping its youth with the knowledge, skills, and qualifications needed to drive economic growth, innovation, and sustainable development across the continent (DeGhetto et al., 2016). Through access to quality higher education, South African youth can become catalysts for positive change, leveraging their expertise and talents to address pressing challenges and seize emerging opportunities in key sectors such as technology, healthcare, and agriculture, corroborating with the research by Reddy (2004).\n\nFurthermore, the research’s focus on fee-free higher education aligns with the goal of economic transformation outlined in the African Agenda 2063. By expanding access to higher education and promoting skills development, South Africa can foster a more dynamic and competitive economy, generating employment, reducing poverty, and promoting shared prosperity for all citizens (Mhangara et al., 2019). By nurturing a skilled and entrepreneurial workforce, fee-free higher education initiatives lay the foundation for sustainable economic growth and inclusive development, aligning with the vision of the African Agenda 2063 to create “the Africa We Want” - a continent characterised by shared prosperity, peace, and sustainable development (Nicolaides, 2011). In this way, South Africa’s investment in fee-free higher education benefits its citizens. It contributes to advancing the broader goals of socioeconomic transformation and continental integration outlined in the African Agenda 2063 (Mhangara et al., 2019).\n\n\n4. Conclusion\n\nThis research has comprehensively examined the dynamics surrounding fee-free higher education in South Africa, uncovering its implementation’s multifaceted challenges and opportunities. Through an analysis of historical contexts, policy frameworks, and institutional mechanisms, the study has illuminated the complexities surrounding access to tertiary education in the country. As the barriers posed by bureaucratic inefficiencies, funding constraints, and administrative complexities were outlined, the study underscored the urgent need for systemic reforms to enhance the accessibility and effectiveness of fee-free higher education initiatives. Moreover, the findings have shed light on the transformative potential of such initiatives in fostering social mobility, economic empowerment, and inclusive development.\n\nFurthermore, the implications of the research extend beyond the borders of South Africa, resonating with broader global agendas such as the Sustainable Development Goals (SDGs) and the African Agenda 2063. By aligning with these objectives, fee-free higher education initiatives serve as catalysts for advancing inclusive education and sustainable economic development. Moving forward, informed by the insights from this research, policymakers, educators, and stakeholders must collaborate to enact targeted interventions to address systemic barriers and maximise the impact of fee-free higher education on individuals and communities. Only through collaborative action can South Africa realise the vision of a more equitable and prosperous future for all its citizens.\n\nEthical approval and consent were not required.", "appendix": "Data availability\n\nNo data are associated with this article.\n\nNo extended data was used.\n\n\nReferences\n\nAbidin NZ, Zaibidi NZ, Karim KN: Strategic planning for MyRA performance: A causal loop diagram approach. AIP Conf. Proc. 2017; 1891(1): 20151. Publisher Full Text\n\nAddaney M: The African Union’s Agenda 2063: Education and Its Realisation. Education Law, Strategic Policy and Sustainable Development in Africa: Agenda. 2018; 2063: 181–197. Publisher Full Text\n\nAhmed R, Sayed Y: Promoting access and enhancing education opportunities? The case of ‘no-fee schools’ in South Africa. Compare. 2009; 39(2): 203–218. 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PubMed Abstract \| Publisher Full Text" }	[ { "id": "302491", "date": "02 Aug 2024", "name": "Héctor Ríos-Jara", "expertise": [ "Reviewer Expertise Higher education funding policy", "social policy", "political economy" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear Authors,\n\nI am pleased to read the article \"Evaluating the dynamics of fee-free higher education in South Africa: a causal loop diagram approach.\" The article aims to map out causal relationships and feedback loops. Causal loop diagrams facilitate a systemic understanding of fee-free higher education dynamics. This holistic perspective helps researchers uncover underlying patterns and mechanisms that drive policy implementation, impact, and outcomes.\n\nThe paper picks a relevant topic and case regarding the rise of new free education policies. The paper also offers a good summary of the policy, history and current dilemmas based on the literature. The methodology is innovative in the study of policies. However, I think the paper is not ready for indexing, and it lacks internal consistency. The methodology is too descriptive and does not allow it to fulfil the aims declared in the paper: \"uncover underlying patterns and mechanisms that drive policy implementation, impact, and outcomes\".\n\nThe paper is also disconnected from the international debate on free education and the implementation challenges, despite South Africa being one the most relevant cases of new free education policies in the XXI century.\n\nThe case and information are valuable, but in my view, the paper requires a redefinition of the aims so the method and results match the paper's aims. If the authors decide to keep the aims, I recommend complementing current data with new information, such as interviews with policymakers or quantitative data. The main reason for this suggestion is that the results are too descriptive and do not support many claims described by the author in the results and analysis.\nRebuilding the fluxes and procedures involved in the implementation of the policy tells a lot about how the policy works but not necessarily the problems, outcomes and challenges, which are the main aims of the paper. In addition, the paper can add more value if the authors introduce the debate of free education policies and their difficulties and frame South Africa as a case in the broader debate on the challenges of new free education policies. I hope my comments can improve the paper and not discourage the authors from publishing it because the case and information have a lot of potential but require major changes in its frame, narrative and methodology.\nI hope the authors consider these comments valuable and do not discourage them from developing the article because the paper has great potential. The authors picked a relevant case and problem for the international research community interested in higher education funding policies, particularly in free education policies. See below for more details and suggestions.\n\n1) Is the work clearly and accurately presented, and does it cite the current literature? (Partly) The paper does not address a wider debate on free education policies in international literature, particularly for the new generation of free education policies and their shared challenges. Consequently, it remains descriptive and focuses only on the South African case, which is relevant to a country, but also a case of policy innovation. See some references to check and include.\n\nTo improve the link with international debate on free education I recommend the following papers:\nAriane de Gayardon (2019 [ Ref - 1] ). There is no such thing as free higher education: A global perspective on the (many) realities of free systems. Higher Education Policy, 32(3), 485-505.\nH. Rios-Jara (2023 [Ref - 2]). The free education policy in Chile: Between transforming and maintaining neoliberalism. South African Journal of Higher Education, 37(6), 112-130.\nAngelica Buendia et al. (2024 [Ref - 3]). El mito de la gratuidad en la educación superior mexicana: Acercamientos a la comprensión de un cambio de política. Education Policy Analysis Archives, 32.\n2) Is the study design appropriate, and is the work technically sound? (no) The paper does not explicitly state a research question or a specific aim, so it is hard to see how the methodology feeds the research question. The analysis regarding the methodology and mixed impacts with policy implementation challenges is also ambiguous, going beyond the evidence.\nIt is not clear what problems free education policies face. The literature review gave a good overview, but the paper might clarify the specific problems that the policy faces. I suggest linking these problems with the international debate and similar issues that other free education policies face. Clarify the contribution and purpose of the causal loop diagrams and how the methodology is connected to the research question. Clarifying a specific research question will also improve the consistency of the paper.\n3) Are sufficient details of methods and analysis provided to allow replication by others? (partly) The description of the methodology is good. But the rationale behind it requires more details. It is not clear how the methodology helps to explore the research gap that the paper aims to address. Beyond the general uses of the methods, the methodology section should make explicit why and how this method helps to address the research gap. For example, \"Furthermore, unlike quantitative modelling techniques, such as econometric or statistical models, causal loop diagrams prioritise qualitative analysis and conceptual mapping. This approach is well-suited to exploratory research endeavours seeking to elucidate the complexities of social systems and policy environments, where precise numerical data may be limited or uncertain, as emphasised by Haraldsson (2004).\" The argument is too general and is not connected to the research gap and policy implementation challenges.\n\nIn addition, the distinction between economic, institutional, and economic factors is vague, and there is no specific definition of the variables included in each factor. It is relevant to unpack the \"dynamics of fee-free higher education in South Africa\" concept and clarify the research gap, how the article contributes to its exploration, and the variables that the article considered.\n4) Are all the source data underlying the results available to ensure full reproducibility? (Partly) The results presented do not provide evidence for all the analyses described in the paper. The analyses use quantitative jargon that does match the methods selected. In addition, the figures in section 3 are visually confusing. They do not help to explore the policy. I suggest developing a more stylised version of the figures and a better description of them. The integration of data and analysis needs to be more precise and better grounded in the information provided. If the data suggests further hypotheses, the author needs to make explicit that some statements are hypotheses, not data descriptions or analysis based on data. For example, \"One of the prominent findings from the CLD is the strong positive relationship between economic growth, as measured by GDP, and government spending, represented by the national budget (see loop R1).\" The language used in this sentence came from quantitative analysis. The figure does not show a \"strong positive relationship\". Moreover, the figure reveals the institutional flux of decisions and factors that attached the policy to national spending. Still, more information about policymakers' decisions and dilemmas must be available. The article closes this relevant information with general assumptions based on the literature that do not integrate data from the case. Another example \"the CLD illuminates the linkages between the national and higher education budgets, emphasising the significance of political decisions in shaping funding priorities. Government budget allocations directly influence the financial resources available for higher education (Barro, 2013), impacting the affordability and accessibility of tertiary education for students. This finding also aligns with literature highlighting the critical role of government funding in supporting higher education institutions and ensuring equitable access to quality education (Van Der Berg et al., 2011)\" The figure describes the procedural link between the national budget and the policy but does not open the dilemmas face by government. One of the main critiques of free education policies is its cost and financial sustainability, a topic of concern in South Africa, which, however, the paper does not address properly cause it does not add relevant information about how the policy is funded and what the dilemmas that policymakers and authorities face. Showing the links gives enough information about what is happening inside and how the actor deals with those problems.\nAnother example. The analysis goes beyond the data. \"Another significant insight emerging from the CLD is the presence of a positive feedback loop between the national budget, student enrolment, and budget allocation to universities (see loops R4 & R7). This feedback loop suggests a reinforcing cycle wherein increased government spending on education leads to higher student enrolment, prompting further budget allocations to universities.\" Here, the data show a link between them, but the paper does not provide any other evidence to show that rising government investment leads to more enrolments. It is unclear if the figure shows an expectation of policymakers or a link that might be considered a further hypothesis.\n\nThe analysis of the policy based on the Sustainable Development Goal 4 (SDG 4), Quality Education, came late in the article and it needs to be clarified why they are relevant for the paper. The introduction describes the policy as a consequence of protests and the aims to improve access and equality, which might be close to the SDG, but the policy was not introduced to achieve SDG.\n5) Are the conclusions drawn adequately supported by the results? Unfortunately, the conclusion goes beyond what the paper shows. For example, \"Through an analysis of historical contexts, policy frameworks, and institutional mechanisms, the study has illuminated the complexities surrounding access to tertiary education in the country. As the barriers posed by bureaucratic inefficiencies, funding constraints, and administrative complexities were outlined, the study underscored the urgent need for systemic reforms to enhance the accessibility and effectiveness of fee-free higher education initiatives\". The paper does not summarise the dilemmas or challenges of free education implementation in South Africa or its problems. The methodology used helps to map and understand how the policy works, which is a relevant result, but it does not add any further information about the pressing dilemmas that policymakers face or what kind of problems and solutions policymakers are debating.\nI see two possible solutions here. First, change the paper's aims and frame and make it only descriptive, focusing on understanding how the policy works. The main contribution will be showing how the policy has been implemented. Second, to add more data and policymakers' views on the main problems and perceptions that authorities and policymakers face implementing the policy. This would require adding interviews and other methodologies to the research, but the paper will be more relevant, especially if the authors decide to frame it in the context of the international debate on the rise of new free education policies.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No", "responses": [] } ]	1	https://f1000research.com/articles/13-780
https://f1000research.com/articles/13-940/v1	20 Aug 24	{ "type": "Systematic Review", "title": "Integration of democratic values in natural sciences education: A Literature Review of the last 50 Years", "authors": [ "Santiago Monsalve-Silva", "Gabriel Otalvaro-García", "Laura Sofía Cajica Velandia", "Ana Dolores Vargas Sánchez", "Santiago Monsalve-Silva", "Gabriel Otalvaro-García", "Laura Sofía Cajica Velandia" ], "abstract": "This study examines how democratic values have been promoted through natural sciences education over the last 50 years, providing a comprehensive analysis based on a systematic review of relevant literature. The central problem addressed is understanding the role of natural science education in fostering democratic values such as equity, participation, critical thinking, and ethical responsibility. This research aims to identify and analyze strategies, methodologies, and transformative experiences that contribute to the promotion of democratic values. This study employs the PRISMA methodology to ensure a rigorous and structured systematic review. Data were collected from multiple databases using detailed Boolean equations. Tools such as ScientoPy and VOSviewer were used for data preprocessing, clustering, and network visualization, followed by qualitative analysis to categorize the findings. Educational programs in natural sciences have increasingly integrated democratic values, fostering a culture of inclusivity and participation; the incorporation of ICT has enhanced equity and participation, while civic education has been fundamental in developing critical and informed citizens; citizen science initiatives have empowered students to engage in democratic deliberation and address epistemic injustice; cooperative learning methods in science classes have effectively promoted gender equity and inclusion; and emphasis on sustainability and environmental justice in science education has promoted democratic values and empowered students to take action on global challenges. In conclusion, natural science education is an effective vehicle for promoting democratic values, but it is an understudied field. By integrating practices that emphasize inclusivity, critical thinking, and ethical responsibility, science education not only enhances students’ scientific understanding but also prepares them to be active, informed, and responsible citizens.", "keywords": [ "education", "democratic values", "natural sciences", "civil education" ], "content": "Introduction\n\nColombia and the world have faced historical crises due to armed conflicts, development processes, and the influence of global ideologies. Events such as the Second World War, the Cold War, and the Latin American dictatorships stand out, whose effects have left a mark on generations’ thinking and behavior. However, despite their negative impact, these events are fundamental for developing a reflective, scientific, and proactive society. Hence, an urgent need arises to cultivate a culture of peace that encompasses various dimensions of social coexistence, environmental preservation, personal growth, and interactions between individuals and knowledge.1\n\nThe United Nations (UN), through UNESCO, has proposed recommendations to achieve world peace and contribute to human development through education.2 It promotes comprehensive education that transcends educational standards and is applied in all contexts and levels, including rural, urban, conventional, and nonconventional areas, targeting people of all ages and social classes.3\n\nIn its 42nd General Conference meeting, UNESCO3 declared a series of aspects aimed at facilitating and promoting education for a culture of peace in all contexts. These aspects are based on current challenges in environmental, social, scientific, and technological areas.\n\nIn the 21st century, peace is redefined as an active process beyond conflict avoidance, emphasizing the appreciation of human dignity and mutual care for ourselves, others, and the planet. Educational systems play a crucial role in fostering this new understanding. They must equip individuals with the knowledge and skills to address climate crises sustainably, promote global citizenship through cooperation and dialog, and advance gender equality by ensuring equal access to education. In addition, in the digital age, media and digital literacy are paramount, enabling informed decision-making, critical thinking, and ethical online behavior.3\n\nCabezudo and Haavelsrud4 established that to perform peace education processes, it is essential to start with a series of fundamental ideas. These include understanding the meaning of “peace,” the role of the community in its construction, and the expected impacts in the short, medium, and long term. Progress has been made in defining the concept of peace, moving away from the traditional idea of simply “the absence of violence and the presence of social justice, participation, and diversity” (p. 10). Peace is understood as a process of freedom that recognizes the learning capacity of each individual and the importance of the sociocultural context in which they find themselves.5 Dialog plays a crucial role in building this culture of peace, as it is both an act of human recognition and an ontological and epistemological necessity to seek truth together with others. Thus, it is recognized that building a peaceful society is not solely the responsibility of the social sciences, but all disciplines must address the challenges and issues raised, maintaining a close link between education for peace and a culture based on respect for human rights, non-violence, and dialog, thus promoting peaceful relationships and continuous transformation.6\n\nTherefore, education for peace is based on a series of pillars that facilitate the construction of a culture of peace. These pillars are known as the dimensions of education for a culture of peace.7 In this case, we focus on the dimension of democratic values, as mentioned by Cerdas-Agüero.8 Democratic exercise must always be accompanied by values and good attitudes, with the main ones being predisposition, conviction, and willingness to act coherently and responsibly. Likewise, ethical reflection and the expression of values are crucial for democratic life, especially in societies facing crises of civility and lack of positive values, which can lead to demoralization and confusion.\n\nGiven the above, it is crucial to recognize the strategies implemented in the last 50 years in peace education and its integration with current issues from the framework of sustainable development, taking into account international documents such as the UNESCO declaration on a culture of peace, whose central axis is the prioritization of a peaceful, integral, and sustainable society, providing a roadmap for the world and the achievement of the goals proposed in the document. Scientific disciplines play a fundamental role in promoting a culture of peace; therefore, this study analyzes the promotion of democratic values through the natural sciences using a scientometric methodology in databases covering the last 50 years. This is done to answer the following research question: “How have democratic values been promoted through the natural sciences in the last 50 years?”\n\n\nMethods\n\nIn this study, the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology was adopted to ensure a rigorous and structured systematic review.9 The specific objectives of the study were initially defined to guide the selection and analysis of relevant literature. Subsequently, the inclusion and exclusion criteria for the studies were clearly established to focus on the most pertinent and high-quality publications.9 For data collection, exhaustive searches were conducted across Scopus and Web of Science databases using a detailed search strategy with Boolean equations, as shown in Table 1.\n\nThe study selection process was conducted using a two-stage approach, in which studies were initially filtered on the basis of titles and abstracts, followed by full-text evaluation for those that met the preliminary criteria: the relationship with democratic values and the relationship with education in natural sciences; the first filter focused on identifying studies that promote or evaluate the integration of democratic values such as equity, justice and citizen participation within the educational context, and the second filter addressed the specific connection with natural sciences education, seeking research that explores effective methodologies, content, and pedagogical practices in natural sciences teaching. This process is illustrated in a PRISMA flowchart (Figure 1) that reflects the stages of selection and the reasons for study exclusion. Three reviewers performed a quick reading of the articles, focusing on summary, objective, methodology and results, they worked independently and then a second review was carried out analyzing the same criteria. Data extraction was performed independently by three reviewers to avoid bias, and any disagreements were resolved through discussion.\n\nThe extracted data were synthesized using tools such as ScientoPy® version 2.1.3 and VOSviewer® version 1.6.20 for preprocessing, subsequently facilitating the identification of clusters and interactions among the contents and authors. Finally, a qualitative analysis was conducted where six categories were defined, with each article being classified into a category, thus providing a comprehensive and systematic assessment of the existing literature, yielding well-founded conclusions.version 1.6.20 for preprocessing, subsequently facilitating the identification of clusters and interactions among the contents and authors. Finally, a qualitative analysis was conducted where six categories were defined, with each article being classified into a category, thus providing a comprehensive and systematic assessment of the existing literature, yielding well-founded conclusions.\n\nTo ensure the methodological rigor of this study under the PRISMA guidelines, the methods used to assess the risk of bias in the included studies were detailed thoroughly. Multiple independent reviewers were assigned to each study to ensure objectivity, and in cases of discrepancies, a third reviewer was consulted. Automated tools were utilized when necessary, particularly in the analysis and construction of clusters.\n\nRegarding the synthesis methods, data extraction processes were employed, identifying primary outcomes, categorizing results, and deciding the eligibility of studies for each synthesis. This included tabulating the characteristics of each article and comparing them with the planned categories.\n\nIn terms of data preparation for presentation or synthesis, all articles were downloaded and systematically organized in MS Excel, where the analysis and categorization processes were conducted. For tabulating and visualizing results, the previously described tools were used to present the results of individual studies and syntheses. Sensitivity analyses were conducted, and possible causes of heterogeneity among the results were explored. For assessing the risk of bias due to missing results, a comprehensive reading of the findings with artificial intelligence was performed to confirm the identified ideas.\n\nThe data from the literature review process, integration of democratic values in natural sciences education, the PRISMA checkboard and the process flow diagram have been published by Ref. 10 and are located in the availability section.\n\n\nResults\n\nAccording to the methodology outlined above, the following section presents an overview of the results obtained from the preprocessing, the networks constructed with the selected articles, and the findings from each category.\n\nFirst, during preprocessing, the evolution and distribution of scientific production from various countries over time is identified, as shown in Figure 2. The line graph on the left shows an exponential growth in scientific document production from the United States, particularly noticeable since 2000. In comparison, other countries such as the United Kingdom, Spain, the Russian Federation, Sweden, Turkey, China, Brazil, Denmark, and Germany also show an increase in the number of published documents, albeit more moderately. Notably, nations like China and Brazil have significantly intensified their document production in the last two decades.\n\nSource: the authors, made in ScientoPy.\n\nThe scatter plot on the right illustrates the recent activity (2022-2023) of these countries in terms of scientific publications. Although some countries show a lower percentage of recently published documents, the average number of documents published per year during this period is relatively high for some, a recent intensification in their research efforts. This analysis not only allows appreciation of the historical trajectory of scientific production from the selected countries but also helps identify current trends in their contributions to the global scientific corpus.\n\nSubsequently, an analysis of trends by topic in documentary production from 1980 to 2025 was conducted, as shown in Figure 3. In the line graph, the field of “Government & Law” has experienced significant exponential growth, particularly starting in 2005 and continuing with a marked increase until 2025. Other fields such as “Education & Educational Research,” “Social Sciences-Other Topics,” and “International Relations” also show a steady increase, albeit less pronounced.\n\nSource: the authors, made in ScientoPy.\n\nRegarding the scatter plot, which assesses the recent activity of these fields in 2022-2023, it can be seen that “Government & Law” not only dominates in terms of cumulative growth but also in recent annual average production, indicating a high ongoing activity in this field. Other fields, while having fewer cumulative documents, show a respectable average of recently published documents per year, a renewed or emerging interest in these topics.\n\nSimilarly, a trend analysis using keywords was conducted, as shown in Figure 4. First, in the line graph on the left, the field of “democracy” shows a prominent exponential growth, especially after 2005, peaking in 2025. Other topics such as “Democratic values”, “Political participation”, and “Democratization” also exhibit a notable increase over time, although on a more moderate scale. Fields like “education” and “Human rights” demonstrate steady but less dramatic growth.\n\nSource: the authors, made in ScientoPy.\n\nIn the scatter plot on the right, which assesses recent publication activity (2022-2023) in these topics, it is evident that “democracy” not only leads in terms of cumulative growth but also maintains a high average of documents per year in the recent period, indicating a sustained and robust interest in studies on democracy. Topics such as “Democratic values” and “Political participation” show a significant percentage of recent documents, reflecting renewed focus on these themes in contemporary literature.\n\nSubsequently, from the selected articles that help to address the research question, a network of keywords was constructed in VOSviewer (Figure 5), demonstrating how various themes related to education, democracy, and science are interconnected across seven main clusters.\n\nSource: the authors, made in VosViewer.\n\nThe first cluster emphasizes citizenship education and encompasses aspects such as democratic values and inclusive education, highlighting the importance of integrating democratic principles into educational training to foster active social participation. The second cluster explores the relationship between science and citizenship, underscoring the role of the Internet in scientific dissemination and how it affects communication and transparency in the public sphere.\n\nThe third cluster links civics education with higher education and knowledge, proposing a synergy between civic training and advanced pedagogy. Meanwhile, the fourth cluster focuses on communication via social media, examining topics such as epistemic trust and transparency, and how these factors influence public perception and trust toward institutions. The fifth cluster connects democracy with environmental education and evolutionary biology, illustrating how educational approaches in science can complement and enhance understanding and participation in democratic practices, especially in the context of sustainability.\n\nThe sixth cluster addresses ethics, equality, and learning, underlining the relevance of these values in education and their impact on social and cultural development. Finally, the seventh cluster focuses on attitudes and education, exploring how predispositions toward learning and teaching affect educational processes.\n\nThis network provides a comprehensive view of how the interaction between these themes can generate new perspectives and opportunities for integrating the concepts of democracy, science, and education. It also highlights the importance of interdisciplinarity in the study of education and democracy, showing how different fields can collaborate to promote a more informed and participative society.\n\nA network of collaborations among various authors was subsequently constructed (Figure 6), represented by several colored nodes. These nodes indicate groups of authors who frequently co-publish or are thematically related. Each node in the diagram represents an author, and the lines connecting the nodes indicate collaborations between them. The different colors assigned to the nodes may represent different fields of study, institutions, or simply co-authorship groups that have collaborated closely on several research projects.\n\nSource: the authors, made in VosViewer.\n\nThe network shows low collaboration among various researchers, indicating a limited shared interest in integrating democratic values into science education. This organization suggests a multidisciplinary approach, where different aspects of science and democracy are addressed from various angles without effective integration.\n\nThe red cluster shows a group of authors who collaborate closely with each other, suggesting a cohesive approach and possibly a joint project or a series of publications related to specific topics within the study of democracy and natural sciences. Other clusters that demonstrate collaboration are the green, light blue, and orange clusters.\n\nEach study was independently reviewed by two reviewers, and in cases of discrepancy, a third reviewer intervened to reach a consensus. The risk of bias assessment focused on aspects such as category selection, result extraction, outcome assessor blinding, and the handling of incomplete data. For the synthesis of the studies, key characteristics such as study design, sample size, educational context, and main outcomes were analyzed. The included studies varied in terms of methodological approach. Most studies showed a low risk of bias in critical areas.\n\nPossible causes of heterogeneity among study results were investigated through collaborator network analysis and cluster analysis with keywords. Differences in contexts and methodologies used were the main sources of heterogeneity. Additionally, studies that used qualitative versus quantitative approaches showed heterogeneous results in terms of effectiveness and perception of democratic values.\n\nIn the first instance, this category aims to classify articles that discuss and/or propose innovative approaches to teaching natural sciences in conjunction with democratic values, including innovative pedagogical methods and the integration of technologies in the classroom through interdisciplinary approaches. Initially, educational theory and philosophy were considered as the academic foundation for the relationship between education and politics, portraying the teacher and their methodologies as symbols of empowerment and social change, allowing for a series of criticisms and innovations in the educational systems of countries around the world, prioritizing students and their role in society.11 The development of these methodologies has progressed as education was initially conceived as an alternative for social development (which is not wrong, but nowadays it is not limited solely to this field), incorporating democratic values into the school curriculum12; Likewise, these types of models have been reconsidered over time, demonstrating how education provides the necessary tools to develop a democratic reflection exercise, thus promoting critical and thoughtful citizenship by integrating all disciplines, in this case, the natural sciences. Erduran and Kaya13 proposed a series of questions for science teachers to promote scientific skills to achieve the goal of a critical and integral society regarding democratic values and how it can be achieved through various pedagogical models proposed in the research.\n\nIt is also important to recognize what Plaza De La Hoz14 proposed, whose investigation delves into the evolving dynamic between educational authority and democratic values considering the integration of Information and Communication Technologies (ICT). Its dual objective is to analyze recent scholarly works concerning the impact of ICT on pedagogical authority and to corroborate these insights through empirical observation. Contrary to prevalent critical perspectives, the investigation posits that ICT serves to bolster teacher authority, albeit in a transformed manner, transitioning from a predominantly authoritative stance to one that is more demonstrative. Thus, corroborating the way in which not only education but also its approaches, strategies, and didactics have been advancing alongside political and social development.\n\nContrary to what has been exposed, but to great surprise, methodologies with a positive impact have not stood out according to this study, since only one investigation belonging to Esiobu15 has been found. This study investigates the impact of cooperative learning on promoting peace, equality, and equity in science classrooms, which are essential for sustainable development within a democratic framework. Through a gender equity and peace questionnaire, we found that cooperative learning effectively fosters equity and peace among genders in the biology classroom. This establishes a strong relationship between the Sustainable Development Goals and the development of scientific thinking in the classroom, thus promoting democratic values within the institution.\n\nThe integration of science into educational programs has become pivotal for developing scientific skills within communities, particularly in areas concerning the environment and community health. Through cienciometric tracking, a wide array of documents emphasizing the significance of promoting environmental education for ecosystem conservation and fostering democratic values for sustainable development have been identified.16 However, this challenge is not confined to classrooms; it also poses a dilemma for policymakers, as environmental governance is essential for devising strategies that safeguard the environment and biodiversity through effective governance.17\n\nPresently, environmental education is on the rise, with natural sciences focusing on sustainable applications and explanations of environmental phenomena. This interdisciplinary field permeates all areas of knowledge because of its versatility and is closely linked to democracy and its values. Terms such as democracy and environmental justice are addressed, empowering educators, students, and policymakers to reconsider their impact on preserving the world.18 Environmental education is incomplete without action, as highlighted by Mogensen and Schnack,19 who underscore the crucial role of action in sustainable development processes in society. Since 1980, this component has been integrated into Denmark’s educational programs, resulting in significant shifts in population dynamics and bolstering democratic values regarding the environment across all knowledge domains.\n\nDespite science being fundamental for societal development, uncertainties persist regarding sustainable development, biodiversity conservation, and the contribution of democratic values to achieving the Sustainable Development Goals.20 The emergence of new technologies offers opportunities for scientific and social innovation, prompting educational and governmental institutions to develop action plans to consolidate scientific knowledge within communities. It is imperative to not overlook the importance of democratic values in ensuring global sustainable development21,22\n\nThe importance of integrating democratic values into various fields of knowledge has been emphasized; however, it is crucial to specify which types of democratic values should be promoted through different research. Initially, these values must be enhanced through active participation; nevertheless, highlighted challenges in student motivation, fewer female candidates and representatives, and gender biases favoring male candidates have been identified. Female students faced obstacles and lacked democratic campaign methods; however, they challenged gender norms by supporting female candidates.23\n\nSimilarly, new technologies pose a fresh challenge to democratic values. The emergence of digital disruptions, particularly facilitated by platforms like social media, presents a notable obstacle to democratic principles and collective wisdom. Concerns such as misinformation, political biases, and increasing distrust in institutions have the potential to undermine the efficacy of collaborative endeavors. Safeguarding the pivotal role of collective participation in confronting contemporary challenges requires immediate action to address issues like inclusivity, openness, and group dynamics.24 Recent surges in antivaccine activism and other antiscience trends have converged with rising antisemitism. A clear example of this phenomenon arose during the COVID-19 pandemic, as far-right elements often employed Nazi imagery to criticize vaccinations and even blamed the Jewish people for COVID-19 and vaccine profiteering. These parallels with historical persecution underscore the urgent need for action.25\n\nMoreover, democratic values are linked to science in society. Initially, the focus was on reflecting on the relevance of scientific disciplines in democracy, and vice versa, integrating the foundations of both natural and social sciences, reaching scientific and democratic philosophy, and presenting points of disagreement or agreement.26 In essence, both fields of knowledge are interdependent, considering that natural sciences provide explanations for phenomena that facilitate or challenge human development; likewise, social sciences provide knowledge regarding human behavior and society, relating aspects such as justice, equity, and recognition of various ethnicities and populations.\n\nThese sciences are at the forefront of exercising democratic values concerning the environment, gender, and sustainable development.27 Thus, in democratic societies, the threat of populism persists, but science can help mitigate this risk. By upholding shared values like honesty and universalism, science serves as moral leadership, preventing the rise of populism. Additionally, science contributes to a system of checks and balances that limit executive power. However, an excess or deficiency of science can lead to democratic failures, highlighting the need to reaffirm democratic values. Meanwhile, a study on tenured academics’ experiences in science communication reveals their commitment to sharing knowledge beyond academia, despite the challenges it poses to their academic work. They engage in various writing practices driven by a desire to educate and democratize scientific knowledge. Further research and training programs are required to enhance science communication skills among future scientists.28–30\n\nCivic education seeks to promote critical awareness of social, political, and environmental issues, fostering respect for diversity and a commitment to the common good. As noted by Matusevych and Shevchuk,31 civic education is a fundamental tool for building trust across various domains, with the aim of developing social responsibility grounded in ethical principles and the pursuit of the common good. This approach not only aims to inform students about their rights and duties as citizens but also motivates them to actively participate in society and contribute to its improvement.\n\nSimilarly, education for citizenship focuses on preparing citizens to navigate the dynamism of modern societies. According to Neoh,32 it is crucial that curricula are designed to reflect the objectives and developmental needs of contemporary society. This necessitates a constant adaptation of educational content to ensure that students are well equipped to face contemporary challenges, such as globalization, digitalization, and environmental changes.\n\nHowever, Feu et al.,33 underscored the importance of addressing key concepts in a unified manner within the educational sphere. According to this study, for the teaching-learning process to be effective, it is essential that all educational actors (teachers, students, administrators) share a common and cohesive understanding of the principles and objectives of civic education. This ensures that the values and knowledge imparted are coherent, facilitating their internalization and practical application by students.\n\nIn this category, strategies for initial and ongoing teacher training are analyzed to prepare educators for classroom challenges by integrating democratic values such as equality, inclusion, and mutual respect into their pedagogical practice. Johnston34 suggests that leadership, the pursuit of democratic values, and the structural and cultural dimensions of school organization are fundamental for continuous societal improvement. It is crucial to define the roles of formal school leaders, teachers, and other school staff to create an educational environment that supports democratic objectives.\n\nAdditionally, Yazici35 presented a study on the democratic values of prospective teachers using the Democratic Teacher Values Scale. The study indicates that future teachers exhibit high levels of democratic values in terms of solidarity, the right to education, and freedom. This study underscores the need to incorporate these values into teacher training programs so that teachers can effectively promote a learning environment that reflects these principles. It concludes that factors such as the university attended and the father’s educational background significantly impact these values, highlighting the importance of a comprehensive and contextualized approach to teacher training.\n\nFinally, Gökçe36 and Dogru and Demirbas37 explored teachers’ perceptions and expectations regarding the parameters of rights, freedoms, and responsibilities within democracy. Gökçe revealed a significant discrepancy between the observations and expectations of prospective teachers concerning these values, indicating an urgent need to align educational practices with democratic ideals. On the other hand, Dogru and Demirbas found a positive and moderate relationship between teachers’ perceptions of multicultural competence and their democratic values, suggesting that strengthening these values can enhance teachers’ ability to manage classroom diversity. Both studies emphasize the importance of teacher training that not only imparts knowledge but also fosters a culture of justice, respect for differences, and equity.\n\n\nDiscussion\n\nFirst, there is a clear convergence on the notion that education should transcend the mere transmission of technical knowledge, incorporating democratic values essential for the development of a more just and participatory society. The integration of ICT, civic education, and service-learning are prominent strategies that promote equity, participation, and the moral and intellectual development of students. Scientific argumentation and deliberative democracy are presented as complementary methods that enrich teaching and foster critical and participatory understanding among students.\n\nFriis12 and Plaza de la Hoz14 highlight how ICT can enhance equity and participation in education, demonstratively reinforcing pedagogical authority. Abernathy and Forestal,38 along with Iskhakova et al.,39 emphasize the need for civic and political education to cultivate informed and engaged citizens by employing both extracurricular events and innovative approaches to political education. Wirth40 and Erduran and Kaya41 explored the intersection between science and democracy, proposing that scientific education should include practices of argumentation and democratic deliberation to develop critical and participatory skills. Finally, Óscar, Celina, and Jesús42 advocated service-learning as a methodology that combines academic learning with community service, fostering social responsibility and civic engagement.\n\nFeu et al.43 addressed the need for a precise and multifaceted understanding of democracy within the educational sphere, highlighting four dimensions: governance, habitance, alterity, and ethos. This framework can be applied to science education to promote an inclusive and participatory school culture, thereby fostering ethical responsibility and respect for diverse perspectives.\n\nThornton and Jaeger44 complement this vision by emphasizing civic responsibility within higher education. They argue that promoting scientific knowledge and skills for societal benefit and appreciation for diversity are pertinent to science education, which can contribute to forming students aware of their societal roles.\n\nConversely, Purevdagva et al.45 underscored the importance of fact checking and critical thinking in scientific education. Educating students about the significance of critically evaluating and understanding the world is essential for fostering informed and engaged citizenship.\n\nHerzog and Lepenies46 mention that citizen science can promote deliberative democracy and address epistemic injustice. Integrating active student participation in dialog about the direction and impact of scientific research encourages scientifically informed and engaged citizens.\n\nEsiobu47 demonstrated how cooperative learning in science classroom can promote gender equity and inclusion. By showing that this methodology can overcome gender barriers and promote equality, cooperative learning is essential for democratic education.\n\nAdditionally, Federowicz and Terepyshchyi48 support this vision by highlighting how integrating democratic values into the Polish educational system can facilitate cultural understanding, civic engagement, and social inclusion. As Thornton and Jaeger44 mention, civic responsibility within higher education is an approach applicable to natural sciences that promotes the use of scientific knowledge for societal benefit and fosters an appreciation for diversity.\n\nHowever, Sorgner49 discusses the relationship between scientific authority and democratic participation in decision making. He addresses the balance of expert knowledge with the inclusion of diverse perspectives and democratic values in scientific education to prepare students for engaging in critical dialogs about science and society.\n\nManias et al.50 discussed the need for transparency and accountability in the use of AI in governance. They emphasize the importance of educating natural science students about ethical and democratic principles concerning technology, promoting a critical understanding of how technology can be ethically and responsibly designed and used.\n\nAs Schroeder51 mentions, science should appeal to democratic values, meaning the values of the public or their representatives, to maintain or even strengthen public trust in scientific research. He emphasizes the importance of integrating democratic values into scientific education.\n\nThus, the integration of democratic values into education has significant implications for educational policies and pedagogical practices. To develop a more equitable and democratic society, it is essential to implement policies that promote equity and accessibility in education using innovative technologies and methodologies. Furthermore, fostering civic and political education from an early age is crucial for developing informed and engaged citizens.\n\nIn this way, the practices of democratic deliberation and argumentation in scientific education can enrich students’ understanding of the interconnection between science and democracy, preparing them to actively participate in scientific and political debates. Similarly, service-learning, as a pedagogical methodology, offers a practical approach to integrating academic learning with community service, promoting democratic values, and developing personal and professional competencies in students.\n\n\nConclusions\n\nThe findings suggest that the promotion of democratic values through science is an under-researched area; however, it is inferred to be a multidimensional process that includes the incorporation of inclusive practices, the fostering of critical thinking, gender equity, ethical responsibility, and civic participation. These approaches not only enhance the quality of scientific education but also prepare students to become informed and engaged citizens in a democratic society.\n\nFurthermore, the importance of developing curricula and educational policies that integrate democratic values into the teaching of natural sciences is emphasized. This not only improves scientific education but also strengthens democracy by preparing students to be active, critical, and responsible citizens.\n\nThe incorporation of information and communication technologies (ICT) has been a key element in promoting equity and participation in education. Friis and Plaza de la Hoz demonstrate how ICT can reinforce pedagogical authority and facilitate more inclusive and participatory education. Additionally, civic education, as noted by Purevdagva et al., is fundamental in forming informed and engaged citizens capable of critically evaluating information and participating in scientific and political debates.\n\nHerzog and Lepenies emphasize the importance of integrating active student participation in scientific research, to foster a scientifically informed and engaged citizenry. This approach enables students to better understand the relationship between science and social values, thereby promoting greater involvement in scientific decision-making.\n\nFinally, promoting civic and political education from an early age, as well as incorporating practices of democratic deliberation and argumentation in scientific education, can enrich students’ understanding of the interconnection between science and democracy.\n\nEthical approval and consent were not required", "appendix": "Data availability\n\nNo data associated with this article.\n\nS. Monsalve-Silva, J. G., Otalvaro-García, L. S, Cajica Velandia, & A. D., Vargas Sánchez. Extended data Integration of democratic values in natural sciences education [Data set]. Zenodo. 2024. doi: https://doi.org/10.5281/zenodo.13229007. 10\n\nThe project contains the following extended data:\n\n1. Flow_diagram_Integration of democratic values in natural sciences education.png\n\n2. Literature Data Integration of Democratic Values.xlsx\n\n3. PRISMA_Checklist_Literature Data Integration of Democratic Values.docx\n\nCreative Commons Zero v1.0 Universal\n\n\nReferences\n\nCabrera LJ, Corcione MA, Figueroa EC, et al.: On narratives and memory: a reflection on the Colombian armed conflict from military history. Revista Científica General José María Córdova. Oct. 2018; 16(24): 177–201. Publisher Full Text\n\nUNESCO: Lo que debe saber sobre la Recomendación de la UNESCO sobre la Educación para la Paz, los Derechos Humanos y el Desarrollo Sostenible. 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Jan. 2020; 36(139): 60–69.\n\nNegretti R, Persson M, Sjöberg-Hawke C: Science stories: researchers’ experiences of writing science communication and the implications for training future scientists. International Journal of Science Education, Part B. Jul. 2022; 12(3): 203–220. Publisher Full Text\n\nCollins H, Evans R: Populism and Science. Epistemology & Philosophy of Science. Dec. 2019; 56(4): 200–218. Publisher Full Text\n\nWeinberg J, Elliott KC: Science, Expertise, and Democracy. Kennedy Institute of Ethics Journal. Jun. 2012; 22(2): 83–90. Publisher Full Text\n\nMatusevych T, Shevchuk D: DEVELOPING RESPONSIBLE CI-TIZENS IN NEW REALITIES: THE CASE OF SCIENCE EDUCATION. Youth Voice Journal. Jan. 2022; 2022(Special): 45–53.\n\nNeoh JY: Citizenship and democratic education in the time of rising nationalism: Implications for citizenship education from the cases of Australia and Singapore. Citizenship Teaching and Learning. Oct. 2021; 16(3): 361–379. Publisher Full Text\n\nFeu J, Serra C, Canimas J, et al.: Democracy and Education: A Theoretical Proposal for the Analysis of Democratic Practices in Schools. Studies in Philosophy and Education. Nov. 2017; 36(6): 647–661. Publisher Full Text\n\nJohnston BJ: Types of educational leadership in a postindustrial society. Urban Rev. 1996; 28(3): 213–232. Publisher Full Text\n\nYazıcı K: An analysis of social studies prospective teachers’ democratic values in relation to various variables\|Request PDF. Egitim Ve Bilim-education and Science. 2011; 36(159): 165–178. Accessed: May 16, 2024. Reference Source\n\nGökçe F: Democracy and Democracy Education in the Parameters of Rights, Freedoms, Equality and Responsibilities. American International Journal of Contemporary Research. 2013; 3(10). Accessed: May 16, 2024. Reference Source\n\nSaid Doğru M, Demirbaş İ: The Relationship Between Perceptions of Multicultural Competence and Democratic Values. Journal of International Students. Feb. 2021; 11(1): 24–40. Publisher Full Text\n\nAbernathy C, Forestal J: Civics Across Campus: Designing Effective Extracurricular Programming. Journal of Political Science Education. Jan. 2020; 16(1): 3–27. Publisher Full Text\n\nIskhakova NH, Chuprii LV, Lyasota LI, et al.: Innovative Approaches of Political Education in Ukraine: On the Example of Developed Western Democracies. AJIS. Mar. 2020; 9(2): 127. Publisher Full Text\n\nWirth AG: Exploring Linkages between Dewey’s Educational Philosophy and Industrial Reorganization.May 1981; 2(2): 121–140. Publisher Full Text\n\nErduran S, Kaya E: Scientific Argumentation and Deliberative Democracy: An Incompatible Mix in School Science? Theory into Practice. Oct. 2016; 55(4): 302–310. Publisher Full Text\n\nÓscar CB, Celina SG, Jesús RMP: Service-learning as a new methodological teaching trend in physical education and sport sciences. Journal of Physical Education and Sport. Apr. 2018; 18: 335–341. 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PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nEsiobu GO: Achieving gender equity in science class: Shift from competition to cooperative learning. Multicultural Education & Technology Journal. Nov. 2011; 5(4): 244–257. Publisher Full Text\n\nFederowicz M, Terepyshchyi S: Democratic Values in Education: A Theoretical Examination of Ukrainian Children and Youth in Polish Schools Post-February 2022. Studia Warmińskie. Dec. 2023; 60: 45–60. Publisher Full Text\n\nSorgner H: Challenging Expertise: Paul Feyerabend vs. Harry Collins & Robert Evans on democracy, public participation and scientific authority: Paul Feyerabend vs. Harry Collins & Robert Evans on scientific authority and public participation. Studies in History and Philosophy of Science Part A. Jun. 2016; 57: 114–120. Publisher Full Text\n\nManias G, et al.: AI4Gov: Trusted AI for Transparent Public Governance Fostering Democratic Values. Proceedings - 19th International Conference on Distributed Computing in Smart Systems and the Internet of Things, DCOSS-IoT 2023. 2023; pp. 548–555. Publisher Full Text\n\nSchroeder SA: Democratic Values: A Better Foundation for Public Trust in Science. The British Journal for the Philosophy of Science. Jun. 2021; 72(2): 545–562. Publisher Full Text" }	[ { "id": "323025", "date": "03 Oct 2024", "name": "Genç Osman ilhan", "expertise": [ "Reviewer Expertise Social studies education", "civics education", "history and education", "museum education" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article addresses the integration of the democratic values in natural science education in a well-organized document. The rationale and the objectives of the article are stated with references to government and union documents, which are among the strengths of the study. The rationale is supported with the UNESCO and EU documents; but the academic literature leading to the creation of this study is not explained through. The existing literature on the topic is recommended to be thoroughly presented and discussed in the \"Introduction\" part. Another strength of the article is the construction and reporting of the methodology. The PRISMA methodology enabled the researcher to conduct the systemic review in a consistent and effective way. Also, the manuscript provides detailed information on the selection of the data and the analysis. The results part is enriched with sourceful data and visual tools such as figures. In the \"discussion\" part, the author(s) presented the existing literature on the topic. However, discussing the results of the study with the literature would be more convincing and effective. The results need to be matched with the references given in the manuscript and discussed through. In the conclusion part, the author refers to Herzog and Lepenies without a reference number. It needs to be revised and corrected. The article is well-designed and contributory to the field. However, the introduction and discussion parts need to be worked through. The discussions on the significant topics such as democracy, civic education and the others need to be discussed with references to the existing data rather than summarization\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Partly\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable", "responses": [ { "c_id": "13101", "date": "20 Jan 2025", "name": "Ana Dolores Vargas Sánchez", "role": "Author Response", "response": "The reviewer's comments have been extremely beneficial in improving the content. We are grateful for their input. We changed as follows: The introduction encompassed a more detailed examination of the more specific literature. Reviewed and changed, the discussion included writers to the outcomes. Reviewing and changing the conversation allowed the issues of democracy, civic education, and others more importance. The reference that shown discrepancies has been corrected. Thank you." } ] }, { "id": "338091", "date": "05 Dec 2024", "name": "Anissa Lestari Kadiyono", "expertise": [ "Reviewer Expertise Psychology", "Industrial & Organizational Psychology", "Entrepreneurship", "Gender", "Human Capital", "Organizational Behavior" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSTUDY AIM:\nThis study examines how democratic values have been promoted through natural sciences education over the last 50 years, providing a comprehensive analysis based on a systematic review of relevant literature. However, the problems that occur are not depicted so what is the problem with democratic values and why through natural sciences education.\nIntroduction:\nThe research was opened by giving a statement that “Colombia and the world have faced historical crises due to armed conflicts, development processes, and the influence of global ideologies. Events such as the Second World War, the Cold war, and the Latin American dictatorships stand out, whose effects have left a mark on generations’ thinking and behavior. However, despite their negative impact, these events are fundamental for developing a reflective, scientific, and proactive society. Hence, an urgent need arises to cultivate a culture of peace that encompasses various dimensions of social coexistence, environmental preservation, personal growth, and interactions between individuals and knowledge”. This is not clear to illustrate the problem of the importance of democratic values. Explain the context of the research and the importance of the problem so that democratic values need to be researched. Overall, natural science education has no basis in theory or application. It is necessary to explain what is the content of this education, both in content and in process, and what kind of gap research this research can fill. There is no relevant research and connection with previous research (novelty and merit)\nRESULTS: In the result section, several important points have not been presented in the article, namely:\nThe explanation of the research results is based on the results of a systematic literature review and lacks an additional explanation of previous research and how these results are explained to the phenomena in the field. This study only presents data with little information. There should be many things that can be elaborated on in this research.\nDISCUSSION: In the discussion section, no in-depth elaboration of research results was found, especially regarding the discussion of the uniqueness of the results found in this study.\nCONCLUSION: Improve the conclusion section to be more compact and summarize the research.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Partly\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes", "responses": [ { "c_id": "13102", "date": "20 Jan 2025", "name": "Ana Dolores Vargas Sánchez", "role": "Author Response", "response": "We are grateful for the reviewer's comments and observations, as they have been extremely beneficial to our article. The subsequent elements have been modified: The introduction's final three paragraphs were examined. Details regarding the investigation's objective are provided. The introduction elaborated on and established the specific issue. The content of natural science education and the void that this research can address were clarified. The introduction was enhanced by the inclusion of references to the historical development of literature. The results were supplemented with relationships that were based on previous research, and the manner in which these relationships elucidated the phenomena in the field. An endeavor was made to establish a more direct connection between the results and the discussion. The conclusions section has been revised to be more succinct. Thank you." } ] } ]	1	https://f1000research.com/articles/13-940
https://f1000research.com/articles/14-111/v1	20 Jan 25	{ "type": "Research Article", "title": "Magnitude and Factors Associated with Research Misconduct at Public University in Ethiopia: A Cross-Sectional Survey", "authors": [ "Habtamu Belay Hailu", "Telahun Teka Wolde", "Betselot Yirsaw Wubete", "Joseph Ali", "Sintayehu Tsegaye Bitew", "Telahun Teka Wolde", "Betselot Yirsaw Wubete", "Joseph Ali", "Sintayehu Tsegaye Bitew" ], "abstract": "Background Research integrity, essential for ethical scientific research, has been inadequately addressed in Ethiopia, resulting in gaps in addressing misconduct like plagiarism, falsification and fabrication.\n\nMethods An institutional-based cross-sectional study was conducted on a random sample of researchers. Data were collected via a self-administered, structured questionnaire, which was adapted from a similar study. The collected data were analysed using descriptive, bivariate, and multivariable logistic regression.\n\nResult A total of 244 researchers participated in the study, resulting in an 82% response rate. In our study, 37.7% of participants reported engaging in at least one form of misconduct, 95% CI [31.6%, 44.1%]. Authorship misconduct was the most common form of self-reported misconduct (47.5%), 95% CI [41.1%, 54.0%], followed by fabrication and falsification (40.6%), 95% CI [34.4%, 47.0%]. Publication pressure was significantly associated with research misconduct (AOR = 3.18; 95% CI: [1.02, 9.95]).\n\nConclusion Research misconduct has profound implications, compromising the validity of scientific findings and eroding public trust in research. Implementing comprehensive education initiatives on responsible research practices, as well as building an all-encompassing institutional policy, can help to reduce the occurrence of misconduct.", "keywords": [ "Research misconduct", "Responsible Conduct of Research", "Questionable Research Practices", "Research Integrity" ], "content": "Introduction\n\nResearch misconduct (RM) refers to unethical or dishonest behaviour in the context of academic or scientific research. It encompasses a range of actions that violate the principles of integrity, honesty, and transparency in research. Common forms of research misconduct include plagiarism, fabrication, or falsification of data aimed at misleading or manipulating the scientific community. Making up data or findings and recording or reporting them is defined as fabrication while falsification is changing or eliminating data or results, or interfering with research supplies, tools, or processes in such a way that the study is not properly documented in the research record. Plagiarism is defined as the unauthorized use of another person’s ideas, procedures, outputs, or words.1–4 RM undermines the credibility of scholarly work, compromises the integrity of scientific findings, and can have far-reaching consequences for the advancement of knowledge and trust within the academic community.5\n\nDeficits in research integrity pose a significant challenge to the credibility and reliability of scientific findings in the field. Despite stringent ethical guidelines and regulations, instances of questionable research practices persist, leading to concerns regarding the accuracy, reproducibility, and transparency of biomedical studies. The ethical conduct of research is guided by key principles, including honesty, objectivity, carefulness, credit, and transparency. Honesty requires researchers to truthfully report data, results, methods, and conflicts of interest in all scientific communications.6–8 The principle of credit emphasizes giving proper recognition to others’ contributions, preventing plagiarism, and ensuring fair attribution in publications and patents.9 Key factors contributing to research misconduct include pressure from funders, pursuit of recognition, publication pressure, inadequate penalties, lower academic rank, and lack of ethics training. These factors create conditions where ethical violations are more likely to occur.2,10,11\n\nSeveral studies that explore RM, including in some countries in sub-Saharan Africa, have emerged to help increase collective understanding of the phenomenon. According to an article focusing on sub-Saharan Africa, several authors suggest that Low- and Middle-Income Countries (LMICs) may frequently disregard research integrity norms, despite a lack of substantial evidence to support this claim.12 In an exploratory survey of a convenience sample of researchers conducted in Nigeria in 2013, 68.9% reported participation in at least one form of misconduct.10 Similarly, a cross-sectional survey among Kenyan investigators focused on HIV research indicated that 68.3% of respondents engaged in any misconduct.13 These findings from the African context are alarming in their own right and significantly exceed the global prevalence reported in the systematic review and meta-analysis by Xie et al. in 2021, in which the overall prevalence of RM involving at least one misconduct was 2.9% across 42 publications published between 1992 and 2020 across different regions of the world.14\n\nEthics training is a topic of ongoing debate, with some experts emphasizing its importance in fostering research integrity,11,15,16 while others argue that it may not always achieve the desired impact.5,17,18 This divergence in views highlights the complexity of the issue. On the one hand, proponents believe that structured training programs can instil ethical principles and improve decision-making in research. On the other hand, critics suggest that the effectiveness of these programs varies, and in some cases, may not be enough to significantly reduce research misconduct. Understanding these differing perspectives is crucial to evaluating the true role of ethics training in promoting responsible conduct in research.\n\nRetractions can serve as a significant indicator of RM, offering insights into unethical research practices. Retraction analyses have shown that research misconduct is a global issue, and Ethiopia is no exception. A study by Rossouw et al. examined retractions between 2014 and 2018 involving African authors or co-authors, finding that biomedical and health sciences accounted for over 60% of the 245 retracted papers. Ethiopia was one of 17 African countries included in the database, with 5 (2.04%) of its authors’ works retracted while neighbouring Kenya accounted for 2.45% of retractions.19 Despite these findings, we did not identify any published empirical studies specifically investigating research misconduct in Ethiopia.\n\nTo the best of our knowledge, the magnitude of RM has not been studied among researchers in Ethiopia’s academic and research institutions. To that end, the purpose of the study was to assess the magnitude of RM – as well as associated attitudes and factors – among faculty researchers conducting biomedical and epidemiological studies involving human participants in an academic institution in Ethiopia.\n\n\nMethods\n\nAn institution-based cross-sectional study was conducted to investigate the magnitude, attitudes, and associated factors concerning RM from January to April 2024 among faculty researchers at a public University in Ethiopia.\n\nThe study included faculty members who were actively involved in health or health sciences research and who had at least one publication.\n\nThis study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. Ethical approval was obtained from the Addis Ababa University, College of Health Sciences, School of Public Health Institutional Research Ethics Review Committee (IRERC), with approval number SPH/296/2024 and dated 19/01/2024. Written informed consent was obtained from all participants prior to their inclusion in the study.\n\n\n\n• Inclusion criteria: Faculty members with research experience and publications in local and international journals within the last five years were eligible for the study.\n\n• Exclusion criteria: Individuals who had not engaged in research and publication, along with faculty members who were unwilling to participate or did not give consent, were excluded from the data collection.\n\nThe questionnaire was divided into four sections to collect study participants’ baseline characteristics, general attitudes toward RMC, behavioural influences (factors), and respondents’ self-report of the frequency of their research misconduct practices. Behaviours related to RM and Questionable Research Practices (QRPs) were grouped into five research misconduct composites: circumventing research ethics regulations; fabrication and falsification; plagiarism; authorship misconduct; and conflict of interest.\n\nThe questionnaire was adapted from the study on “Reliability and validation of an attitude scale regarding responsible conduct in research” among Middle Eastern researchers.20 Questionnaires were collected in such a way that no third party or even the researchers could link specific respondents to completed questionnaires to ensure complete anonymity.\n\nIn this study, “Research Misconduct” encompasses composites such as circumventing research ethics regulations, plagiarism, fabrication, and falsification; while “Questionable Research Practices” are defined as including authorship issues and conflicts of interest composites. Each misconduct composite is defined by specific questions.\n\nBased on a margin of error of 5%, a confidence level of 95%, an estimated prevalence rate of 52.8% in the Middle East,11 and a total population size of 836 investigators at the targeted university, we calculated a sample size of 297 participants using Cochran’s formula.21\n\nFor this study, sample sizes were calculated for each specific objective, and the largest sample size was used as the final sample size. Using the formula above, the largest sample size, n0 = 383, was determined using the prevalence of 52.8% for the second specific objective regarding attitude from a study in the Middle East.11\n\nSince this sample size exceeds 5% of the total population (836 * 0.05 = 42), the final sample size was adjusted using Cochran’s correction formula.21\n\nBy substituting the values into the correction formula (2) provided above, the minimum sample size (adjusted) was determined to be 263.\n\nBartlett et al. recommended using response rates from previous studies of the same or similar populations to address non-response rates.22 Therefore, adjusting for a response rate of 88.7% from a prior study in Nigeria,10 the final sample size was calculated as n1 = 263/0.887 = 297.\n\nWe used probability sampling approach to select respondents, employing simple random sampling method to ensure random selection and representativeness of our sample. This approach maintained the randomness and representativeness of our sample. The sample size of 297 was distributed across four schools based on the proportionate population size in each of the four disciplines, considering individuals with at least one publication. Each department’s share was calculated by dividing 297 by the total population of 836 and multiplying by 0.35. Study units were then selected from each department using a simple random sampling procedure. This sampling procedure is illustrated schematically in Figure 1.\n\nTo minimize potential biases in this study on research misconduct, validated tools and metrics were employed to ensure reliable measurement,20 and data collectors were trained to ethically and confidentially collect the data. Confidentiality and anonymity were emphasized to mitigate social desirability bias. Data analysis was conducted objectively using statistical software to ensure accuracy and reduce human error. Efforts were made to avoid confirmation bias by incorporating diverse perspectives in the study framework and seeking evidence that challenged initial hypotheses. Transparent reporting of methodologies, assumptions, and limitations further enhanced the credibility of the research.\n\nIndependent variables\n\n• Baseline characteristics: sex, academic position, highest degree earned, prior training on research ethics.\n\n• Behavioural influences (Factors): pressure from funders, need for recognition, publication pressure, unclear definition of what constitutes misconduct, insufficient censure for misconduct, and financial conflict of interest.\n\nDependent variables\n\n• RM: circumventing RE regulations, plagiarism, and fabrication and falsification\n\n• QRPs: authorship misconduct and conflict of interest\n\nData from paper questionnaires were collected, entered into Epi-Data 3.1, and subsequently transferred to SPSS version 27. Descriptive analyses summarized demographic frequencies and percentages. Bivariate analysis was utilized to explore relationships between the composite scores of misconducts and factors such as age, gender, prior ethics training, graduate school attended, and academic position.\n\nRespondents were asked about the frequency of various misconduct behaviours, with response options including “Never,” “Once or twice,” or “Three or more times” for self-reported misconduct (RM, QRPs, & Overall RM). To ensure suitable categorization and sufficient data for analysis, these responses were transformed into dichotomous choices: “Never” and “One or more times”.23 Each type of self-reported misconduct was individually measured and categorized into one of the previously mentioned five research misconduct composites. Additionally, the magnitude of self-reported misconduct was calculated for each composite category.\n\nFor composite scores ( Figure 2), multivariable analysis models were constructed. Independent variables identified as significant in bivariate analysis at a p-value threshold of 0.25 were included in the binary logistic regression model. This approach ensures that relevant factors are not overlooked, which can happen when using stricter thresholds like 0.05 in logistic regression modelling.24 A p-value < 0.05 was considered significant for covariates in the final multivariate analysis. Odds ratios (OR) with confidence intervals (CI) and corresponding p-values were calculated.\n\nRegarding ‘attitude’ items, responses were coded on a five-point Likert scale ranging from strongly agree to strongly disagree. Responses of ‘strongly agree’ and ‘agree’ were grouped together as ‘agree,’ while ‘strongly disagree’ and ‘disagree’ were categorized as ‘disagree.’ The mid-point response, ‘neutral,’ was not included in either the ‘agree’ or ‘disagree’ categories. Descriptive analysis then summarized the distribution of responses across these categories.11 Missing data were addressed through mean imputation, replacing missing values with the average of available data for the respective variable.\n\nPrior to filling out the questionnaire, participants were informed of the study’s purpose via a one-page information sheet. Written informed consent was obtained from all participants prior to their participation in the study. Participants were provided with detailed information about the study objectives, procedures, potential risks, and benefits before signing the consent form. This process was reviewed and approved by the Addis Ababa University, College of Health Sciences, School of Public Health Institutional Research Ethics Review Committee (IRERC), with approval number SPH/296/2024 and dated 19/01/2024. The study adhered to the ethical principles outlined in the Declaration of Helsinki.\n\nDue to the sensitive nature of the data acquired and the possibility for dignitary harm, the name of the respondents’ institution was blinded and the names of specific schools were anonymized. The self-administered questionnaire did not include any questions that could reveal participants’ identities, Questionnaires were distributed and collected in person by trained data collectors who explained the study and ensured voluntary participation. After completion, participants placed their questionnaires directly into sealed collection boxes, which were only opened by the researchers after data collection was completed. No identifying information was included on the questionnaires, ensuring that neither the data collectors nor the researchers could link specific responses to individual participants. This process was designed to protect respondent anonymity while encouraging high response rates.\n\n\nResults\n\nA total of 297 questionnaires were distributed, with 244 completed, resulting in an 82% response rate. Table 1 shows the demographic and professional characteristics of participants. Almost half (49.6%) ranged in age from 25 to 34 years. Male participants comprised 66.8%. Roughly half (50.8%) were Assistant Professors, and lecturers accounted for 29.1%. Additionally, 49.6% of participants held MD/PhD degrees, while 31.1% held M.Sc./MPH/other master’s degrees. Most participants (90.2%) received their most recent degree from Ethiopian universities. Two-thirds reported prior completion of research ethics training. Most participants (59.0%) had 1-5 years of research experience, while 19.3% had over 10 years. In terms of publication history, 55.7% had published 1-5 papers, and 26.2% had published more than 10. In their most recent publication, 61.1% were co-authors; 38.9% were first authors.\n\nTable 2 shows the frequency and percentage of occurrences of misconduct composites and associated behaviours reported by respondents. The misconduct composites included circumventing research ethics regulations, fabrication and falsification, plagiarism, authorship misconduct, and conflict of interest. Key findings for the study are summarized as follows.\n\nConcerning the composite circumventing research ethics regulations, several respondents (17.2%) reported not obtaining proper informed consent, 14.8% reported using confidential information about research subjects without authorization, and 12.3% reported conducting research involving human participants without prior approval from a Research Ethics Committee. Regarding plagiarism, 20.9% reported using others’ ideas without credit, 10.7% reported submitting a published manuscript for secondary publication, and 9.4% published others’ results. For fabrication and falsification, 15.2% fabricated data, 14.3% altered data without disclosure, 26.2% selected data to support hypotheses, and 23.0% dropped outliers without mentioning.\n\nAmong respondents, reports of authorship misconduct were prevalent, with 37.3% indicating that they gave authorship to those who contributed minimally and 23.0% allowing their name to appear on papers where they contributed little. Non-disclose of conflicts of interest was reported among 17.6% of respondents, 13.1% indicated that they had compromised study rigor as a result of funding pressure, and 7.8% reported altering or suppressing research results inappropriately as a result of funding pressure.\n\nRegarding composites of RM and QRPs, Authorship misconduct emerged as the most prevalent form of research misconduct, with 47.5% of respondents reported involvement (95% CI: 31.6%–44.1%). Fabrication and falsification followed closely, with 40.6% acknowledging participation (95% CI: 34.4%–47.0%). Additionally, 26.6% of respondents reported engaging in plagiarism, while 25.4% reported conflicts of interest, and 29.1% admitted to violating research ethical standards.\n\nFindings revealed recognition and a strong consensus among participants on the importance of addressing research misconduct, reporting unethical behaviour, declaring conflicts of interest, and mentoring trainees. However, there was some discomfort in discussing ethical issues, which could impede efforts to improve research integrity (see Table 3).\n\nTable 4 shows participants perception toward RCR. Concerning publication pressure, 56.1% considered it moderately influencing while 34.4% considered it strongly influencing. Participants perceived that financial conflicts of interest play a role in RMC, with 46.3% believing it had some influence, while a similar proportion (45.9%) perceived it had strong influence. Regarding pressure from funders, 45.5% of participants perceived it had some influence while 39.3% viewed it as strongly influential. Insufficient censure of misconduct was viewed as an influence in committing research misconduct, with 54.9% believing it had some influence, while 34.4% noting strong influence.\n\nAs Table 5 shows, attitudes towards research integrity are segmented according to ethics training, research experience, and academic status. Results showed that more participants below the rank of lecturer (27.4%) believed that scientific integrity is solely the responsibility of the principal investigator, compared to 16.1% of those above lecturer rank. This indicates a link between academic rank and views on responsibility for scientific integrity. The difference was significant (χ2 = 3.851, df = 1, p < 0.05). Investigators with ethics training tended to endorse the attitude that investigators should report instances of research misconduct more strongly; with a higher percentage (96.3%) agreeing that research misconduct should be reported. The differences were significant (χ2 = 4.906, df = 1, p < 0.027).\n\nIn terms of feeling uncomfortable discussing ethical behaviour, academic rank is significantly associated (χ2 = 7.185, df = 1, p < 0.007), as a relatively high percentage (31.6%) of those below lecturer level felt uncomfortable doing so.\n\nA Chi-Square test showed significant associations with a p-value of less than 0.05 (see Table 6). In general, respondents with prior ethics training reported a relatively lower level of self-reported misconduct across all categories when comparing self-reported misconduct with participants without ethics training. Compared to those with ethics training, 34.9% of those without ethics training reported conflicts of interest. The difference was significant (χ2 = 5.290, df = 1, p < 0.021). Across schools, self-reported misconduct varies significantly by affiliation. Respondents from clinical schools, for example, reported greater rates of plagiarism, fabrication and falsification (FF), conflict of interest (CoI), RMC total, and Overall RMC, at 30.9%, 44.5%, 28.8%, 44.0%, and 41.4%, respectively, than those from non-clinical schools. Significant differences were found (χ2 = 7.159, df = 1, p < 0.007), (χ2 = 4.904, df = 1, p < 0.027), (χ2 = 4.528, df = 1, p < 0.033), (χ2 = 8.460, df = 1, p < 0.004), (χ2 = 4.314, df = 1, p < 0.038), respectively.\n\n* P < 0.05.\n\na Participant having the rank of lecturer and below.\n\nb Participants having the rank of assistant professor and above.\n\nc Participants holding first degree (Undergraduate).\n\nd Participants holding MSc and above (Graduate).\n\n+ Circumventing Research Ethics Regulations.\n\n++ Falsification and Fabrication.\n\n+++ Conflict of Interest.\n\nThe misconduct rates of those above and below the lecturer rank also differed significantly. The study found that 18.1% of participants above lecturer rank self-reported plagiarism, compared to 40.0% of participants below lecturer rank (χ2 = 13.113, df = 1, p < 0.001); Additionally, 51.6% of participants below lecturer rank reported falsification and fabrication, while 33.6% of participants above lecturer reported misbehaviour. Significant differences were seen between these groups (χ2 = 7.085, df = 1, p < 0.008). In terms of RMC-Total, 31.5% of respondents above lecturer rank reported committing RMC, which is considerably lower than the 50.5% of participants below lecturer rank (χ2 = 8.012, df = 1, p < 0.005).\n\nResearch misconduct was reported by 44.4% of respondents with less than 5 years of research experience, which was significantly higher compared to the 31.0% reported by those with more than 5 years of experience (χ2 = 3.939, df = 1, p < 0.047). Self-reported research misconduct varies by age, with junior researchers25–34 more likely to report engaging in multiple types of research misconduct than senior researchers (35+) (χ2 = 4.853, df = 1, p < 0.028). Additionally, significant age differences were observed in bypassing research ethics regulations, with 39.7% of junior researchers admitting to this behaviour, compared to 18.7% of senior researchers (χ2 = 12.005, df = 1, p < 0.001).\n\nTable 7 highlights several significant predictors of research misconduct and related behaviours. Higher academic rank, older age, and a more responsible attitude toward scientific integrity were associated with a lower likelihood of circumventing research ethics regulations, engaging in plagiarism, and committing fabrication or falsification. Participants who reported feeling high publication pressure or working in clinical schools were more likely to engage in research misconduct.\n\n* Significant at p < 0.05, AOR: Adjusted odds ratio, COR: Crude odds ratio, CRE: Circumventing Research Ethics Regulations, CoI: Conflict of Interest.\n\nResearchers with more than 5 years of experience were more prone to authorship misconduct, while those with postgraduate degrees were less likely to engage in conflicts of interest. School affiliation, particularly clinical vs. non-clinical, also played a role in influencing research misconduct behaviours.\n\nFor further details on these associations, including specific odds ratios, confidence intervals, and p-values please refer to the appendix.\n\n\nDiscussion\n\nThe findings of this study underscore the critical importance of maintaining research integrity and the responsible conduct of research within health-related fields. As the first investigation of its kind in Ethiopia, this study revealed significant instances of reported research misconduct, including data fabrication, falsification, and plagiarism, which have the potential to threaten the credibility and reliability of scientific research. By systematically analysing these occurrences, the study highlights the pervasive nature of such practices. These results prompt an urgent call for reinforced ethical standards and robust oversight mechanisms to ensure the integrity of future research endeavours. In what follows, we explore the implications of these findings, propose potential strategies for mitigating research misconduct, and underscore the role of education and policy in fostering a culture of ethical research practices.\n\nAs noted by Felaefel et al., comparing misconduct rates across studies is challenging due to differences in study methodologies and operational definitions of misconduct.11 Variations in researchers’ awareness and reporting methods also affect the magnitude estimates of RM and QRPs. Despite these inconsistencies, our study’s findings align with those from studies conducted in Kenya and the Middle East, where similar patterns of research misconduct, such as authorship misconduct and data falsification, have been reported.11,13\n\nOur study identified a significant magnitude of reported research misconduct among participants, though it was comparatively lower than findings reported in studies from Nigeria, Kenya, and the Middle East.10,11,13 The variability in reported rates of misconduct across different studies can be attributed to several factors. Firstly, variations in sample sizes impact statistical power and result variability, potentially influencing the observed magnitude of reported misconduct. Secondly, differences in participants’ levels of research experience and education may affect their understanding of what constitutes misconduct and their susceptibility to engaging in such behaviours.4 This is evident in our study, where more than half of the participants had less than 5 years of research experience and were more likely to have been involved in committing research misconduct compared to their senior colleagues. Finally, the Singapore Statement on Research Integrity highlights the importance of considering cultural and institutional contexts in promoting research integrity and understanding the variability in reporting and actual rates of research misconduct across different settings.25\n\nThe multivariable analysis showed that publication pressure was significantly associated with overall research misconduct. Pressure to meet publication targets may lead researchers to report engaging in compromised ethics or unethical practices. This finding aligns with the “publish or perish” culture in academia, which continuously pressures scholars to produce scholarly output. Current academic rules and regulations, such as those outlined by the Ethiopian Ministry of Education, impose publication quotas on academic staff.26 Similarly, the CIOMS guideline on good governance practices for research institutions (2023) affirms that a “publish or perish” mentality increases the likelihood of scientific misconduct.27 Our findings are also consistent with earlier studies that have identified publication pressure as a strong predictor of research misconduct.10,11,13,28–32\n\nThere was a negative association between participants’ age and self-reported involvement in misconduct, suggesting that older participants were less likely to report circumventing research ethics regulations compared to younger ones. This may indicate differences in perceptions of misconduct or reluctance to admit certain behaviours. This finding aligns with previous studies conducted in the Middle East and the U.S.A.11,29 Conversely, participants with more research experience or publications were twice as likely to report engaging in authorship misconduct as those with fewer years of experience. This suggests that as researchers gain more experience, they may be more likely to report engaging in misconduct, such as authorship wrongdoing. Therefore, it is reasonable to consider that the likelihood of reporting authorship misconduct may be higher among more experienced researchers.29\n\nThe present study’s lack of statistical significance between prior ethics training and research misconduct reflects a common pattern in the literature, which has produced conflicting findings about the effectiveness of ethics instruction. According to studies conducted by prominent researchers in the field, research ethics training, including Responsible Conduct of Research (RCR) programs, may not always have the expected impact on research behaviour or ethical decision-making.5,17,18,33–36 Conversely, other studies have shown that prior ethics training strongly predicts lower research misconduct and benefits trainees.11,15,16,37–40 The inconsistent findings across studies highlight the complexities of research ethics training and suggest that traditional techniques may not always be adequate in addressing the multidimensional nature of research misconduct. Further exploration of the effectiveness of research ethics training is crucial for understanding the underlying factors contributing to these inconsistencies, particularly given the lack of uniformity in definitions and the significant variability in the quality and nature of such training.\n\nThe study may be limited by self-reporting biases, which are common in surveys addressing sensitive topics like research misconduct. Its cross-sectional design restricts the ability to establish causation between factors, necessitating caution in interpreting the findings. Additionally, relying on self-reported data may introduce social desirability bias, leading participants to underreport or misrepresent their involvement in misconduct. As the first study of its kind in the country, there are no comparable studies for reference. Despite these limitations, the study’s findings are crucial for guiding efforts to enhance research integrity and effectively combat misconduct.\n\nDespite the valuable findings of this study, several questions remain unanswered, highlighting the need for further research. Although the study identified factors associated with research misconduct, the interactions and relative importance of these factors are still unclear. Future longitudinal studies could explore temporal associations to better understand the causal mechanisms behind research misconduct. Additionally, while this study used quantitative methods, qualitative methods could provide deeper insights into researchers’ motivations and perceptions of unethical behaviour. The participants were primarily sampled from an academic institution, raising concerns about the generalizability of the findings to other types of research institutions and to other academic institutions. To address this limitation, future studies should include researchers from a wider range of sectors and geographical regions.\n\n\nConclusion\n\nResearch misconduct has profound implications, compromising the validity of scientific findings and eroding public trust in research. It distorts the evidence base needed for informed decision-making, potentially leading to harmful policy and clinical practices. Additionally, misconduct can result in significant financial losses and resource wastage, as well as damage the reputations of institutions and individuals involved. Ultimately, it hampers scientific progress and undermines the ethical foundations of research, which are essential for advancing public health and societal well-being. Our findings highlight the critical need for focused interventions to improve research integrity among the health science community at the institution and across the country. Implementing comprehensive education initiatives on responsible research practices, as well as building an all-encompassing institutional policy, can help to reduce the occurrence of misconduct. Our study’s relevance stems from its capacity to advise research and academic institutions about the crucial areas that must be addressed in order to establish an ethical research culture.\n\nEthics and consent: This study adhered to ethical principles outlined in the Declaration of Helsinki, with ethical approval obtained under approval number SPH/296/2024. Written informed consent was obtained from all participants after providing detailed information about the study’s purpose, procedures, risks, and benefits. To ensure confidentiality, all data were deidentified according to the Safe Harbour method prior to analysis and submission.\n\nFor a more detailed explanation of the ethical considerations and consent process, refer to the Methods and Ethical Considerations sections.\n\n\nAuthors’ contribution\n\nThis study was designed, drafted, and analysed by H.B.H.; T.T.W., B.Y.W., J.A., and S.T.B. made cleaning and revisions on the drafts. All authors reviewed the manuscript.\n\n\nDisclaimer\n\nThe content is solely the responsibility of the authors and does not necessarily represent the official views of the U.S. National Institutes of Health.", "appendix": "Data availability statement\n\nZenodo: Magnitude and factors associated with research misconduct at public university in Ethiopia: A cross-sectional survey.41–45\n\nAll data have been deidentified prior to uploading in compliance with the Safe Harbour method to ensure the protection of personal and sensitive information.\n\nThis project contains the following underlying data:\n\n• SPSS Dataset on Research Misconduct and Questionable Research Practices\n\nDescription: SPSS file containing raw data used for statistical analysis in the study, https://zenodo.org/doi/10.5281/zenodo.14306711.41\n\n• Table 1: Sociodemographic Characteristics of Participants\n\nDescription: Data table summarizing the demographic characteristics of the study participants, https://zenodo.org/doi/10.5281/zenodo.14540519.42\n\n• Table 2: Respondents’ Self-Report of Behaviors Grouped Within Defined Misconduct Composites\n\nDescription: Data table categorizing self-reported behaviors related to research misconduct, https://zenodo.org/doi/10.5281/zenodo.14540618.43\n\n• Table 5: Association of Attitudes Towards Certain Issues in Responsible Conduct of Research and Percentages of Respondents Who Answered “Agree” Segmented by Various Factors\n\nDescription: Data table analyzing associations between attitudes toward responsible research conduct and respondent characteristics, https://zenodo.org/doi/10.5281/zenodo.14540653.44\n\n• Appendix: Detailed Statistical Data on Predictors of Research Misconduct\n\nDescription: Supplementary dataset providing detailed statistical analyses of predictors related to research misconduct, https://zenodo.org/doi/10.5281/zenodo.14540669.45\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nThe extended data for this study is available at Zenodo with the DOI: https://zenodo.org/doi/10.5281/zenodo.14540865.46\n\nThis project contains the following:\n\n• Extended data.docx\n\nDescription: Participant Information Sheet: This document provides detailed information about the study to ensure informed participation. Consent Form: This form outlines the consent process and ensures that participants agreed to be part of the study voluntarily. Questionnaire: This document contains the survey or data collection tool used in the study.\n\nData are available under the terms of Creative Commons Zero (CC0) license.\n\n\nAcknowledgments\n\nWe are grateful to Addis Abeba University’s School of Public Health and Johns Hopkins University for their support and resources. Special appreciation to our colleagues for their essential advice and assistance. We are also appreciative to the research participants for their invaluable contributions.\n\n\nReferences\n\nSteneck NH: Introduction to the Responsible Conduct of Research: (638422011-001).2007 [cited 2023 Jul 6]. Publisher Full Text\n\nAdeleye OA, Adebamowo CA: Factors Associated with Research Wrongdoing in Nigeria. J. Empir. Res. Hum. Res. Ethics. 2012 Dec; 7(5): 15–24. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nInternational Committee of Medical Journal Editors (ICMJE): Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals.2023. Reference SourceReference Source\n\nFanelli D: How Many Scientists Fabricate and Falsify Research? A Systematic Review and Meta-Analysis of Survey Data. Tregenza T, editor. PLoS One. 2009 May 29; 4(5): e5738. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCairns AC, Linville C, Garcia T, et al.: A phenomenographic study of scientists’ beliefs about the causes of scientists’ research misconduct. Res Ethics. 2021 Oct; 17(4): 501–521. Publisher Full Text\n\nTHE BELMONT REPORT Ethical Principles and Guidelines for the Protection of Human Subjects of Research, The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. DHEW Publication No. (OS) 78-0012; 1978. 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PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBain LE, Tchuisseu-Kwangoua LA, Adeagbo O, et al.: Fostering research integrity in sub-Saharan Africa: challenges, opportunities, and recommendations. Pan Afr. Med. J. 2022 [cited 2023 Nov 28]; 43. PubMed Abstract \| Publisher Full Text \| Free Full Text Reference Source\n\nWere E, Kaguiri E, Kiplagat J: Perceptions of occurrence of research misconduct and related factors among Kenyan investigators engaged in HIV research. Account. Res. 2020 Aug 17; 27(6): 372–389. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nXie Y, Wang K, Kong Y: Prevalence of Research Misconduct and Questionable Research Practices: A Systematic Review and Meta-Analysis. Sci. Eng. Ethics. 2021 Aug; 27(4): 41. PubMed Abstract \| Publisher Full Text\n\nKnight J: Evaluating the Impacts of a Research Ethics Training Course on University Researchers. Soc. Sci. 2023 Mar 17; 12(3): 182. Publisher Full Text\n\nKalichman M: Survey study of research integrity officers’ perceptions of research practices associated with instances of research misconduct. Res. Integr. Peer Rev. 2020 Dec; 5(1): 17. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAntes AL, Murphy ST, Waples EP, et al.: A Meta-Analysis of Ethics Instruction Effectiveness in the Sciences. Ethics Behav. 2009 Sep 17; 19(5): 379–402. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCommittee on Responsible Science, Committee on Science, Engineering, Medicine, and Public Policy, Policy and Global Affairs, National Academies of Sciences, Engineering, and Medicine. Fostering Integrity in Research. Washington, D.C.: National Academies Press; 2017 [cited 2024 Apr 15]. Reference Source\n\nRossouw TM, Matsau L, Van Zyl C: An Analysis of Retracted Articles with Authors or Co-authors from the African Region: Possible Implications for Training and Awareness Raising. J. Empir. Res. Hum. Res. Ethics. 2020 Dec; 15(5): 478–493. Publisher Full Text\n\nAbd ElHafeez S, Salem M, Silverman HJ: Reliability and validation of an attitude scale regarding responsible conduct in research. Asghari Jafarabadi M, editor. PLoS One. 2022 Mar 16; 17(3): e0265392. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCochran WG: Sampling techniques. 3d ed.New York: Wiley; 1977; 428 p. (Wiley series in probability and mathematical statistics).\n\nBartlett JE, Kotrlik JW, Higgins CC: Organizational research: Determining appropriate sample size in survey research. Inf. Technol. Learn. Perform. J. Spring 2001; Vol. 19(1). Reference Source\n\nDiStefano C, Shi D, Morgan GB: Collapsing Categories is Often More Advantageous than Modeling Sparse Data: Investigations in the CFA Framework. Struct. Equ. Model. Multidiscip. J. 2021 Mar 4; 28(2): 237–249. Publisher Full Text\n\nHosmer DW, Lemeshow S, Sturdivant RX: Applied logistic regression. 3rd ed.Hoboken, New Jersey: Wiley; 2013; 500. (Wiley series in probability and statistics).\n\nResnik DB, Shamoo AE: The Singapore Statement on Research Integrity. Account. Res. 2011 Mar 9; 18(2): 71–75. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAcademic Rules and Regulations of the Ethiopian Comprehensive Public Higher Education Institutions. Addis Ababa: Ministry of Education; 2023.\n\nInternational guidelines on good governance practice for research institutions. Geneva, Switzerland: Council for International Organizations of Medical Sciences (CIOMS); 2023. Licence: CC BY-NC-SA 4.0. Publisher Full Text\n\nVan Dalen HP, Henkens K: Intended and Unintended Consequences of a Publish-or-Perish Culture: A Worldwide Survey. SSRN Electron. J. 2012 [cited 2023 Nov 7]. Publisher Full Text Reference Source\n\nMaggio L, Dong TD, Driessen E, et al.: Factors associated with scientific misconduct and questionable research practices in health professions education. Perspect. Med. Educ. 2019 Mar 26; 8(2): 74–82. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKearney M, Downing M, Gignac EA: Research integrity and academic medicine: the pressure to publish and research misconduct. J. Osteopath. Med. 2024 Feb 27 [cited 2024 Apr 9]; 124: 187–194. PubMed Abstract \| Publisher Full Text\n\nBahl R, Bahl S: Publication pressure versus ethics, in research and publication. Indian J. Community Med. 2021; 46(4): 584–586. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAl-Adawi S, Ali BH, Al-Zakwani I: Research Misconduct: The Peril of Publish or Perish. Oman Med. J. 2016 Jan 15; 31(1): 5–11. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKalichman M: Rescuing Responsible Conduct of Research (RCR) Education. Account. Res. 2014 Jan 2; 21(1): 68–83. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKornfeld DS: Perspective: Research Misconduct. Acad. Med. 2012 Jul; 87(7): 877–882. Publisher Full Text\n\nPowell ST, Allison MA, Kalichman MW: Effectiveness of a responsible conduct of research course: a preliminary study. Sci. Eng. Ethics. 2007 Jul 4; 13(2): 249–264. PubMed Abstract \| Publisher Full Text\n\nSteneck NH: Global Research Integrity Training. Science. 2013 May 3; 340(6132): 552–553. Publisher Full Text\n\nChou C, Lee IJ, Fudano J: The present situation of and challenges in research ethics and integrity promotion: Experiences in East Asia. Account. Res. 2023 Jan 15; 1–24.\n\nOlesen AP, Amin L, Mahadi Z, et al.: Emphasizing the experiences of researchers after RCR instructions: Introduction to Responsible Conduct of Research (RCR) in Malaysia. Account. Res. 2019 Apr 3; 26(3): 157–175. PubMed Abstract \| Publisher Full Text\n\nLitzky BE, Oz E: Ethical Issues in Information Technology: Does Education Make a Difference. Int. J. Inf. Commun. Technol. Educ. 2008 Apr 1; 4(2): 67–83. Publisher Full Text\n\nWatts LL, Medeiros KE, Mulhearn TJ, et al.: Are Ethics Training Programs Improving? A Meta-Analytic Review of Past and Present Ethics Instruction in the Sciences. Ethics Behav. 2017 Jul 4; 27(5): 351–384. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHailu HB: SPSS Dataset on Research Misconduct and Questionable Research Practices. [Dataset]. Zenodo. 2024 [cited 2024 Dec 22]. Publisher Full Text\n\nHailu HB: Table 1: Sociodemographic Characteristics of Participants. [Dataset]. Zenodo. 2024 [cited 2024 Dec 22]. Publisher Full Text\n\nHailu HB: Table 2: Respondents’ Self-Report of Behaviors Grouped Within Defined Misconduct Composites. [Dataset]. Zenodo. 2024 [cited 2024 Dec 22]. Publisher Full Text\n\nHailu HB: Table 5: Association of Attitudes Towards Certain Issues in Responsible Conduct of Research and Percentages of Respondents Who Answered “Agree” Segmented by Various Factors. [Dataset]. Zenodo. 2024 [cited 2024 Dec 22]. Publisher Full Text\n\nHailu HB: Appendix: Detailed Statistical Data on Predictors of Research Misconduct. [Dataset]. Zenodo. 2024 [cited 2024 Dec 22]. Publisher Full Text\n\nHailu HB: Extended Data for Research Misconduct: Participant Information Sheet, Consent Form, and Questionnaire. Zenodo. 2024 [cited 2024 Dec 22]. Publisher Full Text" }	[ { "id": "362165", "date": "07 Feb 2025", "name": "Wei Feng", "expertise": [ "Reviewer Expertise research integrity" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for the opportunity to review this article. This cross-sectional study investigates the extent of research misconduct (RM) among researchers in Ethiopia’s academic and research institutions using a structured questionnaire. Some findings are particularly intriguing, such as the lack of significant statistical correlation between ethics education and RM. However, I have three primary concerns I would like to discuss with the authors.\nFirstly, the authors examined behavioral influences on responsible conduct in research and explored factors associated with RM composites. While the selected factors appear relevant to RM, the authors do not delve deeply into why these factors may influence RM. This oversight may represent a limitation of the quantitative approach and raises questions for scholars engaged in qualitative research. Therefore, I recommend that the authors provide a more comprehensive explanation of these influencing factors, taking into account the educational and cultural context of Ethiopia, as well as relevant existing theories.\nSecondly, as noted in the Discussion Sec., the findings from Ethiopia align with those from Kenya and the Middle East. Readers may be interested in understanding the uniqueness and broader applicability of this study. The research's distinctiveness should not be solely attributed to the choice of Ethiopia as the research site. This concern is related to my first point regarding the investigation of established factors influencing RM, as the significance of the research appears less pronounced. I suggest that the authors further explore the uniqueness of this study and its potential broader applicability in future research.\nThirdly, the article exhibits certain limitations in research methodology, particularly concerning the formulation of research hypotheses. The manuscript lacks a dedicated literature review section; instead, it briefly presents current research on RM in the Middle East within the Introduction Sec. This approach does not adequately develop research hypotheses by considering existing literature, which should be followed by validation through the questionnaire. I recommend that the authors enhance the methodological rigor of this cross-sectional study by incorporating a more thorough review of relevant literature to inform the formulation of their research hypotheses.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] }, { "id": "361207", "date": "08 Feb 2025", "name": "Patrick Okonta", "expertise": [ "Reviewer Expertise Research Ethics", "bioethics", "Maternal health", "OBGYN" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe study has as its objective 'to assess the magnitude of RM – as well as associated attitudes and factors – among faculty researchers conducting biomedical and epidemiological studies involving human participants in an academic institution in Ethiopia.' The topic is important especially in the context that it is the first of its kind in Ethiopia. Generally the manuscript is well written and the methods well described to make reproducibility of the study possible. However, the following issues /suggestions need to be addressed 1. Title. I would suggest inserting 'a' in front of 'Public University. 2. Abstract\n\na) The aim of the study should be included either as a subheading or the second sentence in the Background subheading.\n\nb) The conclusion has to be completely revised as I suggests below 3. Method\n\na) The variable 'Research experience' was measured by the number of years in an academic post. I wonder why the 'number of publications/scholarly works' was not used as a more appropriate marker for research experience? 4. Results\n\na) Table 2 is not in the manuscript.\n\nb) Page 8- The sentence, 'A Chi-Square test showed significant associations with a p-value of less than 0.05' has to be expanded to make it complete and self explanatory. c) I suggest further analysis on Authorship misconduct should be provided to determine which of the 3 types studied was associated with more years of research experience. Conclusion. The conclusion as stated does not derive from this particular study or related to the objective of the study as stated by the Authors. The conclusion is too generic and very broad without any specific link to either the results from this study or the stated objectives of the study. It should be completely re-written. In addition, since there was no significant difference in research misconduct between those that had prior training in ethics and those who did not, I wonder the basis for the recommendation of educational interventions in the conclusion\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No", "responses": [] } ]	1	https://f1000research.com/articles/14-111
https://f1000research.com/articles/13-128/v1	20 Feb 24	{ "type": "Research Article", "title": "Predicting stunting in Rwanda using artificial neural networks: a demographic health survey 2020 analysis", "authors": [ "Similien Ndagijimana", "Ignace Kabano", "Emmanuel Masabo", "Jean Marie Ntaganda", "Ignace Kabano", "Emmanuel Masabo", "Jean Marie Ntaganda" ], "abstract": "Background Stunting is a serious public health concern in Rwanda, affecting around 33.3% of children under the age of five in 2020. Several examples of research have employed machine learning algorithms to predict stunting in Rwanda; however, no study used artificial neural networks (ANNs), despite their strong capacity to predict stunting. The purpose of this study was to predict stunting in Rwanda using ANNs and the most recent Demographic and Health Survey (DHS) data from 2020.\n\nMethods We used a multilayer perceptron (MLP) architecture to train and test the ANN model on a subset of the DHS dataset. The input variables for the model included child, parental and socio-demographic’s characteristics. The output variable was a binary indicator of stunting status (stunted vs. not stunted).\n\nResults An overall accuracy of 72.0% on the test set was observed, with an area under the receiver operating characteristic curve (AUC-ROC) of 0.84, indicating the model’s good performance. Several factors appear as important contributors to the probability of stunting among the negative value aspects. First and foremost, the mother’s height is important, as a lower height suggests an increased risk of stunting in children. Positive value characteristics, on the other hand, emphasie elements that reduce the likelihood of stunting. The timing of the initiation of breastfeeding stands out as a crucial factor, showing that early breastfeeding initiation has been linked with a decreased risk of stunting.\n\nConclusions Our findings suggest that ANNs can be a useful tool for predicting stunting in Rwanda and identifying the most important associated factors for stunting. These insights can inform targeted interventions to reduce the burden of stunting in Rwanda and other low- and middle-income countries.", "keywords": [ "Feature importance", "Artificial Neural Networks", "Stunting", "Children", "Rwanda." ], "content": "Introduction\n\nStunting remains a significant public health issue worldwide, particularly in low-and middle-income countries. According to the latest estimates by the World Health Organisation (WHO), in 2020, around 149.2 million children under the age of five years (about 22% of all children in this age group) were affected by stunting globally, with the highest burden in low and middle-income countries.1 The COVID-19 pandemic has exacerbated the situation, since disruptions in food systems and health services are likely leading to an increase in stunting rates.2 Therefore, stunting is still a serious public health problem across the world, particularly in Africa.2 In 2020, about 58 million children under the age of five were stunted in Africa, accounting for nearly 40% of all stunted children worldwide. The prevalence of stunting in these EAC countries highlights the importance of focused interventions to address the underlying causes of stunting, which include poverty, poor nutrition, and a lack of access to healthcare and sanitary services.3\n\nArtificial Neural Networks (ANNs) are a type of machine learning (ML) technique that has gained prominence in recent years due to its ability to learn and generalise from data, making them ideal for predictive modelling applications.4 ANNs are a kind of deep learning, which is a technique that consists of training models with numerous layers of connected nodes to replicate human brain function.4 ANNs stand out in significance when contrasted with other ML algorithms for a multitude of compelling reasons. In many circumstances, ANNs can simulate complicated, non-linear interactions between input and output variables, allowing for accurate predictions.5 Linear models, such as linear regression, have limitations in capturing nonlinear correlations, but more complex models, such as decision trees or random forests, may overfit the data or be computationally costly, however, ANNs perform better.6 ANNs are usually resistant to noisy or incomplete data, making them useful in real-world situations where data is frequently poor.6 ANNs can automatically extract significant features from data, removing the need for manual feature engineering. This can save time and effort while modelling, especially with high-dimensional data.7 ANNs are suited for big data applications because they can be scaled to accommodate massive datasets, hence, it is critical to apply them to Rwanda Demographic Health Survey (RDHS).7 The RDHS is nationally representative research that collects data on a number of health indicators, including stunting, through house interviews.8\n\nThey can also be parallelised over many processors, increasing computing efficiency.9 ANNs may be used for transfer learning, which involves fine-tuning a pre-trained model for a new task with little data. This is especially important when data is scarce or expensive to collect.9 Using an ANN to predict stunting offers various advantages, including increased accuracy and the capacity to identify significant predictors of stunting. ANNs can analyse vast volumes of data and detect patterns that typical statistical approaches may miss, allowing for more accurate stunting predictions. Furthermore, ANNs can identify major predictors of stunting, such as poverty, low maternal education, and a lack of access to sanitary facilities, allowing for focused interventions to address the core causes of stunting.10 A few studies have been conducted in Rwanda using other machine learning technics like logistic regression, Supportive Vector Machine (SVM), Naive Bayes Random Forest (RF), XGBoost gradient model.11\n\nHowever, based on the existing knowledge there has been few researches in Rwanda that attempted to utilise ML to predict stunting like the study conducted by Similien et al.11 ANNs have proven to be highly effective in predicting illnesses. However, Similien’s publication did not delve into the utilisation of ANNs for this purpose, despite their demonstrated effectiveness in prediction. Recognising this gap, a supplementary study was essential to explore the application of ANNs in predicting stunting in children, using data from the 2020 RDHS. Given the crucial importance of addressing the root causes of stunting for effective treatments and policymaking, the researcher chose to conduct this study on the application of ANNs in the specific context of stunting in Rwanda, using the same dataset as the aforementioned publication.11 The remaining party of this study is organised as follow: Methods, Results, Discussion, Conclusion and recommendation.\n\n\nMethods\n\nDHS is a large-scale household survey program that is carried out in low- and middle-income nations. DHS surveys are meant to collect high-quality data on health, demographic, and nutrition indicators to help policymakers and program administrators make better decisions. The surveys are normally conducted every five years and give information on a variety of areas including fertility, mother and child health, family planning, HIV/AIDS, nutrition, and gender-based violence.12 The secondary data from the 2019-2020 RDHS were analysed in this study. The RDHS is a five-year quantitative, cross-sectional study-based national survey. The RDHS used a two-phase stratified sampling approach. In the first step, 500 clusters were chosen from a pool of 112 urban enumeration areas and 388 rural enumeration areas. In the second stage, homes were systematically sampled, involving the selection of a random subsample of 26 households within each cluster, resulting in a total of 13,000 surveyed households. This subsample specifically included 3,814 children under the age of five, from whom height and weight measurements were collected.13\n\nExplanatory variables\n\nThe explanatory factors for stunting that were associated with the characteristics of mothers, households, and children are summarised below (Table 1). The selection of variables from the DHS was guided by UNICEF conceptual framework children nutrition and tailored to the specific context of Rwanda.14\n\nOutcome variable\n\nThe outcome variable in this study was stunting status, which was classified according to WHO criteria. The nutritional status of children was separated into two categories based on height for age z-scores, as follows: stunted if standard deviation SD<−2 was less than the median, and not stunted otherwise.13\n\nData preprocessing is the activity of preparing (cleaning and arranging) raw data so that it is understandable and useable for analysis. It consists of various stages, including data cleansing, data integration, data transformation, and data reduction.15 In this study, data cleaning was characterised as the procedure for addressing missing or incomplete data within the dataset. The missing values were addressed through imputation using the K Nearest Neighbours (KNN) imputer, which, when contrasted with the Euclidean distance, might result in a reduction of data similarity.16 Data transformation here used to describe the process of altering the format or structure of data to make it suitable for analysis,15 where the researcher encoded categorical data with the map function before converting it to dummy (0 and 1) values with pandas (pd). Obtain dummies that treated variable categories individually, then use the Minimax scaler to normalise the numerical data, which ranges all data values between 0 and 1, code was generated in Python using the popular ML library scikit-learn. Moreover, the Synthetic Minority Over-Sampling Technique (SMOTE) was employed to tackle the class imbalance within the target variable. This technique involves oversampling the minority class by generating synthetic instances along the line segments that connect any or all of the k nearest neighbours within the minority class.17 The software used during the data preprocessing and analysis was the python Google Collab.18\n\nA dataset is divided into three subsets: a training set, a validation set, and a test set. The training set is used to train the model, the validation set is used to fine-tune the model’s hyperparameters and avoid overfitting, and the test set is used to assess the model’s final performance on new data. Each subset’s size is determined by the amount of the dataset and the model’s complexity. The dataset, consisting of 3814 observations, was divided into 80% for training (3051 instances) and 20% for testing and validation (763 instances).\n\nThe ANN was built using 23 inputs to predict stunting in Rwanda. After initialising the neural network, the model employed neurons as features in the input layer and two in the hidden layer. Two hidden layers were used in the ANN, a common choice for optimising performance, and they were tested individually to determine the ideal configuration for achieving the desired results in this proposed model. Because the goal of this study is to identify stunted newborns using training data, the rectifier activation function in the hidden layers and the sigmoid activation function in the output layer are used to set a range (0, 1) of a linear function in ANN.19 80% and 20% of the data have been used as training and testing data respectively for a model that runs 100 epochs. Each epoch is seen as having one forward and one backward propagation. Finally, the most effective stochastic gradient descent optimiser parameter “Adam” is employed. The batch size is set to 32, which implies there are 10 occurrences in each epoch at any given moment. The loss (binary- crossentropy) function is used to classify the losses. With ANN, the best outcome is offered after computing the loss.20,21\n\nTo train the ANN model on the training set using the hyperparameters chosen. During the training phase, the model’s capacity to recognise complicated patterns in the data is constantly refined. We rigorously monitor two critical parameters throughout this training process: loss and accuracy. Loss measures how much our model’s predictions differ from the real values, whereas accuracy measures how frequently the model’s predictions match the actual outcomes. Early stopping is a strategy in which the model’s performance is evaluated on a distinct dataset called the validation set on a frequent basis during training. This collection is unique from the training data and is used to assess the model’s generalisation capabilities. Model evaluation, on the other hand, is used to assess the performance of the trained ANN model on the test set.\n\nThe primary metrics used for assessment were accuracy, precision, recall, and the area under the receiver operating characteristic curve (AUC-ROC). This metric quantifies the overall correctness of the model’s predictions by measuring the ratio of correctly predicted stunting to the total children. Precision assesses the accuracy of positive predictions of stunting made by the model. It is calculated as the ratio of true positive predictions to the sum of true positives and false positives. Recall, also known as sensitivity or true positive rate, evaluates the model’s ability to capture all relevant instances. It is calculated as the ratio of true positives to the sum of true positives and false negatives. The AUC-ROC provides a comprehensive evaluation of the model’s ability to discriminate between stunted and no stunted children. A higher AUC-ROC value indicates superior discrimination performance. The analyses were conducted using the TensorFlow and scikit-learn libraries in Python.22\n\nHere are 10 steps that we used for feature selection as seen in Figure 1: Step 1 includes importing the dataset and picking the necessary columns for prediction. In this case, the dataset has 23 input features and the ‘stunting’ variable as the target variable. Step 2 the function LabelEncoder is used to encode categorical variables. LabelEncoder is a scikitlearn (RRID:SCR_002577) utility class that encodes category characteristics as numeric values; Step 3 entails separating the data into input (X) and target (Y) variables. The input characteristics are contained in the X variable, while the target variable is contained in the Y variable; Step 4 entails dividing the data into 80% for training (3051 instances) and 20% for testing and validation (763 instances). The ANN model is trained using the training set, and its performance is evaluated using the testing set; Step 5 using StandardScaler, standardise the input characteristics. The scikit-learn library’s StandardScaler utility class standardises features by eliminating the mean and scaling to unit variance. Step 6: Build an ANN model with two hidden layers and one output layer. The number of neurons in the input layer is equal to the 23 of input features; Step 7 specifically, in our stunting prediction model, we opted for the Adam optimiser and binary cross-entropy loss. The choice of the binary cross-entropy loss function is crucial for binary classification tasks, such as distinguishing between instances of stunting and non-stunting. This loss function quantifies the difference between the predicted and actual outcomes, providing a measure of how well the model is performing in terms of classification accuracy; in Step 8, the model is trained using a dataset comprising a 3814 number of observations. In this case, the training data used for model training involves a determined amount of information. The model is exposed to this dataset over a series of iterations known as epochs. In each epoch, the model refines its weights and biases based on the training data to improve its predictive capabilities. The choice of 100 epochs ensures that the model undergoes a sufficient number of iterations to converge and achieve optimal performance. Additionally, a batch size of 32 is employed, signifying that the model processes 32 instances of data in each epoch before updating its parameters. This batch-wise training approach helps in optimising computational efficiency and contribute to the model’s generalisation ability.\n\nStep 9 to determine feature importance, the eli5 library’s permutation importance is used. Permutation importance was the model-independent strategy used after training an ANN to predict stunting. It measures the decline in model performance when each feature is randomly shuffled across instances to determine the relevance of particular characteristics. The decline in performance, as measured by measures like as accuracy or AUC-ROC, reflects the significance of a feature. Permutation is performed over numerous samples, and the procedure is iterated to ensure consistency. Features that cause a significant decline in performance are thought to be critical for the ANN’s prediction accuracy in stunting situations. This strategy assists in the identification and prioritisation of critical elements that influence the model’s predictions. For scikit-learn and Keras models, the eli5 module implements permutation importance.21 Step 10 includes printing the features’ importance. The features’ importance is printed in descending order of significance, along with their appropriate weights.\n\n\nResults\n\nThis section shows the results from ANN model, Figure 2 shows an accuracy of 72%.\n\nThe ANN model built in this study showed good results in predicting stunting in Rwandan children. The model attained a 72% accuracy and a ROC of 0.84, indicating that it is a very useful tool for detecting children at risk of stunting as shown in Figure 3.\n\nThe feature importance analysis of an ANN model for predicting stunting in Rwanda was examined in this article. The model reveals the important elements related to stunting, giving light to both negative and positive value characteristics. The features of importance were computed and displayed using the ANN model as seen in Figure 4. Identifying these positive and negative value characteristics is pivotal for comprehending the intricate dynamics of stunting and devising targeted interventions to mitigate its prevalence.\n\nFigure 4 shows the realm of stunting prediction, certain factors exhibit a negative correlation with the likelihood of a child experiencing stunting. These include the mother’s height, child’s size at birth, gender of the child, mother’s education, place of residence, reading newspapers, and the mother’s age. These aspects, when present, tend to indicate a reduced risk of stunting.\n\nThere are characteristics associated with a positive correlation, suggesting an increased risk of stunting in children. These positive value features encompass the initiation of breastfeeding, the presence of mother’s anaemia, marital status, province of residence, occurrences of diarrhoea, altitude, birthweight, and the age of the baby as shown in Figure 4.\n\n\nDiscussion\n\nThe ANN model’s results show considerable promise. The model displays its capacity to correctly categorise cases of stunting and non-stunting within the dataset with a significantly high degree of precision, with an accuracy of 72%. This demonstrates the model’s ability to detect critical patterns and variables associated with stunting in Rwandan children as also shown by Uddin et al.23 This paper also show that ANN is very powerful compared to other models.24 Furthermore, the model’s ROC score of 0.84 demonstrates its excellent discriminative capabilities. A higher ROC score indicates better distinction between the stunted and non-stunted child. The algorithm excels at reliably rating stunted children above non-stunted children, as indicated by an ROC score of 0.84, which is crucial in identifying individuals at high risk. These findings highlight the ANN model’s potential as a useful tool for predicting and mitigating stunting in Rwanda.25 This study reveals that it is crucial to note that the ROC curve and AUC-ROC should be assessed in conjunction with other assessment measures like accuracy, precision, and recall to provide a thorough picture of the model’s performance and applicability for practical application in stunting prediction, however, this study used only the ROC.25\n\nEarly identification of children at risk of stunting allows treatments to be targeted to those who need them the most, decreasing the burden of stunting on both the individual and society as a whole.26 The use of ANN in stunting prediction offers the potential to improve early detection and intervention tactics. Policymakers and healthcare professionals may prioritise targeted treatments and deploy resources more efficiently if the primary factors leading to stunting are identified.27 The study’s findings suggest that focusing on initiatives to enhance maternal nutrition, promote breastfeeding practices, and improve access to high-quality healthcare services could be of paramount importance in addressing the identified risk factors highlighted in the research as shown in Figure 4. Breastfeeding start appears as an important element, showing that early breastfeeding starting is connected with a decreased chance of stunting. These findings agree with the study conducted with Saberi-Karimian et al.27 Understanding the factors that contribute to childhood stunting gives vital information to policymakers, healthcare professionals, and communities.28\n\nThe same as the finding of this study suggested that efforts should be directed at improving maternal nutrition and health, supporting exclusive breastfeeding practices, and guaranteeing access to healthcare services that successfully manage maternal anaemia as well as the prevention and treatment of diarrhoea disorders, the mother’s height is important, as a lower height suggests an increased risk of stunting in children.29 Additionally, customised treatments should be developed for certain provinces with a greater rate of stunting. The awareness among mothers and caregivers about the importance of child proper nutrition, breastfeeding practices, hygiene, and the significance of regular healthcare visits should be increased.30 The research recommended that regular health checkups, growth monitoring, and testing to detect potential growth and developmental delays should be improved. Early measures, including nutritional supplements, caregiver counselling, and relevant healthcare interventions, can then be administered.31 The gender of the child is also associated with the outcome of the stunting of the child as seen in Figure 4. The mothers giving birth to boys should pay close attention to the nutrition of their babies, as different studies revealed boys are more stunted than girls.32\n\nBeing at higher altitudes is associated with a high risk of stunting in children in Rwanda as revealed by the study.11 It is crucial to emphasise that altitude is only one of several factors that contribute to stunting, and its influence varies depending on other contextual factors such as economic status, healthcare facilities, and dietary choices.33 To alleviate stunting in high-altitude locations, a comprehensive approach is required, which includes increasing access to healthcare, nutrition, sanitation, and education, as well as addressing the underlying socioeconomic determinants of health,34 this study also confirm the findings shown in the different studies. Finally, encourage collaboration among government agencies, healthcare providers, non-governmental organisations, and community-based organisations in order to execute comprehensive and multi-sectoral stunting elimination strategies. This partnership can ensure a comprehensive strategy to address the recognised stunting feature importance by combining the expertise and resources provided by different stakeholders.34\n\nHowever, while the model worked well in this study, it is possible that it may not generalise well to other populations or circumstances. Further study is needed to test the model’s generalisability and to uncover other factors that may improve its performance. Another limitation pertained to the discussion phase, primarily due to the scarcity of existing ANN literature focused on stunting prediction. Consequently, it was challenging to draw meaningful comparisons between this research and prior studies. The contribution of this research is the use of ANN analysis in stunting prediction in Rwanda results in improved identification of significant characteristics, real-time monitoring, targeted interventions, and useful policy decision-making assistance. These contributions increase our understanding of stunting, guide targeted interventions, and may eventually contribute to lowering stunting rates and enhancing children’s well-being in Rwanda.\n\n\nConclusions\n\nThe feature significance analysis of the ANN model in predicting stunting in Rwanda demonstrates the intricate interaction of numerous factors in affecting child growth and development. Positive value features stress the relevance of breastfeeding habits, mother health, and socioeconomic variables, whereas negative value features emphasise the importance of maternal qualities, education, and environmental factors. Rwanda may adopt targeted interventions and policies to minimise stunting prevalence and promote healthy growth and development for its children by addressing these major causes. In conclusion, the ANN model developed in this study provides a promising approach to predicting stunting in Rwanda. With further validation and refinement, it has the potential to significantly contribute to efforts aimed at reducing the stunting prevalence and improving child health outcomes in the country.", "appendix": "Data availability\n\nIn this study, we analysed datasets that are publicly available in the DHS program repository.\n\nhttps://www.dhsprogram.com/data/dataset_admin/login_main.cfm. The request was address to DHS program after providing the purpose of the use of data then after we obtained authorisation from the DHS administration to use them. Data access is granted to individuals who create an account and submit a request. The DHS team reviews the request and, upon approval, provides access to the requested data.\n\n\nAcknowledgments\n\nThis research could not have been completed without the contribution of different people who deserve acknowledgement: The African Centre of Excellence in Data Science at the University of Rwanda, World Bank financing (ID: ESC 91) project sponsored this research.\n\n\nReferences\n\nWHO: The unicef/who/wb joint child malnutrition estimates (jme) group released new data for 2021.2021.\n\nOsendarp S, Akuoku JK, Black RE, et al.: The covid-19 crisis will exacerbate maternal and child undernutrition and child mortality in low-and middle-income countries. Nature Food. 2021; 2(7): 476–484. 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Publisher Full Text\n\nThurstans S, Opondo C, Seal A, et al.: Boys are more likely to be under-nourished than girls: a systematic review and meta-analysis of sex differences in undernutrition. BMJ Glob. Health. 2020; 5(12): 004030. Publisher Full Text" }	[ { "id": "274786", "date": "17 May 2024", "name": "Billy Ogwel", "expertise": [ "Reviewer Expertise Enteric Research", "health informatics" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript addresses a significant public health challenge and provides valuable insights. To further enhance its impact, the authors may consider the following suggestions: Abstract: -Add detail on the modelling approach in the methods section. - Report 95% CI around the estimates -Be very explicit on the targeted interventions in the conclusion of the abstract. Introduction -More recent estimates of stunting are available 148.1 million as at 2022 (https://www.who.int/data/gho/data/themes/topics/joint-child-malnutrition-estimates-unicef-who-wb) -The authors can add successful implementations of ANNs in the healthcare domain in the paragraph where they talk about the strengths of ANNs. -The authors need to add the justification of their study why it is important to use ANNs to the same dataset that was used by authors in reference 11 in the same setting using SVM, NB, RF, LR, and XGBoost algorithms . Do they aim to achieve a higher predictive accuracy? Methods The authors say the data was partitioned into a training set, a validation set, and a test set. Yet talk only of a 80%:20% split. They could clarify this. Results: -The authors could refer to the TRIPOD checklist on reporting of diagnostic or prognostic prediction studies (Collins GS ,et.al., 2015 [Ref1]) . Specifically, they could : \"Describe the flow of participants through the study, including the number of participants with and without the outcome and, if applicable, a summary of the follow-up time. A diagram may be helpful.\" -They also need to report performance measures (with CIs) for the prediction model according to this guideline.\nDiscussion: The authors could improve the discussion by comparing their results to those of other studies that have used DHS to predict stunting and particularly reference 11 that was done in the same setting using the same data. Did their ANN model improve performance as hypothesized in the background? the authors could also discuss the potential clinical use of the model, highlighting where and when it can be used in the healthcare system\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13055", "date": "20 Jan 2025", "name": "Similien NDAGIJIMANA", "role": "Author Response", "response": "For the abstract The modelling approach has been added - The percentage mentioned in the abstract is derived from the figure; therefore, the 95% confidence intervals have not been provided. - The target interventions have been explained in detail in the abstract, however, due to the limited number of words more have been given in the conclusion For introduction - The reference and the estimated number of stunted children were added in the introduction section -The successful applications of ANN have been added - The reason was explained in the background of this paper “Given the crucial importance of addressing the root causes of stunting for effective treatments and policymaking, the researcher chose to conduct this study on the application of ANNs in the specific context of stunting in Rwanda, using the same dataset as the aforementioned publication” For Methodology -This explanation clarifies that the validation set is a subset of the training data, not the testing data, which helps to refine and tune the model before the final evaluation of the test set. Hence testing and validation share 20% For results -The proportion of Stunted children was given in the results section For Discussion -The incorporation of Artificial Neural Networks (ANN) within various healthcare applications has been integrated into the discourse; nevertheless, due to the constraints of the paper's length, I have included some additional insights." } ] }, { "id": "274789", "date": "22 May 2024", "name": "Mashfiqul Huq Chowdhury", "expertise": [ "Reviewer Expertise Statistics and Data Science" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study employs a deep learning model to predict stunting status among children under the age of five in Rwanda. The findings are intriguing. However, several improvements are necessary. The comments are detailed below: Title can be modified to: Predicting stunting status among under-5 children in Rwanda using neural network model: Evidence from 2020 Rwanda demographic and health survey In the Abstract, the results section needs improvement. The authors should rewrite the following sentence: Several factors appear as important contributors to the probability of stunting among the negative value aspects. Introduction section: a) Discuss the consequences of stunting and the overall situation of stunting in Rwanda among under-5 children. b) In the second paragraph, the author critically evaluates the linear regression and decision tree models. It is recommended that the author also discuss the logistic regression model. c) This sentence is not relevant to me: \"They can also be parallelised over many processors, increasing computing efficiency.9 ANNs may be used for transfer learning, which involves fine-tuning a pre-trained model for a new task with little data. This is especially important when data is scarce or expensive to collect.\" d) Spelling mistake: Supportive Vector Machine e) Give a reference to this sentence: ANNs have proven to be highly effective in predicting illnesses. f) The authors need to provide a more detailed description of the motivation behind this study. g) The literature review is very limited. I suggest adding more references to existing studies and relevant literature. h) This sentence is not clear: \"Given the crucial importance of addressing the root causes of stunting for effective treatments and policymaking, the researcher chose to conduct this study on the application of ANNs in the specific context of stunting in Rwanda, using the same dataset as the aforementioned publication. Methods section: a) This section can be split into the following sub-sections: Data Source and Sampling Design, Study Population, and Variables (Explanatory and Outcome Variables). The authors need to discuss the data file used from the DHS website, including information on any missing variables and whether they were discarded or handled in some other way. b) In Table 1, the following changes are recommended: replace \"Baby's age\" with \"Child's age,\" \"Antenatal\" with \"Antenatal care visits,\" and \"Reading\" with \"Media access.\" For variables such as source of drinking water, toilet facilities, and place of delivery, define the categories clearly in the variables sub-section. Specify the definitions for unimproved and improved statuses earlier in the text. Also, clarify which places are considered health facilities. Instead of using mother's height, the authors may consider the mother's BMI variable. c) The variables \"size of a child\" and \"birthweight\" are essentially the same. Should both variables be included? d) The authors need to clarify why the altitude variable is crucial for this analysis. e) Authors can create a new subsection titled \"Experimental Setup\" to systematically outline the experimental procedures. This section should be written in a clear and organized manner to ensure ease of understanding for readers. f) In the section discussing the Artificial Neural Network (ANN) model, it's important to specify the size of the hidden layer and provide justification for this choice, possibly citing relevant references. Additionally, authors should explain how they tuned the hyperparameters of the model. Including a reference for the Adam optimizer would also be beneficial. To improve clarity and prevent redundancy, it's recommended not to repeat the discussion of Scikit-learn, TensorFlow, and Python many times. g) The authors should clarify the context in which they use both standardization methods, Minimax scaler and Standard scaler, in their paper. It's important to explain why each method is chosen and how they are applied to the data. This clarification will help readers understand the rationale behind using different scaling techniques and their impact on the results. i) Use observations instead of instances. j) Figure 1 title needs to be improved. Results section: a) In Figure 2, the x-axis and y-axis titles should be clearly labeled. The legends also need to be improved to indicate \"Training Loss,\" \"Test Loss,\" \"Training Accuracy,\" and \"Test Accuracy.\" Additionally, the main title of the figure should be rewritten for clarity. b) Write a general comment based on Figures 2, 3, 4. Write in 2-3 paragraphs without sub-sections. c) If feasible, conduct a comparison with a machine learning model like logistic regression. This comparative analysis will elucidate which type of model (ML or DL) is best suited for this type of dataset. d) This sentence is not clear to me: \"This study reveals that it is crucial to note that the ROC curve and AUC-ROC should be assessed in conjunction with other assessment measures like accuracy, precision, and recall to provide a thorough picture of the model’s performance and applicability for practical application in stunting prediction, however, this study used only the ROC\". Discussion section: Authors can emphasize identifying similarities or consistency with other existing works.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13056", "date": "20 Jan 2025", "name": "Similien NDAGIJIMANA", "role": "Author Response", "response": "For title The title is modified as suggested For abstract I added some results, however, there is a limited number of words The sentence has been rephrased like this: Factors appear to contribute to stunting among the negative value aspects. Introduction section: The discussion was added As in the paper I published before and due to the limitation of the article I did not discuss this model here. The sentence is removed Supportive is changed into supporting The reference is given More details were given The references are added I paraphrased this sentence Methods section: The subsections have been added The variables were changed The variables \"size of a child\" and \"birthweight \" are not almost the same since one measures the height while the other measures the weight. From the analysis made before we find that altitude contributes to stunting being at high altitude is an associated risk factor for stunting, even in this analysis, ANN shows altitude as the associated factor to stunting. The section was not added due to the limited number of words however were explained in the methods The comment was accepted and adjusted as suggested. The clarification is given The comments are considered the observation replaced the instances The title is improved Results section: a) The title and legends have been added b) I did it as suggested c) the comparison made in the previous study d) The sentence is paraphrased, “This study highlights the importance of evaluating the ROC curve and AUC-ROC alongside other metrics such as accuracy, precision, and recall to gain a comprehensive understanding of the model's performance and its practical applicability in predicting stunting. However, it is important to note that this study only used the ROC for assessment. Discussion section: The emphases on similarities or consistency with other existing works were added" } ] }, { "id": "274788", "date": "12 Jun 2024", "name": "Mediana Aryuni", "expertise": [], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper needs some justifications for these concerns:\n\nThe reason why they only applied 1 Machine learning algorithm (ANN), while their previous research (11) applied 6 algorithms? The reason why they chose kNN for data imputation and SMOTE for data balancing Reconsider differentiating validation and testing data. Feature importance is done before or after learning model development Figure 1 is not systematic and clear It will be interesting if they also compare the accuracy with and without SMOTE They must explain why ANN doesn't perform better than Random forest, SVM, extreme gradient boosting, and gradient boosting in the discussion.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "13057", "date": "02 Jan 2025", "name": "Similien NDAGIJIMANA", "role": "Author Response", "response": "The reason was explained in the background of this paper “Given the crucial importance of addressing the root causes of stunting for effective treatments and policymaking, the researcher chose to conduct this study on the application of ANNs in the specific context of stunting in Rwanda, using the same dataset as the aforementioned publication” Choosing kNN for data imputation ensures that missing values are filled in a manner that maintains the natural relationships within the data, while SMOTE for data balancing addresses class imbalance, enhancing the model's ability to learn from and predict both stunted and non-stunted cases effectively. These preprocessing steps are crucial for building a robust and reliable ANN model for stunting prediction in Rwanda. The validation and testing were differentiated in the methodology section The feature importance was done after model development I am sorry I did not get what did you mean by this question is it to refine the diagram? I keep it as it was however the title has been changed I did however I get the same before balancing and after balancing While ANNs have shown substantial effectiveness in various predictive tasks, including illness prediction, their performance may not always surpass that of other algorithms like Random Forest, SVM, XGBoost, and Gradient Boosting in specific contexts, such as stunting prediction. The reasons include the higher complexity and risk of overfitting, significant data requirements, sensitivity to data quality, need for extensive feature engineering, and the inherent strengths of other algorithms in handling structured data, computational efficiency, and ease of hyperparameter tuning. Thus, the choice of algorithm should be guided by the specific characteristics of the dataset and the problem at hand." } ] } ]	1	https://f1000research.com/articles/13-128
https://f1000research.com/articles/13-812/v1	18 Jul 24	{ "type": "Research Article", "title": "Enhancing comparative politics education in the Asia-Pacific region: A study on the effectiveness of Chinese checkers game for strategy and negotiation learning", "authors": [ "Mario De La Puente", "Heidy Rico", "Elkyn Lugo Arias", "Jose Torres", "Heidy Rico", "Elkyn Lugo Arias", "Jose Torres" ], "abstract": "Background This research conducted an extensive exploration in 2021 and 2022 to investigate the implications of integrating Chinese checkers into Comparative Politics courses across the Asia-Pacific region. The primary aim was to enhance students’ strategic thinking and negotiation skills and determine if active engagement with Chinese checkers could significantly improve academic performance.\n\nMethods The study employed paired-samples t-tests and independent-samples t-tests to evaluate the impact of Chinese checkers. It involved assessing the academic performance and strategic thinking abilities of students who engaged with the game. The study encompassed a thorough design, participant selection, and procedures related to the intervention, including various outcome measures.\n\nResults The investigation revealed notable improvements in academic performance, especially in strategic thinking, among students who actively participated in Chinese checkers gameplay. This research also substantiated the enhanced strategic thinking abilities of students who integrated Chinese checkers into their curriculum, contributing to the corpus of knowledge on innovative pedagogical practices.\n\nConclusions The findings of this study are relevant to educators, students, and policymakers, emphasizing the educational value of unconventional teaching methods like Chinese checkers. In light of the increasing importance of the Asia-Pacific region in global politics, this research underscores the significance of nurturing strategic thinking skills among undergraduate students. The study contributes to the cultivation of critical thinking and strategic acumen within higher education, potentially benefiting society by fostering superior academic performance and the development of strategic thinking abilities.", "keywords": [ "Chinese Checkers", "Strategic Thinking", "Negotiation Skills", "Comparative Politics", "Higher Education" ], "content": "Introduction\n\nIn the realm of higher education, nurturing cognitive skills takes precedence, as it equips students with the intellectual prowess needed to dissect intricate scenarios, make informed choices, and strategically plan for the future. Among these cognitive competencies, strategic thinking emerges as a fundamental aptitude, bearing immense significance in academic accomplishments and personal growth. It encompasses the capacity to approach challenges with foresight, evaluate multifaceted situations, and devise efficacious, forward-looking strategies. Acknowledging the pivotal role of strategic thinking in undergraduate education, this research endeavors to delve into the intricate nexus between the development of strategic thinking and the integration of Chinese checkers, a venerable strategic board game, within the academic curriculum.\n\nStrategic thinking is an indispensable skillset widely acknowledged as critical for success across diverse domains. It encompasses a spectrum of problem-solving and decision-making proficiencies that empower individuals to navigate intricate and uncertain terrains. This paper sets out to elucidate the construct of strategic thinking, its significance, and its applicability in varied contexts. To accomplish this, an extensive literature review is conducted, drawing upon seminal works such as Grant (2019), Mintzberg et al. (2009), Porter (1996), Rumelt (2011), and Shoemaker and Reese (2013). Grant (2019) offers an exhaustive dissection of contemporary strategy, underscoring the pivotal role of strategic thinking in shaping and executing effective strategies. The author underscores the necessity for an in-depth comprehension of the external milieu, internal capabilities, and the ability to foresee and respond to transformations. This perspective resonates with Mintzberg et al. (2009), who posit that strategic thinking encompasses a holistic approach to crafting strategies by considering multiple vantage points and exploring a multitude of strategic avenues. Porter (1996) contributes a seminal article that delineates the essence of strategy and sets it apart from operational efficiency. The author underscores the significance of making choices and crafting a distinct value proposition to attain a competitive edge. This endeavor necessitates strategic thinking to identify opportunities, evaluate risks, and efficiently allocate resources. Rumelt (2011) further scrutinizes the dichotomy between sound and unsound strategies, emphasizing the role of strategic thinking in formulating lucid and cogent strategies. The author accentuates the importance of diagnosing the underlying causes of issues and devising actions that adeptly address them. This perspective dovetails with Shoemaker and Reese’s (2013) stance on strategic thinking in the realm of intricate problem-solving, accentuating the ability to dissect and amalgamate information, spot patterns, and generate inventive solutions (Fisher et al., 2011; Pruitt and Rubin, 1986; Rico et al., 2021).\n\nAs students progress through their undergraduate journey, they inevitably acquire cognitive skills that not only serve as preparations for the complexities of their future professional endeavors but also enhance their analytical and decision-making capacities. However, the intriguing question arises: can we intentionally nurture strategic thinking within the academic environment, taking it beyond its natural development? It is within this intriguing context that the present study finds its motivation.\n\nThe fundamental research objective of this investigation is to explore the influence of incorporating the strategic board game Chinese checkers into the academic curriculum on the advancement of strategic thinking skills among undergraduate students. The study seeks to evaluate whether active engagement with Chinese checkers as a part of their coursework enhances the strategic thinking abilities of students. This objective arises from the profound understanding of the critical role of strategic thinking in academic achievements and its wider applications in personal and professional domains.\n\nTo address this primary objective, the research presents the following question: Does the integration of Chinese checkers into the academic curriculum result in a significant enhancement of undergraduate students’ strategic thinking skills? This question acts as the guiding beacon for the study, steering the exploration of the potential impact of Chinese checkers on students’ cognitive development within the academic realm.\n\nThe study revolves around two central hypotheses. Hypothesis 1 delves into the effects of employing Chinese checkers as an educational tool within a Comparative Politics class on students’ strategic thinking and negotiation skills. The hypothesis posits that students exposed to Chinese checkers would exhibit a statistically significant improvement in these skills compared to their peers who did not utilize Chinese checkers.\n\nData collection involved initial pre-test scores, which represented the baseline measurements of strategic thinking and negotiation skills for both the Chinese checkers group and the non-Chinese checkers group, collected prior to any exposure to the game. Subsequently, post-test scores were obtained to evaluate the students’ skills after they completed the Comparative Politics class.\n\nThe analytical approach entailed the utilization of the Paired-Samples T-Test, a method designed to scrutinize whether any statistically significant disparities emerged in the skill levels of the same group of students prior to and post their engagement with Chinese checkers. Additionally, the Independent-Samples T-Test was employed to compare the post-Chinese checkers performance scores between the two distinct groups, shedding light on whether the use of Chinese checkers indeed yielded noteworthy variations in skill sets.\n\nIn scenarios where multiple groups, such as diverse class sections, were involved, the Analysis of Variance (ANOVA) was set in motion. This statistical technique played a pivotal role in assessing whether significant disparities in skill enhancement were observable among these varied groups. In summation, these retrospective statistical methodologies facilitated a comprehensive exploration of Hypothesis 1, yielding insights into its implications for students’ strategic thinking and negotiation abilities.\n\nTurning to Hypothesis 2, it centered on the inquiry into the influence of incorporating Chinese checkers as an educational tool in Comparative Politics classes attended by eighth-semester students pursuing an undergraduate program in International Relations. The primary focus was on discerning whether this pedagogical strategy engendered heightened engagement and enthusiasm among the students regarding the subject matter. The evidence for this presumed effect was sought in the form of heightened class participation and an augmented enthusiasm for the course, especially when compared to their counterparts who had not been exposed to Chinese checkers.\n\nTo address this hypothesis, a diverse range of data was requisitioned. Initially, engagement data took center stage, encompassing meticulous observations and meticulous record-keeping to monitor students’ contributions to class discussions, the frequency of their queries, and their overall active involvement during the course. Complementing this, enthusiasm data was also diligently amassed. This facet of the investigation revolved around students’ levels of enthusiasm for the course and was quantified through surveys and self-assessments. These surveys featured pre-and post-course enthusiasm ratings, offering students the opportunity to express their sentiments through either a Likert scale or qualitative responses. Moreover, the classification of students into respective groups was of paramount importance. This categorization served to distinguish between the experimental group, comprising students who had been exposed to Chinese checkers, and the control group, consisting of those who had not encountered the game in their learning experience.\n\nThroughout the analytical process, a set of statistical methodologies was employed to comprehensively investigate the research questions. The examination began with the application of the Chi-Square Test, an instrumental tool in discerning the presence of a meaningful association between the incorporation of Chinese checkers and the discernible enhancement in classroom participation. This was particularly pertinent when considering a categorical variable, which discerned whether students exhibited greater or lesser participation.\n\nFurthermore, the research incorporated Student Surveys and Likert Scale Analysis, an approach aimed at the meticulous statistical scrutiny of Likert scale responses. This method facilitated the determination of substantial disparities in enthusiasm levels, both prior to and subsequent to the course, effectively distinguishing between the two distinct groups under investigation.\n\nIn addition to these quantitative measures, a qualitative analysis was undertaken to explore the depths of students’ experiences and perceptions. Open-ended survey responses and interviews were thoughtfully conducted, providing a comprehensive comprehension of the influence of Chinese checkers on students’ levels of engagement and interest in Comparative Politics classes. This multifaceted approach was pivotal in painting a holistic portrait of the subject matter under examination.\n\nThe study recognized certain constraints, encompassing conceivable confounding variables, the particularity of the academic milieu, and the extensiveness of the results’ applicability to more comprehensive educational environments. Nevertheless, this investigation yielded contributions to novel understanding by imparting illuminations regarding the educational utility of strategic board games for the advancement of cognitive abilities, while also shedding light on the interplay between culture and cognitive maturation.\n\n\nLiterature review\n\nIn the realm of undergraduate political education, the cultivation of strategic thinking emerges as a pivotal skill. Scholars acknowledge the fundamental mission of political science programs to nurture critical thinking within their student body (Manweller & Harvey, 2013). Critical thinking, widely deemed a cornerstone of undergraduate education, carries profound significance (Loeb et al., 2017). In the context of political science, strategic thinking encompasses the capacity to dissect intricate political scenarios, foresee potential ramifications, and construct effective tactics for the realization of desired objectives. This emphasis on strategic thinking underscores the need to bridge the gap between theoretical and practical coursework (Park & Lee, 2021). A tangible example is found in the domain of design undergraduates, who must transcend their shortsighted perspectives and apply strategic thinking within practical, multicultural, and interdisciplinary settings (Park & Lee, 2021). To internalize strategic thinking and design thinking, it is imperative to sustain a steady stimulus (Park & Lee, 2021). Therefore, infusing practical applications and real-world instances into political education holds the potential to facilitate the acquisition of strategic thinking skills.\n\nMoreover, the maturation of strategic thinking is intricately tied to the advancement of critical thinking competencies. Within undergraduate political science programs, pedagogical strategies commonly employ the concept of critical thinking (Manweller & Harvey, 2013). The deliberate and strategic integration of assignments focused on critical thinking has been empirically proven to substantially enhance the critical thinking prowess of undergraduate students (Ralston & Bays, 2015). Thus, the infusion of critical thinking exercises and assignments into the landscape of political education serves as a pivotal avenue for nurturing strategic thinking skills.\n\nFurthermore, it is noteworthy that various other factors exert influence over the development of strategic thinking abilities among undergraduates. Research indicates that the quality of instruction, the nature of the learning environment, and the motivation levels of students wield a substantial and affirmative correlation with critical thinking skills (Kua et al., 2018). As such, the creation of a supportive and intellectually stimulating educational milieu, the delivery of high-quality pedagogy, and the encouragement of students’ motivation collectively contribute to the evolution of strategic thinking proficiencies within the domain of undergraduate political education.\n\nGamified learning has garnered significant attention within the realm of higher education as an innovative approach aimed at tackling challenges related to student motivation and engagement (Subhash & Cudney, 2018; Buckley & Doyle, 2014; Dichev & Dicheva, 2017). This educational strategy integrates game elements into the learning process, with the primary goal of enriching motivation, enhancing engagement, and ultimately improving learning outcomes (Sailer & Homner, 2019). Its prominence extends across diverse fields, encompassing education, health professions, and mathematics education (Gaalen et al., 2020; Gentry et al., 2019; Chen et al., 2023; Kaya & Ercag, 2023).\n\nEmpirical studies underscore the constructive impact of gamified learning on various learning facets. A comprehensive review of empirical research in educational gamification has consistently shown that its implementation results in elevated levels of motivation, engagement, and overall enjoyment of learning tasks (Hamari & Koivisto, 2014). In the context of health professions education, a systematic review has indicated that well-structured gamified learning experiences are conducive to reinforcing students’ learning behaviors and nurturing a positive attitude toward learning, ultimately culminating in improved learning outcomes (Gaalen et al., 2020). Nevertheless, the effects of gamified learning on specific skill outcomes exhibit variability, as articulated in a systematic review within health professions education, revealing that while some studies reported favorable outcomes, the overall effects were not uniform (Gentry et al., 2019). This underscores the notion that the efficacy of gamified learning is context-dependent and contingent on the specific skills under consideration.\n\nWithin the theoretical framework of gamified learning, the indirect influence of gamification on learning outcomes is postulated (Sailer & Homner, 2019). This suggests that gamified learning can be instrumental in enhancing learning outcomes by stimulating motivation and promoting engagement, thereby contributing to improved learning performance. Additionally, the strategic design and execution of gamified learning activities wield substantial influence over their effectiveness. Research has demonstrated that the utilization of multiple representations and scaffolding techniques within gamified mathematics teaching can stimulate students’ critical thinking and advance their problem-solving skills (Chen et al., 2023). Correspondingly, a study probing into the impact of a challenge-based gamification program on learning outcomes noted an augmentation in learners’ flow levels, albeit not of statistical significance (Kaya & Ercag, 2023). This underscores the significance of factoring in instructional design principles and theories, such as flow theory, when embarking on gamified learning initiatives (Buckley & Doyle, 2014; Alsawaier, 2018; Kalogiannakis et al., 2021).\n\nThe integration of gamification within educational settings represents a pedagogical approach that seeks to harness game-like elements, including challenges, rewards, and competitive aspects, in order to enhance the interactive and enjoyable facets of the learning experience (Buckley & Doyle, 2014; Alsawaier, 2018). This methodology is rooted in the idea of stimulating students’ intrinsic motivation by affording them opportunities to tackle complex problems, surmount obstacles, and actively engage in critical thinking endeavors (Alsawaier, 2018). Extensive research supports the contention that gamified learning interventions can have a favorable impact on the participation and academic performance of undergraduate students (Buckley & Doyle, 2014). A comprehensive investigation involving a sizable cohort of undergraduate students revealed the influence of intrinsic and extrinsic motivation on their levels of engagement and performance within an online gamified learning intervention (Buckley & Doyle, 2014). The inherent fun and captivating nature of gamified environments serve as motivating factors, prompting students to eagerly partake in learning activities and cultivate their cognitive and problem-solving proficiencies (Alsawaier, 2018).\n\nAdditionally, the implementation of gamified learning has been explored across various academic disciplines, spanning health professions education (Gentry et al., 2019), science education (Kalogiannakis et al., 2021), mathematics education (Chen et al., 2023; Zainol, 2022), and entrepreneurship education (Isabelle, 2020). In health professions education, the assessment of serious gaming and gamification has revolved around their efficacy concerning patient outcomes, knowledge acquisition, skill development, professional attitudes, and satisfaction (Gentry et al., 2019). Within the realm of science education, the adoption of gamification strategies has yielded increased student engagement and heightened learning efficacy (Kalogiannakis et al., 2021; Rico et al., 2023). Similarly, in mathematics education, gamified learning activities, which incorporate multi-representational scaffolding and cognitive tools, have proven effective in fostering advanced problem-solving skills (Chen et al., 2023). Furthermore, the gamification of entrepreneurship education has been shown to enrich students’ educational experiences, bolster their engagement, and enhance their self-efficacy within the entrepreneurial domain (Isabelle, 2020).\n\nIt is worth noting that while gamified learning can significantly boost motivation and performance, some students may continue to encounter challenges in specific subjects, even within a gamified learning context (Palaniappan & Noor, 2022). Nonetheless, the integration of gamification strategies can still yield tangible improvements in students’ academic performance and motivation within these disciplines (Palaniappan & Noor, 2022). Gamified learning offers notable advantages compared to alternative pedagogical approaches, such as peer-learning strategies and active learning methods, as it underscores the development of higher-order thinking skills, problem-solving capabilities, and critical analytical skills (Cheng et al., 2022).\n\nChinese checkers has been recognized for its association with strategic thinking among undergraduate students. The acquisition of strategic thinking skills, a pivotal cognitive ability encompassing situation analysis, decision-making, and future planning, has garnered significant attention (Rua et al., 2021; de la Puente Pacheco et al., 2022; Rico et al., 2022).\n\nEngaging in a game of Chinese checkers necessitates the employment of strategic thought processes, as participants are tasked with contemplating numerous moves in advance while considering their opponents’ potential actions (Rua et al., 2021). Research has aptly highlighted that participation in board games, including Chinese checkers, can substantially augment students’ strategic thinking proficiencies. Board games construct a controlled environment wherein players can hone their skills in strategic decision-making and problem resolution (Rua et al., 2021). Such games impel students to adopt a critical outlook, scrutinize the gaming board, and devise ingenious strategies to outmaneuver their rivals (Rua et al., 2021). In consequence, students, through active participation in such endeavors, have the opportunity to cultivate their strategic thinking competencies.\n\nAdditionally, an array of studies underscores the role of undergraduate research experiences in fostering the development of students’ strategic thinking abilities. These research ventures provide students with valuable opportunities to grapple with intricate problem-solving tasks, decipher data, and render informed judgments (Seymour et al., 2004; Hunter et al., 2007). These experiences inherently mandate strategic contemplation concerning research objectives, methodological approaches, and eventual outcomes (Hunter et al., 2007; de la Puente Pacheco et al., 2021; Landazury et al., 2022). Consequently, students emerge from these engagements possessing the prowess to think strategically and apply their erudition in real-world contexts.\n\nMoreover, insights derived from the realm of cross-cultural decision-making styles suggest that Chinese students may inherently possess a predilection for strategic thinking. Enriched by Confucian principles, Chinese culture places a premium on harmonious consensus and decision-making compromise (Park et al., 2015). Consequently, Chinese undergraduate students, historically and societally steeped in these cultural values, may exhibit a proclivity toward strategic thinking, especially when partaking in group decisions (Park et al., 2015). This postulation intimates that Chinese students may possess an innate inclination for strategic thinking, which can be further nurtured through activities like playing Chinese checkers. The document acknowledges strategic thinking as a fundamental cognitive ability encompassing the aptitude to dissect intricate situations, make prudent decisions, and formulate forward-thinking plans (Rua et al., 2021). Chinese checkers, a strategic board game, necessitates players to engage in profound strategic thought processes by requiring them to contemplate several moves ahead and anticipate opponents’ actions (Rua et al., 2021). Prior research has already elucidated that participation in board games, particularly Chinese checkers, offers promising avenues to augment the strategic thinking abilities of students. These games provide a constructive, simulated milieu for students to immerse themselves in strategic decision-making and problem-solving (Rua et al., 2021).\n\nIn this context, the primary research hypothesis assumes a pivotal role, asserting that undergraduate students who integrate Chinese checkers into their academic endeavors will manifest conspicuous enhancements in their strategic thinking capabilities in comparison to their counterparts who do not engage in such activities. This hypothesis emanates from the notion that the inherent strategic components of Chinese checkers significantly contribute to the development of strategic thinking skills. It lays the foundation for a comprehensive exploration of the influence of this strategic board game on the cognitive growth of undergraduate students.\n\nBeyond the strategic merits of Chinese checkers, the document also underscores the significance of undergraduate research experiences in fostering strategic thinking skills among students. These research undertakings equip students with the proficiency to tackle intricate problem-solving, engage in rigorous data analysis, and make informed, strategic decisions (Seymour et al., 2004; Hunter et al., 2007; Pozo-García et al., 2020). Such experiences mandate students to adopt a strategic perspective when delineating research objectives, selecting methodologies, and deciphering research outcomes (Hunter et al., 2007). Moreover, given the profound impact of culture on decision-making styles, the document posits that Chinese undergraduate students, steeped in the values of their cultural heritage influenced by Confucian principles that emphasize harmony and compromise, may inherently exhibit an inclination toward strategic thinking (Park et al., 2015). This lays the groundwork for the second research hypothesis, proposing that Chinese students, owing to their cultural values and potential proclivity towards strategic thinking, will display heightened strategic thinking skills. This intrinsic predisposition can be further nurtured through activities such as playing Chinese checkers, extending beyond the confines of the academic realm.\n\nThese two hypotheses anchor the research, offering a structured framework for the study’s exploration of the multifaceted relationships between Chinese checkers, strategic thinking development, and the influence of cultural values.\n\n\nMethods\n\nThe experimental group comprised 93 undergraduate students currently pursuing the Asia Pacific Comparative Politics course. Within this cohort, a predominant age bracket ranged from 21 to 22 years, signifying a group of young adults in the advanced stages of their academic journeys. Their age distribution attests to a level of academic maturity and experience. Notably, the majority of this group is composed of female students, aligning with the broader trend of increased female enrollment within social science and political science programs. This gender representation contributes to the diverse and dynamic academic milieu.\n\nIn terms of academic backgrounds, the experimental group exhibited a wide spectrum of prior academic performance, evident from their respective GPAs, which spanned from 3.7 to 4.3. These GPAs underscore the group’s dedication to their studies, with most students achieving above-average academic results. The diversity in GPA range suggests a mix of individuals who consistently excelled in their coursework and others who displayed substantial potential for academic growth. This range highlights the prospect for academic enhancement through the integration of Chinese checkers gameplay within their Comparative Politics curriculum.\n\nCrucially, all 93 students within the experimental group shared enrollment in the Asia Pacific Comparative Politics course, demonstrating a collective academic interest in the political landscape and governance of the Asia-Pacific region. This course specialization offers a focused and contextually relevant platform for the incorporation of strategic board games, such as Chinese checkers. Their mutual enrollment reflects a shared aspiration to gain deeper insights into the political dynamics, policies, and comparative analyses specific to the Asia-Pacific region.\n\nThe control group is comprised of 86 undergraduate students pursuing a degree in International Relations, with a specialized focus on Asia Pacific Comparative Politics. These students, aged between 21 and 22, form a relatively homogeneous age group within the control cohort. Notably, the gender distribution within the control group is skewed towards females, indicating a predominantly female demographic engaged in this academic pursuit.\n\nWithin the control group, students present a spectrum of prior Grade Point Averages (GPAs), serving as a metric for their academic backgrounds. GPAs range from 3.7 to 4.3, reflecting a diverse range of academic experiences and levels of scholastic achievement. This GPA diversity offers a valuable foundation for evaluating the introduction of Chinese checkers into their curriculum as a potential enhancer of strategic thinking and negotiation skills. These collective attributes of the control group render it a suitable benchmark for comparison against the experimental group, which underwent a similar academic journey but without the incorporation of the game into their coursework.\n\nIt is noteworthy that the control group, while sharing similarities with the experimental group, did not receive exposure to the game of Chinese checkers as an instructional tool during their Asia Pacific Comparative Politics course. This distinction allows for a controlled investigation into the game’s influence on strategic thinking and negotiation skills within the confines of this specialized academic context.\n\nThe Comparative Politics in Asia Pacific course provided students with a comprehensive and immersive exploration of the region’s diverse facets, encompassing geography, economics, politics, and negotiation processes. In the initial phase, students embarked on a journey into the geographical dimensions of Asia Pacific, delving into physical geography and the region’s remarkable biodiversity. These foundational aspects not only contributed to a deeper understanding of the local ecosystems but also played a pivotal role in negotiations involving resource allocation and environmental accords.\n\nIn addition to geography, the course offered a thorough investigation into the economic landscape of Asia Pacific, shedding light on trade agreements categorized by geographical sectors and spatial agglomeration. This comprehension of economic geography proved instrumental in the negotiation of international trade agreements and deciphering the intricate web of economic interests prevalent in the region. Furthermore, the course emphasized the influence of philosophy and religion on the region’s dynamics, recognizing the profound impact of cultural elements on diplomatic negotiations.\n\nA pivotal component of the curriculum was the study of political geography in Asia Pacific. Students were exposed to the geopolitical landscape, including territorial disputes that often necessitated negotiation and diplomatic resolutions. The negotiation aspect of the course was enriched with immersive simulations and case studies, ranging from historical negotiations to contemporary diplomatic dialogues within the region.\n\nMoreover, the course directed its focus towards an examination of political, economic, and social development indicators unique to Asia Pacific, all of which held significant relevance in the context of negotiations. Students were equipped with the skills to utilize economic indicators and qualitative analyses to inform their negotiation strategies. Exploring the historical underpinnings of economic development in the region served as a vital backdrop for trade negotiations, while the study of social indicators provided valuable insights into the social dynamics of the region and their profound influence on political negotiations.\n\nIn addition to the internal dynamics within the region, the course placed considerable emphasis on the global interactions of the Asia Pacific, particularly in the context of negotiation processes. The curriculum included a comprehensive examination of the region’s political-economic relationships with other global entities, such as its negotiations with the European Union, Latin America, the United States, Africa, and Russia. Through the study of these global negotiations, students were afforded valuable insights into the Asia Pacific’s role on the world stage and the intricate nature of international diplomacy and trade negotiations. The course also delved into the significance of regional organizations and forums, including APEC and ASEAN, underscoring their pivotal roles in shaping regional policies, fostering cooperation, and influencing negotiation strategies.\n\nWithin the experimental group, the implementation of Chinese checkers transpired during the six to eleven-week period of a 14-week academic semester. Throughout this interval, a dedicated professor took on the responsibility of guiding and overseeing the seamless integration of Chinese checkers into the curriculum. This professor ensured that the game harmoniously aligned with the objectives and subject matter of the Asia Pacific Comparative Politics course.\n\nSpanning four academic semesters from 2021 to 2022, this study evolved as an ongoing experiment. The introduction of Chinese checkers to the students in the experimental group was carried out with meticulous care. Prior to commencing the gameplay, an extensive briefing on the game’s rules, strategic components, and its relevance to the study’s objectives was provided to the students. This introductory session served as a vital cornerstone for the subsequent integration of Chinese checkers into the classroom environment.\n\nSignificantly, all students in the experimental group were duly informed about the nature and purpose of the study, which encompassed the validation of the two hypotheses. They were unequivocally assured that their participation was entirely voluntary, and the confidentiality of their personal information was of utmost priority. The research team acquired written consent from each participating student in strict compliance with the ethical guidelines stipulated by the EDUCATION FOR ALL ONLINE organization, which both funded and granted approval for the study. This meticulous adherence to ethical principles ensured that the study adhered to the highest ethical standards, meticulously safeguarding the rights and privacy of all participants.\n\nThe integration of Chinese checkers into the curriculum of the Asia Pacific Comparative Politics course was a pioneering initiative aimed at enriching students’ strategic thinking and negotiation skills. It provided an interactive platform for students to actively immerse themselves in the subject matter, fostering a dynamic and engaging learning environment. This longitudinal experiment, spanning multiple academic semesters, was meticulously designed to evaluate the pedagogical impact of game-based learning in the realm of international relations education. Through this research endeavor, the study sought to yield valuable insights into effective teaching methodologies and their profound influence on student academic outcomes.\n\nAdditionally, as an integral facet of the study’s implementation, the instructor conscientiously observed and evaluated the participation of students in the experimental group throughout the duration of six to eleven weeks. This comprehensive observation encompassed multifaceted dimensions of their academic engagement, including active involvement in discussions pertaining to the course’s academic themes, their perspectives on contemporary geopolitics, and the depth of their contributions to classroom discourse. This holistic assessment not only enabled the instructor to assess the influence of Chinese checkers on students’ strategic thinking and negotiation skills but also provided a profound understanding of their overall academic engagement and critical thinking capabilities within the framework of the Asia Pacific Comparative Politics course. The observational component thus enriched the study with qualitative insights that complemented the quantitative data, culminating in a comprehensive and well-rounded evaluation of the study’s outcomes.\n\nThe research hypotheses in this study underwent stringent statistical analyses to assess their validity. Initially, the first hypothesis, which proposed that students’ participation in strategic gameplay using Chinese checkers would lead to a statistically significant enhancement in their academic scores, was rigorously examined through a Paired-Samples T-Test. This statistical method involved comparing the mean academic scores of the participants before and after their engagement with Chinese checkers. The selection of the Paired-Samples T-Test was apt for this study since it is well-suited for analyzing changes within the same group following an intervention. The outcomes of this analysis indicated a notable improvement in academic performance for both the experimental group (p = 0.017) and the control group (p = 0.023) following their respective encounters with Chinese checkers. The presence of modest p-values underscores the statistical credibility of the first hypothesis by ruling out random chance, thus providing substantive support for its validity.\n\nIn addition, the validation of the first hypothesis was approached from an alternative perspective through the implementation of an Independent-Samples T-Test. This quantitative analysis was specifically conducted to assess the effect of Chinese checkers on students’ academic performance, comparing the post-Chinese checkers academic scores between the experimental and control groups. The results derived from the Independent-Samples T-Test revealed a statistically significant discrepancy in academic performance, with the experimental group demonstrating superior performance over the control group (p = 0.042). These findings served as corroborating evidence that students actively engaging with Chinese checkers exhibited significantly enhanced academic performance concerning strategic thinking and negotiation skills. The application of Independent-Samples T-Tests not only reinforced the statistical validity of the first hypothesis but also furnished supplementary confirmation of the constructive influence of Chinese checkers on academic performance.\n\nFurthermore, the researchers performed an additional Analysis of Variance (ANOVA) to examine the influence of Chinese checkers on students’ academic performance concerning strategic thinking across various distinct groups. The ANOVA findings revealed statistically significant disparities between the control group and the different experimental subgroups, further substantiating the educational efficacy of Chinese checkers. The F-Value, standing at 3.78, coupled with a corresponding p-value of 0.026, served to underscore the statistical significance of the initial hypothesis. This extensive array of statistical methodologies, including the Paired-Samples T-Test, Independent-Samples T-Test, and ANOVA, collectively fortified the validation of the first hypothesis, delivering a rigorous analysis of the research queries pertaining to the enhancement of students’ strategic thinking in the realm of a Comparative Politics course through the assimilation of Chinese checkers.\n\nThe initial phase of assessment was primarily aimed at establishing a foundational understanding of the participants’ pre-existing levels of strategic thinking and negotiation skills prior to the integration of Chinese checkers into the academic curriculum. Following this, the subsequent phase of evaluation focused on identifying any observable changes or enhancements in these skills subsequent to their exposure to the game. The design of the questionnaires for this purpose was characterized by a thoughtful approach, encompassing Likert-scale inquiries to gather quantitative data and open-ended questions aimed at eliciting qualitative insights. This comprehensive methodological framework enabled the research team to carry out a comprehensive and well-rounded analysis of the development of these skills.\n\nIn parallel with the administration of questionnaires, the assessment of the first hypothesis relied significantly on game performance metrics. As Chinese checkers was seamlessly integrated into the educational curriculum, records were maintained concerning students’ performance within the game environment. This encompassed the systematic documentation of game outcomes, the tracking of participants’ strategic moves, and the in-depth analysis of the strategic methodologies employed during the course of gameplay. These multifaceted assessment strategies collectively provided valuable insights for the research endeavor. The data that support the findings of this study are available on request from the corresponding author under certain restrictions.\n\nThe research instruments employed in the study provided invaluable insights into the interaction between students in the experimental group and Chinese checkers, offering a comprehensive understanding of their gaming strategies and performance. The participants’ gameplay choices and decisions were meticulously observed, facilitating a nuanced comprehension of their approaches. Ten key findings were derived from this analysis:\n\nInitially, a prominent pattern emerged within the participants, featuring distinct gameplay styles. Some students opted for an aggressive approach, rapidly expanding their territory and engaging in early confrontations. In contrast, others leaned towards a more defensive strategy, methodically consolidating their pieces and positioning for strategic advantages. Additionally, the students exhibited remarkable adaptability in their gameplay, showcasing their capacity to adjust their strategies in response to evolving in-game circumstances. This adaptability was particularly noticeable when students encountered unforeseen challenges or opportunities throughout the gameplay.\n\nFurthermore, the analysis highlighted that students who actively participated in class discussions and expressed strong opinions regarding contemporary geopolitics often displayed assertive gameplay styles. They demonstrated a greater willingness to undertake strategic risks and engage in confrontational situations during the game. These findings collectively contribute to a comprehensive understanding of the students’ engagement with Chinese checkers and its potential impact on their strategic thinking and negotiation skills.\n\nIn the course of the investigation, a noteworthy revelation surfaced: a penchant for cooperative play became evident among several students. In their engagement with Chinese checkers, certain individuals opted to forge alliances and engage in collaborative efforts with their peers. This cooperative endeavor distinctly underscored the social facet of the game, accentuating the pivotal roles of negotiation and coordination in achieving collective goals.\n\nFurthermore, the study unveiled a correlation between strategic piece placement and spatial thinking abilities. Those students who exhibited adeptness in adroitly positioning their pieces on the board demonstrated a heightened capacity for spatial cognition. Their aptitude for exercising control over key areas within the game’s framework was frequently linked to elevated success rates.\n\nThe analysis shed light on a recurrent theme: a penchant for forward movement and offensive maneuvers was closely intertwined with students who emerged victorious. Those who embraced an assertive approach, characterized by deftly capturing opponent’s pieces and expanding their territorial dominion, often found themselves in the winner’s circle.\n\nAdditionally, the research emphasized the role of precision moves and outmaneuvering tactics as defining characteristics of consistently successful students. This discovery underscored the significance of meticulous planning and judicious decision-making during the game. By scrutinizing the students’ in-game performance, the researchers were able to discern tangible enhancements and shifts in their strategic thinking and negotiation tactics over the study’s duration. This real-world assessment added a dynamic and empirical dimension to the research, furnishing palpable evidence of the game’s influence on the targeted skills.\n\nThe study also incorporated focus group interviews conducted at strategic junctures during the research endeavor. These interviews served as invaluable tools for delving into the participants’ subjective experiences and perceptions. They offered qualitative insights into the impact of Chinese checkers on students’ strategic thinking and negotiation skills. Participants were encouraged to share their thoughts, strategies, and any noticeable alterations in their problem-solving approaches and negotiation techniques, both within the context of the game and in broader settings, such as classroom discussions and their viewpoints regarding contemporary geopolitics. These interviews, replete with contextual richness and personal narratives, added depth to the study’s findings, enriching the overall comprehension of the intervention’s effects.\n\nThe academic performance of students within both the experimental and control groups played a pivotal role in the examination of the study’s hypotheses. These academic records, in conjunction with the research instruments and gaming metrics, furnished essential quantitative data for evaluating the influence of integrating Chinese checkers into the curriculum on the enhancement of students’ strategic thinking and negotiation skills. Through an analysis of the shifts in academic achievements, combined with the data extracted from gameplay and questionnaire responses, the study aimed to deliver a comprehensive appraisal of the hypotheses and their implications for student educational outcomes.\n\nIn alignment with the assessment of students’ gaming performance and academic standings, a Likert scale questionnaire was applied to assess their grasp of political strategic thinking and negotiation skills concepts. This questionnaire comprised a set of meticulously crafted statements designed to probe various facets of strategic thinking and negotiation skills. These statements offered participants the opportunity to articulate their perspectives and self-evaluate their competencies, providing valuable self-reported insights to complement the quantitative and qualitative insights derived from the gaming metrics and academic data.\n\nThe creation of the Likert survey focusing on political strategic thinking and negotiation skills concepts drew upon the utilization of several pertinent references. Specifically, Waring et al. (2022) had previously conducted a qualitative interview study with the aim of comprehending the political skills and behaviors indispensable for steering the implementation of health services transformation. Their discoveries had identified five overarching categories of political skills and behaviors, encompassing personal and interpersonal attributes, strategic thinking, communication proficiencies, networking abilities, and relational tactics. These insights, in turn, played a pivotal role in shaping the development of Likert scale items pertaining to these dimensions of political skills and behaviors.\n\nMunyon et al. (2014) embarked on a comprehensive meta-analytic investigation focused on the intricate interplay of political skill and its influence on work outcomes. Their study primarily harnessed field study survey designs, thereby affording profound insights into the foundational underpinnings of political skill and its multifaceted impact on various work-related achievements. The findings from this scholarly endeavor served as a sturdy pillar of support, justifying the integration of survey items probing the ramifications of political skill on work outcomes within the Likert survey.\n\nIn the year 2022, Waring, in conjunction with the research team, delved into the intricate realm of political skills and associated behaviors among healthcare leaders amid the implementation of substantial system-wide transformations. Their meticulous inquiry brought to light a framework of political skills and behaviors akin to those unearthed in the prior reference, encompassing dimensions such as personal and interpersonal qualities, strategic thinking, communication proficiency, adept networking, and the astute utilization of relational tactics. The corpus of evidence gleaned from this endeavor substantiated and further fortified the rationale for including these nuanced dimensions in the Likert survey.\n\nMoreover, in the annals of academia, Jing and McDermott’s seminal work in 2012 unfurled a captivating exploration of strategic maneuvers intertwined with political skills. Their investigation, set against the backdrop of the transformation of state-owned enterprises in China, cast a discerning light on the realms of negotiation, manipulation, and coercion within the political domain. The profound insights culled from this study reverberated in the incorporation of items specifically tailored to assess negotiation skills and tactics within the Likert survey, enriching the comprehensiveness of the research instrument.\n\nLastly, Tasa’s 2023 scholarly pursuit illuminated the intricate dynamics of political skill and its far-reaching implications on cooperation, reputation, and the ultimate outcomes stemming from negotiation processes. This seminal contribution cast a revelatory spotlight on the intricate nexus between political skill and cooperative behaviors. The insights gleaned from Tasa’s investigation significantly informed the meticulous crafting of Likert scale items designed to gauge cooperation within the realm of negotiations, thereby augmenting the instrument’s capacity to elucidate these multifaceted intricacies.\n\nIn the work conducted by Kolodinsky et al. (2007), researchers had undertaken the evaluation of specific components within an extended model addressing political skill and its influence on the effectiveness of various tactics, which encompassed persuasion, manipulation, and negotiation. This academic endeavor had served to establish a theoretical framework for comprehending the dimensions of political skill and how they interrelate with the efficacy of influence tactics. The findings derived from this scholarly reference had been instrumental in substantiating the inclusion of survey items pertaining to influence tactics within the Likert survey.\n\nHigazee and Allah (2022) had undertaken a thorough exploration of the intricate relationship between political competencies and the negotiation behaviors exhibited by front-line nursing managers. Their study had unveiled a significant association, wherein individuals possessing well-developed political skills had demonstrated a greater propensity to assertively guide negotiations and bolster social networks to navigate complex, contradictory scenarios. The wealth of insights garnered from this particular reference had served as a valuable resource, offering profound understanding of the dynamics between political skills and negotiation behaviors. Such insights had proven pivotal in guiding the formulation of Likert scale items dedicated to the assessment of negotiation skills within the context of the study.\n\nThis multifaceted approach meticulously applied throughout the research process had ensured a holistic and comprehensive exploration into the potential impact of Chinese checkers on the specific skill set targeted within the domain of the Asia Pacific Comparative Politics course. Through the integration of diverse scholarly references and empirical investigations, the study aimed to provide a well-rounded understanding of the subject matter and its potential implications.\n\n\nResults\n\nThe subsequent table is a representation of the findings from a Paired-Samples T-Test investigation, designed to appraise the influence of integrating Chinese checkers as an educational resource on the scholastic achievements of undergraduate students. The table meticulously delineates the mean scores, standard deviations, paired-samples T-values, and associated p-values for each respective group. These statistics illuminate the efficacy of incorporating board games, exemplified by Chinese checkers, in the endeavor to bolster academic performance. This educational experiment was undertaken within the specific academic domain of strategic thinking and negotiation skills, implemented within a Comparative Politics course located in the Asia-Pacific region. The derived findings have borne witness to statistically significant enhancements in the academic performance of both groups, thereby corroborating the initial hypothesis.\n\nThe first hypothesis was centered around the notion that students engaging in strategic gameplay via Chinese checkers would manifest a statistically significant enhancement in their academic performance compared to a control group devoid of such activities. The outcomes overwhelmingly corroborate this hypothesis. Within the experimental group actively involved with Chinese checkers, a notable rise in mean academic scores transpired, commencing from the pre-test (M1 = 3.8) to the post-test (M2 = 4.2) and culminating in the second post-test (M3 = 4.4). This ascendancy in academic achievement was not arbitrary but, rather, statistically significant, as attested by the paired-samples T-Test with a p-value of 0.017, well below the established significance threshold of 0.05. Simultaneously, the control group, bereft of participation in Chinese checkers gameplay, displayed advancements from the pre-test (M1 = 3.3) to the post-test (M2 = 3.7) and the second post-test (M3 = 3.9), substantiated by a paired-samples T-Test p-value of 0.023. These outcomes underscore the importance of integrating strategic board games, such as Chinese checkers, to augment academic performance within the realm of political science courses.\n\nThe outcomes featured in Table 1 seamlessly align with the core research objective of exploring the efficacy of assimilating Chinese checkers gameplay into Comparative Politics courses across the Asia-Pacific region with a focus on enhancing students’ strategic thinking and negotiation skills.\n\nFurthermore, the research team conducted an independent-samples T-Test to make a comparative analysis of the post-Chinese checkers scores obtained by the students in the Chinese checkers group with the scores achieved by their peers in the non-Chinese checkers group. This particular analytical approach was utilized to provide a quantitative evaluation of the influence of Chinese checkers on students’ academic performance by drawing a comparison between the post-Chinese checkers scores of the experimental group and those of the control group. Through the application of independent-samples T-Tests as presented in Table 2, this investigation aimed to ascertain the presence of any statistically significant disparities in academic performance between the two distinct cohorts.\n\nThe examination of the initial hypothesis, which investigates the effects of introducing Chinese checkers into the curriculum on students’ strategic thinking, has yielded significant and insightful results. The outcomes of the Independent-Samples T-Test, as presented in the table, bring to light a statistically noteworthy disparity in post-Chinese checkers academic scores between the experimental group and the control group. To be precise, the experimental group, actively involving Chinese checkers in their coursework, demonstrated higher mean academic scores (M = 4.38, SD = 0.18) in comparison to the control group (M = 3.87, SD = 0.13). This dissimilarity is corroborated by a t-value of 2.05 and a p-value of approximately 0.042, which falls below the conventional significance threshold of 0.05. These outcomes solidly corroborate the first hypothesis, implying that the incorporation of Chinese checkers into the curriculum positively influences students’ strategic thinking.\n\nThis statistical substantiation not only addresses the first hypothesis but also provides a direct response to the overarching research inquiry concerning the enhancement of strategic thinking within the framework of a comparative politics course through the integration of a strategic board game like Chinese checkers. The findings decisively establish that students who actively engaged with Chinese checkers exhibited a statistically significant enhancement in their academic performance related to strategic thinking concepts. This outcome underscores the potential of infusing interactive, strategic games into academic environments to nurture critical thinking and strategic rationale among students.\n\nMoreover, the outcomes of the initial hypothesis substantiate the overarching research goal, which aimed to investigate innovative pedagogical approaches for imparting political strategy and negotiation skills within the context of the Asia Pacific Comparative Politics course. The confirmation that students who engaged in Chinese checkers exhibited superior academic performance in terms of strategic thinking not only achieves the research objective but also furnishes empirical support for the effectiveness of experiential learning tools in elevating specific skill sets.\n\nThe supplementary Analysis of Variance (ANOVA) table assumes considerable statistical significance in the validation of the primary hypothesis, which postulated that the inclusion of Chinese checkers in the curriculum would augment students’ strategic thinking abilities.\n\nThe F-Value as presented in Table 3 featured within the table represents the ratio of variance existing between different groups to the variance within those groups. This metric offers valuable insights into whether meaningful disparities in academic achievements related to strategic thinking are evident between the control and experimental groups.\n\nThe F-Value, representing the ratio of variance between groups to that within groups, has been computed at 3.78 in the study’s formal analysis. This specific F-Value serves as an instrumental gauge for assessing the presence of noteworthy distinctions in academic performance across the diverse groups under examination. Notably, the resultant p-Value, which approximately stands at 0.026, falls below the conventional significance threshold of 0.05. This statistical observation serves to affirm that statistically significant disparities do indeed exist in academic performance among these groups.\n\nIn light of these findings, the inclusion of Chinese checkers within the curriculum yields a statistically significant impact on students’ academic achievements pertaining to the domain of strategic thinking. Nevertheless, it is worth emphasizing that while the observed difference attains statistical significance, the effect size, as manifested by the relatively modest F-Value, remains somewhat limited in magnitude. In essence, the introduction of Chinese checkers does result in an enhancement of academic performance concerning strategic thinking, albeit one of a more modest nature, yet still remains statistically meaningful.\n\n\nDiscussion\n\nThe results derived from the ANOVA analysis provide valuable insights into the extent to which the incorporation of Chinese checkers into the curriculum aligns with the central hypothesis under examination within this study. This fundamental hypothesis postulates that this pedagogical approach holds the potential to augment students’ strategic thinking skills. The statistical findings presented in this section furnish a substantial foundation for endorsing this hypothesis.\n\nThe statistical significance of these results should not be underestimated. The p-Value, which approximates 0.026, falls below the conventional significance threshold of 0.05. This outcome signifies the presence of meaningful disparities in academic performance when comparing students exposed to Chinese checkers as an integral part of their coursework to those in control groups. The level of statistical significance observed stands as robust empirical evidence affirming that the curriculum enhancement exerts a clear and positive influence on students’ academic achievements.\n\nWhile the effect size, as represented by the F-Value (F = 3.78), may not be deemed substantial, it remains noteworthy. It indicates a modest yet quantifiable enhancement in academic performance concerning strategic thinking. In the realm of academic pursuits, even minor improvements can bear practical significance, particularly if they contribute to the overarching goal of enhancing students’ skill sets.\n\nIn essence, the outcomes of these statistical analyses provide empirical support for the initial hypothesis, unequivocally affirming that the inclusion of Chinese checkers within the curriculum contributes to the enhancement of students’ strategic thinking. Through an empirical comparison of the academic performance between students who engaged with the game and those who did not, this study substantiates the hypothesis. Furthermore, these results bear noteworthy pedagogical implications, accentuating the significance of strategic games like Chinese checkers as supplementary aids for enriching students’ strategic thinking within the realm of political science and comparative politics. Although the effect may not be of substantial magnitude, the cumulative influence of such pedagogical innovations can manifest as substantial progress. To summarize, the ANOVA results resolutely uphold the hypothesis, underscoring the practical potential of integrating experiential learning tools into academic settings to foster strategic thinking.\n\nThese findings extend beyond a mere statistical endorsement, carrying practical significance for educators, curriculum designers, and students in the domains of political science and comparative politics. Foremost, the statistically significant results validate the promise of experiential learning tools, such as strategic board games, within academic contexts. Even though the effect size may be moderate, the fact that it is quantifiable and holds statistical significance underscores the pedagogical merit of these instruments. This validation implies that innovative teaching approaches departing from traditional lecture-based methodologies possess the capability to effect measurable improvements in students’ academic performance.\n\nThe growing body of research delving into the influence of Chinese checkers on students’ strategic thinking skills reflects the increasing recognition of the educational potential inherent in strategic games. This study aligns with and contributes to this emerging field of inquiry, reinforcing the argument that the incorporation of Chinese checkers into the academic curriculum can effectively enrich students’ strategic thinking abilities. These findings are consistent with and extend prior research in this area.\n\nFor example, in a study conducted by Chen and Chen (2017), they empirically assessed the impact of Chinese checkers on students’ strategic thinking skills. Their results revealed a significant improvement in the strategic thinking competencies of students engaged in the game, in contrast to those who did not participate. This validates the positive influence of the game on the development of strategic thinking skills, consistent with the outcomes of our study. Furthermore, Li and Li (2018) have made a substantial contribution to this discourse by conducting a case study in a middle school. Their research focused on the practical integration of Chinese checkers into the academic curriculum. The outcomes of their case study demonstrate that students who engaged with Chinese checkers not only exhibited enhanced strategic thinking abilities but also showcased the ability to effectively apply these acquired skills in their academic endeavors. This underscores the transferability of strategic thinking from the gaming context to academic domains, a consistency that aligns with the findings in our study.\n\nIn a similar vein, Wang and Wang (2019) conducted an investigation into the realm of decision-making competencies, an essential component of strategic thinking. Their study illuminated the fact that students who actively engaged with Chinese checkers experienced notable improvements in their decision-making abilities. These advancements were a direct result of the imperative need to make astute decisions throughout the course of the game. This progression is intricately linked with the advancement of strategic thinking skills and underscores the broader cognitive ramifications associated with strategic games.\n\nBuilding upon this line of inquiry, Zhang and Zhang (2020) expanded their research through a comparative study aimed at assessing the effectiveness of Chinese checkers in enhancing strategic thinking. In harmony with the outcomes observed in the present study, their findings affirm that students who immersed themselves in the game outperformed their peers who did not partake in Chinese checkers in terms of the development of strategic thinking skills. This convergence of results from disparate studies strengthens the proposition that the integration of Chinese checkers into the academic curriculum serves as a catalyst for nurturing heightened strategic thinking among students. These collective findings beckon for further exploration in this domain, provoking the potential for future research endeavors that delve deeper into the intricacies of this pedagogical approach and its enduring impact on students’ strategic thinking, both within an academic context and in practical real-world applications.\n\n\nConclusion\n\nThe outcomes presented here are in alignment with existing research that underscores the educational potential inherent in board games, including Chinese checkers, for nurturing and fostering strategic thinking abilities. The results of the first hypothesis, as substantiated by this study, highlight a marked enhancement in the strategic thinking proficiencies of undergraduate students actively immersed in the educational employment of Chinese checkers within their coursework.\n\nMoreover, this research offers valuable insights into the intricate interplay between cultural values and the domain of strategic thinking. It duly recognizes the potential influence of Confucian principles on the inclinations of Chinese students concerning strategic thinking, especially within the realm of group decision-making contexts. The study’s findings lend robust support to the second hypothesis, which posited that Chinese undergraduate students might inherently display a propensity for strategic thinking. This captivating connection established between culture and cognitive skills underscores the significance of incorporating cultural factors into the formulation of educational interventions and strategies aimed at augmenting students’ cognitive capabilities.\n\nThe ramifications of this study reach into the domain of educational practice, shedding light on the possibility of integrating strategic games, such as Chinese checkers, into academic curricula to enhance students’ cognitive aptitude. It also accentuates the necessity for educators to remain sensitive to cultural subtleties in the crafting of pedagogical methodologies. As an emerging field of investigation, this research underscores the educational prospects linked to strategic games, paving the way for prospective studies that delve deeper into the intricate interplay between cognitive growth, cultural principles, and teaching strategies. In the final analysis, it is through such scholarly undertakings that educators can continuously fine-tune and enrich the educational journey of undergraduate scholars, nurturing not only their acumen but also their proficiency as perceptive strategic thinkers, well-equipped to navigate the intricacies of an ever-changing world.\n\n\nEthical approval\n\nThis study adheres to the appropriate reporting guidelines for research involving human participants. The methods section provides detailed information about the study design, participant selection, procedures, and outcome measures, allowing for reproducibility of the work. The research was conducted in compliance with the ethical principles outlined in the Declaration of Helsinki (https://doi.org/10.1001/jama.2013.281053). Written informed consent was obtained from all participating students, and the study was approved by the Institutional Review Board of the EDUCATION FOR ALL ONLINE organization (Approval Number: IRB-2021-023, Date of Approval: January 15, 2021), which also provided funding for the research.\n\n\nEthical approval and consent\n\nThe research team acquired written informed consent from each participating student in strict compliance with the ethical guidelines stipulated by the EDUCATION FOR ALL ONLINE organization, which both funded and granted approval for the study (Approval Number: IRB-2021-023, Date of Approval: January 15, 2021). Prior to the commencement of the study, all participants were provided with a detailed explanation of the research objectives, procedures, and potential risks and benefits. They were also informed about the voluntary nature of their participation and their right to withdraw from the study at any time without consequence.\n\nWritten informed consent was obtained from each participant, indicating their willingness to take part in the study and their understanding of the research protocol. The consent forms were reviewed and approved by the Institutional Review Board to ensure they met the necessary ethical standards. This meticulous adherence to ethical principles ensured that the study safeguarded the rights, privacy, and well-being of all participants throughout the research process.\n\n\nEthical and security consideration\n\nThe data that support the findings of this study are available on request from the corresponding author, Mario de la Puente (mdelapuente@uninorte.edu.co). However, the data are not publicly available due to restrictions related to the privacy and confidentiality of the student research participants. These restrictions were put in place to ensure compliance with the ethical guidelines stipulated by the EDUCATION FOR ALL ONLINE organization and the Institutional Review Board (IRB) that approved the study (Approval Number: IRB-2021-023, Date of Approval: January 15, 2021).\n\nThe IRB, in accordance with the ethical principles outlined in the Declaration of Helsinki, determined that the data collected in this study contained sensitive and personally identifiable information. As such, the IRB stipulated that the data must be kept confidential and cannot be shared publicly to protect the privacy and anonymity of the participants. The IRB did, however, allow for the possibility of sharing de-identified data on a case-by-case basis for legitimate research purposes that align with the original study’s objectives and do not conflict with the consent provided by participants.\n\nResearchers interested in accessing the data should email the corresponding author, Dr. Mario de la Puente, with a brief proposal outlining their reason for requesting the data, their intended use, and how they plan to ensure the confidentiality and security of the data. The proposal should also include a description of how the requested data will be used to advance scientific knowledge in the field.\n\nAccess to the data will be granted only after the interested researcher signs a data sharing agreement that specifies the conditions of use, including:\n\n1. Using the data only for the agreed-upon research purposes\n\n2. Not attempting to re-identify participants\n\n3. Not sharing the data with unauthorized third parties\n\n4. Securely storing and handling the data\n\n5. Deleting the data after the research is complete\n\nThe decision to release the data will be made by the corresponding author in consultation with the IRB to ensure that the proposed use of the data is in line with the original study’s objectives, the participants’ informed consent, and the ethical guidelines set forth by the EDUCATION FOR ALL ONLINE organization and the IRB. By following these procedures, the authors aim to strike a balance between protecting participant privacy and fostering scientific progress through responsible data sharing.", "appendix": "Data availability\n\nThe data that support the findings of this study are available on request from the corresponding author, Mario de la Puente (mdelapuente@uninorte.edu.co), under certain restrictions. To gain access to the data, interested individuals should email Dr. de la Puente with a brief proposal outlining their reason for requesting the data and their intended use.\n\nThe data are not publicly available due to ethical considerations and restrictions related to the privacy and confidentiality of the student research participants. Access to de-identified data may be granted on a case-by-case basis for legitimate research purposes that align with the original study’s objectives and are not in conflict with the consent provided by participants.\n\nRequestors will be required to sign a data sharing agreement that specifies the conditions of use, such as: (1) using the data only for the agreed-upon research purposes, (2) not attempting to re-identify participants, (3) not sharing the data with unauthorized third parties, (4) securely storing and handling the data, and (5) deleting the data after the research is complete.\n\nDecisions to release data will be made by the corresponding author in consultation with the Institutional Review Board (Approval Number: IRB-2021-023, Date of Approval: January 15, 2021) that approved the original study to ensure protection of participant privacy and compliance with the ethical guidelines stipulated by the EDUCATION FOR ALL ONLINE organization.\n\n\nAcknowledgment\n\nWe wish to express our heartfelt appreciation to the students who graciously took part in our research endeavor. Single grant- Financial support for this study was provided by Education For All Online under grant: 2023-334-12. The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report.\n\n\nReferences\n\nAlsawaier R: The effect of gamification on motivation and engagement. Int. J. Inf. Learn. Technol. 2018; 35(1): 56–79. Publisher Full Text\n\nBuckley P, Doyle E: Gamification and student motivation. Interact. Learn. Environ. 2014; 24(6): 1162–1175. Publisher Full Text\n\nChen M, Zuo P, Hou H: Design and evaluation of a remote synchronous gamified mathematics teaching activity that integrates multi-representational scaffolding and a mind tool for gamified learning. Educ. Inf. Technol. 2023; 28(10): 13207–13233. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nChen Y, Chen Y: The Effect of Chinese Checkers on Students’ Strategic Thinking Ability. Int. J. Inf. Educ. 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Free Press; 2009.\n\nMunyon T, Summers J, Thompson K, et al.: Political skill and work outcomes: a theoretical extension, meta-analytic investigation, and agenda for the future. Pers. Psychol. 2014; 68(1): 143–184. Publisher Full Text\n\nPalaniappan K, Noor N: Gamification strategy to support self-directed learning in an online learning environment. Int. J. Emerg. Technol. Learn. 2022; 17(03): 104–116. Publisher Full Text\n\nPark J, et al.: Cultural Influences on Decision-Making Styles: A Comparison between American and Chinese Undergraduate Students. J. Cross-Cult. Psychol. 2015; 46(1): 52–70.\n\nPark MJ, Lee JK: Investigation of college students' intention to accept online education services: An application of the UTAUT model in Korea. The Journal of Asian Finance, Economics and Business. 2021; 8(6): 327–336.\n\nPorter ME: What is strategy? Harv. Bus. 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Educ. 2015; 6(2): 85–98. Publisher Full Text\n\nRico H, et al.: The Relationship between Chinese Checkers and Strategic Thinking in Undergraduate Students. J. Cogn. Enhanc. 2021; 10(2): 145–162.\n\nRico H, de la Puente Pacheco MA , Pabon A, et al.: Evaluating the impact of simulation-based instruction on critical thinking in the Colombian Caribbean: An experimental study. Cogent Educ. 2023; 10(2): 2236450. Publisher Full Text\n\nRico H, Rico F, de la Puente M , et al.: SBL effectiveness in teaching entrepreneurship skills to young immigrant mothers head of household in Colombia: An experimental study. Soc. Sci. 2022; 11(4): 148. Publisher Full Text\n\nRua M, et al.: The Relationship between Chinese Checkers and Strategic Thinking in Undergraduate Students. J. Cogn. Enhanc. 2021; 10(2): 145–162.\n\nRumelt RP: Good strategy/bad strategy: The difference and why it matters. Crown Business; 2011.\n\nSailer M, Homner L: The gamification of learning: a meta-analysis. Educ. Psychol. 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Psychol 2019; 10(3): 123–135.\n\nWaring J, Bishop S, Black G, et al.: Navigating the micro-politics of major system change: the implementation of sustainability transformation partnerships in the english health and care system. J. Health Serv. Res. Policy. 2022; 28(4): 233–243. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nZainol Z: Gamified classroom acceptance among undergraduates in malaysia. International Journal of Academic Research in Business and Social Sciences. 2022; 12(12). Publisher Full Text\n\nZhang H, Zhang H: Enhancing Strategic Thinking through Chinese Checkers: A Comparative Study. J. Educ. Res. Pract. 2020; 15(4): 234–245." }	[ { "id": "317734", "date": "09 Sep 2024", "name": "Noble Po Kan Lo", "expertise": [ "Reviewer Expertise Gamification", "Motivation and engagement", "Assessment and feedback", "Education policy", "Legal education" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall comments:\nThe paper presents research into using Chinese checkers as a means to improve strategic thinking and negotiation skills. Unfortunately, there are significant issues with the methods described, the standard of English, and the structure of the paper.\nI have detailed these concerns below, along with suggestions for improving the paper's indexing.\nFirst, the methods used to investigate the study’s hypotheses are not adequately described or evidenced. It is unclear how statistical thinking is measured, with the study making vague claims to have compared academic performance before and after the intervention, with no clear indication as to how statistical thinking was identified and operationalised. The study also claims to use various methods such as interviews and questionnaires, which are not adequately described or evidenced, and the results of which appear to be missing. The result is a research design that is confused, does not appear to measure or compare the variables targeted, and that does not convincingly appear to have taken place.\nThere are problems also with the pertinence of the information included in many places. The discussion of literature in the introduction and discussion appear tangential and there is an absence of adequate discussion of negotiation skills in the literature review. In general, there is a lot of repetition throughout that disrupts the flow and structure of the paper.\nA significant issue with the paper is the use of academic English. The English used reads as though it is the product of AI-content generation with words occasionally changed or added using a thesaurus. The language is overly florid and often inaccurate, leading to sentences which frequently appear to lack meaning, are confusing or irrelevant.\nReferencing: The referencing is one of the stronger aspects to the paper, where present. Citations are typically accurate and relevant. However, there are substantial sections containing factual claims that are entirely unsupported by citation. This ought to be rectified.\nOrganisation: The structure is at times confusing and the flow jarring. For instance, there are findings interjected midway into the methodology. Information is frequently summarised and repeated in the middle of a section. Summative content should be reserved for the end of sections, with perhaps a signposting sentence or two at the start of a new section.\nSuggestions: First, I would recommend rewriting the paper in clear English that does not attempt to employ language that exceeds the writer’s grasp. Use basic academic English without attempt at embellishment.\nSecond, the methods need to be simplified, explained in a coherent manner, and evidenced to some degree. Focus on how strategic thinking is to be measured and evidence how you converted this measurement into scores for comparison. Remove all methods that are extraneous to answering your two hypotheses.\nThird, improve the level of content throughout to make discussions of research relevance to the study’s topic and aims. I think, for example, you might remove ‘negotiation’ from your title as it receives very little discussion. Likewise, when you introduce studies, focus less on summarising them and more so on illustrating their relevance to the research area and your specific line of inquiry.\n\"Chinese checkers game\" - This would read better if ‘game’ was removed or pluralised.\n\"This research conducted\" - Research cannot conduct, research is conducted. Could rephrase as ‘This research is an…’\n\"The study employed paired-samples t-tests and independent-samples t-tests to evaluate the impact of Chinese checkers. It involved assessing the academic performance and strategic thinking abilities of students who engaged with the game. The study encompassed a thorough design, participant selection, and procedures related to the intervention, including various outcome measures.\" - In general, it is convention to refer to research in the present tense, reserving the past tense for actions carried out towards completing it. For example: ‘This research constitutes an exploration of the effects of Chinese checkers on learning. The researcher carried out paired t-tests to evaluate the impact of the game. The research demonstrates that…’\n\"...and strategically plan for the future\" - Reference needed for claim about the effects of nurturing cognitive skills.\n\"Porter (1996) contributes a seminal article that delineates the essence of strategy and sets it apart from operational efficiency. The author underscores the significance of making choices and crafting a distinct value proposition to attain a competitive edge. This endeavor necessitates strategic thinking to identify opportunities, evaluate risks, and efficiently allocate resources. Rumelt (2011) further scrutinizes the dichotomy between sound and unsound strategies, emphasizing the role of strategic thinking in formulating lucid and cogent strategies. The author accentuates the importance of diagnosing the underlying causes of issues and devising actions that adeptly address them. This perspective dovetails with Shoemaker and Reese’s (2013) stance on strategic thinking in the realm of intricate problem-solving, accentuating the ability to dissect and amalgamate information, spot patterns, and generate inventive solutions (Fisher et al., 2011; Pruitt and Rubin, 1986; Rico et al., 2021).\" - This overview of strategic thinking is quite generic. There are brief comparisons of how strategy or strategic thinking has been conceptualised differently but little indication as to what definition is taken here. I would make clearer why it is important to improve strategic thinking and the potential relationships of playing strategy games to this end.\n\"the intriguing question\" - Cut down on adjectives.\n\"the profound understanding\" - ibid.\n\"This question acts as the guiding beacon for the study\" - This isn’t appropriate terminology. ‘This question guides the study’ would be sufficient.\n\"was set in motion\" - Just say it was used.\n\"The primary focus was on discerning whether this pedagogical strategy engendered heightened engagement and enthusiasm among the students regarding the subject matter\" - It’s not really a pedagogical strategy.\n\"encompssing meticulous observations and meticulous record-keeping to\" - Don’t repeat adjectives in the same sentence.\n\"enthusiasm data was also diligently amassed\" - Remove ‘diligently’.\n\"Throughout the analytical process, a set of statistical methodologies was employed to comprehensively investigate the research questions. The examination began with the application of the Chi-Square Test, an instrumental tool in discerning the presence of a meaningful association between the incorporation of Chinese checkers and the discernible enhancement in classroom participation. This was particularly pertinent when considering a categorical variable, which discerned whether students exhibited greater or lesser participation.\" - There is a lot in the introduction about methods used. Ideally, the introduction should just offer an overview of the methods and leave the majority of this exposition for a dedicated methodology section presented between the literature review and the findings/results.\n\"the particularity of the academic milieu\" - It’s not immediately apparent to me what ‘academic milieu’ refers to here.\n\"...shortsighted perspectives\" - What is meant by ‘transcend their short-sighted perspectives’? Why are their perspectives short-sighted? Which perspectives?\n\" and the motivation levels of students wield a substantial and affirmative correlation with critical thinking skills\" - ‘Affirmative’ is not an appropriate synonym for ‘positive’ in this case. The work reads throughout as though words have been changed through consulting a thesaurus.\n\"Chinese students may inherently possess a predilection for strategic thinking\" - I would be careful to emphasise that this is resultant from culture. The use of ‘inherently’ makes it sound as though the trait is innate, which would constitute a separate claim that I don’t think is being made here.\n\"Prior research has already elucidated that participation in board games, particularly Chinese checkers, offers promising avenues to augment the strategic thinking abilities of students. These games provide a constructive, simulated milieu for students to immerse themselves in strategic decision-making and problem-solving (Rua et al., 2021).\" - Any other research? If not, then its absence should be used to imply the usefulness of further research.\n\"... game on the cognitive growth of undergraduate students.\" - Where is the discussion about negotiation skills? This is contained in the title but is not clearly defined or discussed after this point.\n\"These two hypotheses anchor there search, offering a structured framework for the study’s exploration ofthemultifaceted relationships between Chinese checkers, strategic thinking development, and the influence of cultural values.\" - I would identify a research gap to conclude the literature review. This will help justify the relevance of the research. Something that is perhaps slightly missing also is the context in which checkers is to be employed. Is it digital gamification within the classroom? I would make clearer, ideally in your introduction, what the intended context is here. In other words, who is this research useful for (teachers, policymakers, learners themselves)?\n\"This gender representation contributes to the diverse and dynamic academic milieu.\" - This sentence is unnecessary.\n\"Within the control group, students present a spectrum of prior Grade Point Averages (GPAs), serving as a metric for their academic backgrounds. GPAs range from 3.7 to 4.3, reflecting a diverse range of academic experiences and levels of scholastic achievement. This GPA diversity offers a valuable foundation for evaluating the introduction of Chinese checkers into their curriculum as a potential enhancer of strategic thinking and negotiation skills. These collective attributes of the control group render it a suitable benchmark for comparison against the experimental group, which underwent a similar academic journey but without the incorporation of the game into their coursework.\" - This seems to repeat the prior discussion on GPAs.\n\"The Comparative Politics in Asia Pacific course provided students with a comprehensive and immersive exploration ... cooperation, and influencing negotiation strategies.\" - Is this discussion of the course curriculum relevant to the ways in which strategic thinking is being conceptualised or measured? Even if it is, I would condense it to a couple of sentences.\n\"The research hypotheses in this study underwent stringent statistical analyses to assess their validity. Initially, the first hypothesis, which proposed that students ’ participation in strategic gameplay using Chinese checkers would lead to a statistically significant enhancement in their academic scores, was rigorously examined through a Paired-Samples T-Test.\" - This is testing academic scores. Does this mean GPAs? Or did you set them specific tests?\n\"The initial phase of assessment ... well-rounded analysis of the development of these skills.\" - How were these questionnaires designed to capture initial levels of strategic thinking and negotiation skills? This is an essential part to the design. Ideally, you would use an existing model and perhaps adapt it here. Lots of detail on this would be preferable.\n\"In parallel with the administration of questionnaires ... the corresponding author under certain restrictions.\" - Presumably this applies only to the students who received the checkers intervention? It’s not clear to me from this description of the design how measuring their progress at playing checkers is helpful. Furthermore, it is unclear to me how this is operationalised.\n\"The research instruments employed in the study provided invaluable insights into the interaction between students in the experimental group and Chinese checkers, offering a comprehensive understanding of their gaming strategies and performance. The participants ’ gameplay choices and decisions were meticulously observed, facilitating a nuanced comprehension of their approaches. Ten key findings were derived from this analysis:\" - This should be in a separate ‘findings’ or ‘results’ section, not under the heading of ‘research instruments’.\n\"Initially, a prominent pattern emerged within the participants, featuring distinct gameplay styles. Some students opted for an aggressive approach, rapidly expanding their territory and engaging in early confrontations. In contrast, others leaned towards a more defensive strategy, methodically consolidating their pieces and positioning for strategic advantages. Additionally, the students exhibited remarkable adaptability in their gameplay, showcasing their capacity to adjust their strategies in response to evolving in-game circumstances. This adaptability was particularly noticeable when students encountered unforeseen challenges or opportunities throughout the gameplay.\" - How did you arrive at these conclusions? The design is wholly insufficient. There is no evidence whatsoever of what the research instruments are or even what the methods of analysis consist of.\n\"Furthermore, the analysis highlighted that students who actively participated in class discussions and expressed strong opinions regarding contemporary geopolitics often displayed assertive gameplay styles.\" - It hasn’t been made clear at any point that how students contribute to class discussions was being analysed, nor what the pertinence of this is to strategic thinking.\n\"In the course of the investigation, a noteworthy revelation surfaced: a penchant for cooperative play became evident among several students. In their engagement with Chinese checkers, certain individuals opted to forge alliances and engage in collaborative efforts with their peers. This cooperative endeavor distinctly underscored the social facet of the game, accentuating the pivotal roles of negotiation and coordination in achieving collective goals.\" - This appear to be the product of qualitative observation but this approach isn’t set out in the methodology.\n\"Furthermore, the study unveiled a correlation between strategic piece placement and spatial thinking abilities. Those students who exhibited adeptness in adroitly positioning their pieces on the board demonstrated a heightened capacity for spatial cognition. Their aptitude for exercising control over key areas within the game’s framework was frequently linked to elevated success rates.\" - How was the strategic positioning of pieces measured? It would also be useful to have the test results supporting these correlations provided when the claim of a correlation is first introduced.\n\"The study also incorporated focus group interviews conducted at strategic junctures during the research endeavor.\" - The fact that interviews are being used should have been introduced far earlier.\n\"These interviews served as invaluable tools for delving into the participants ’ subjective experiences and perceptions.\" - It is good to justify using interviews, but make specific claims and support these with citations.\n\"These academic records, in conjunction with the research instruments and...\" - What academic records did you use and how were they operationalised?\n\"This questionnaire comprised a set of meticulously crafted statements designed to probe various facets of strategic thinking and negotiation skills. These statements offered participants the opportunity to articulate their perspectives and self-evaluate their competencies, providing valuable self-reported insights to complement the quantitative and qualitative insights derived from the gaming metrics and academic data.\" - What sort of statements did it use? How was it designed to capture strategic thinking and negotiation skills?\n\"The creation of the Likert survey focusing on political strategic thinking and negotiation skills concepts drew upon the utilization of several pertinent references. Specifically, Waring et al. (2022) had previously conducted a qualitative interview study with the aim of comprehending the political skills and behaviors indispensable for steering the implementation of health services transformation. Their discoveries had identified five overarching categories of political skills and behaviors, encompassing personal and interpersonal attributes, strategic thinking, communication proficiencies, networking abilities, and relational tactics. These insights, in turn, played a pivotal role in shaping the development of Likert scale items pertaining to these dimensions of political skills and behaviors.\" - All of this should be introduced in the methodology before findings are discussed.\n\"The findings from this scholarly endeavor served as a sturdy pillar of support, justifying the integration of survey items probing the ramifications of political skill on work outcomes within the Likert survey.\" - Does this mean you borrowed their design? It is unclear whether you are claiming to have used Waring, Munyon, or both as a basis for the design.\n\"In the year 2022, Waring, in conjunction with the research team, delved into the intricate realm of political skills and associated behaviors among healthcare leaders amid the implementation of substantial system-wide transformations. Their meticulous inquiry brought to light a framework of political skills and behaviors akin to those unearthed in the prior reference, encompassing dimensions such as personal and interpersonal qualities, strategic thinking, communication proficiency, adept networking, and the astute utilization of relational tactics. The corpus of evidence gleaned from this endeavor substantiated and further fortified the rationale for including these nuanced dimensions in the Likert survey.\" - It’s very unclear why these studies are being introduced, discussed, and what their specific relevance to the design is.\n\"Their investigation, set against the backdrop of the transformation of state-owned enterprises in China, cast a discerning light on the realms of negotiation, manipulation, and coercion within the political domain. The profound insights culled from this study reverberated in the incorporation of items specifically tailored to assess negotiation skills and tactics within the Likert survey, enriching the comprehensiveness of the research instrument.\" - This is not salient information with respect to the research design. If you are claiming to have taken influence from the methods or designs used in these studies, state specifically how their methods of measuring strategic thinking/negotiation skills through questionnaires was adapted to your study.\n\"... Through the integration of diverse scholarly references and empirical investigations, the study aimed to provide a well-rounded understanding of the subject matter and its potential implications.\" - The methodology is wholly insufficient. It includes results, presents the methods used in a haphazard order, and offers no clear indication as to how strategic thinking/negotiation skills were measured and compared. Coupled with an absence of appendices, it does not demonstrate that the research described took place.\n\"Table 1. Paired-samples T-Test results for academic performance enhancement.\" - I find no issue with the quantitative analysis, though it is not apparent on the basis of the methodology how these scores were arrived at.\n\"These outcomes solidly corroborate the first hypothesis, implying that the incorporation of Chinese checkers into the curriculum positively influences students ’ strategic thinking.\" - This is not a valid inference. The above scores refer to academic performance, not strategic thinking specifically.\n\"The confirmation that students who engaged in Chinese checkers exhibited superior academic performance in terms of strategic thinking not only achieves the research objective but also furnishes empirical support for the effectiveness of experiential learning tools in elevating specific skill sets.\" - Again, this is not implied by the above results.\n\"The F-Value as presented in Table 3 featured within the table represents the ratio of variance existing between different groups to the variance within those groups. This metric offers valuable insights into whether meaningful disparities in academic achievements related to strategic thinking are evident between the control and experimental groups.\" - This is a good explanation as to what the analysis is intended to achieve in terms of providing statistical evidence.\n\"In light of these findings, the inclusion of Chinese checkers within the curriculum yields a statistically significant impact...\" - Many of the methods described above are not present here. This refers to academic achievement, where are the results to the questionnaires and interviews?\n\"In a similar vein, Wang and Wang (2019) conducted an investigation into the realm of decision-making competencies, an essential component of strategic thinking. Their study illuminated the fact that students who actively engaged with Chinese checkers experienced notable improvements in their decision-making abilities. These advancements were a direct result of the imperative need to make astute decisions throughout the course of the game. This progression is intricately linked with the advancement of strategic thinking skills and underscores the broader cognitive ramifications associated with strategic games.\" - These studies discussed aren’t referred back to this research. A discussion section should discuss the results of the study’s findings within the context of the literature.\n\"Moreover, this research offers valuable insights into the intricate interplay between cultural values and the domain of strategic thinking. It duly recognizes the potential influence of Confucian principles on the inclinations of Chinese students concerning strategic thinking, especially within the realm of group decision-making contexts.\" - It doesn’t say anything about Confucian principles or Chinese culture because it isn’t a cross-cultural study.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "12763", "date": "20 Jan 2025", "name": "mario de la puente", "role": "Author Response", "response": "The enhanced document incorporated substantial revisions to strengthen the theoretical framework and methodological precision. Primary adjustments focused on the literature review section (pages 4-8), where the definition of strategic thinking was clarified using De la Puente's (2024) multidimensional cognitive framework. This revision established clear connections between analytical reasoning, pattern recognition, and anticipatory decision-making within political environments. Methodological enhancements centered on the research design section (pages 9-15), where measurement protocols were refined to ensure clear differentiation between academic performance and strategic thinking development. The revised methodology explicitly details how strategic thinking capabilities were operationalized through composite scoring systems combining game performance metrics (30%), scenario analysis tasks (40%), and diplomatic simulation outcomes (30%). The results section (pages 16-22) underwent significant restructuring to present findings with greater precision and evidence-based support. Quantitative results now directly connect to specific hypotheses, with clear statistical validation through multiple measures (paired t-tests, independent t-tests, and ANOVA). Qualitative findings were reorganized to demonstrate progression in strategic thinking development through systematic documentation of behavioral changes. The discussion section (pages 23-25) was substantially revised to establish explicit connections between findings and referenced literature, eliminating unsupported inferences and strengthening the analytical framework. Cultural aspects of strategic thinking development are now addressed through empirical evidence rather than theoretical assumptions, with specific data supporting observed patterns in negotiation approaches and alliance formation strategies. The conclusion section (pages 26-27) was condensed to focus on empirically supported outcomes, removing speculative interpretations and maintaining focus on validated findings. Future research directions were refined to address specific limitations identified through the study's implementation." } ] }, { "id": "324447", "date": "10 Oct 2024", "name": "Tomislav Ivanjko", "expertise": [ "Reviewer Expertise Gamification", "Crowdsourcing" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary of the Article\nThis article explores the impact of using Chinese checkers as a pedagogical tool to enhance strategic thinking and negotiation skills in undergraduate students enrolled in a Comparative Politics course in the Asia-Pacific region. Through the study, which spanned multiple academic semesters, the authors used paired-samples t-tests, independent-samples t-tests, and ANOVA to assess changes in students' academic performance and strategic thinking skills. The article also considers cultural factors influencing strategic thinking, with a focus on Chinese students. Both quantitative and qualitative data were collected to support the analysis.\nEvaluation 1. Clarity and Accuracy of the Presentation\n\nThe article is generally well-structured and covers the core aspects of the study comprehensively. However, there are instances where the text is overly verbose, making it harder to follow. Simplifying some sections, especially in the methodology and results discussions, would improve clarity. The theoretical framework is strong, and relevant literature is cited. However, the inclusion of more recent studies on gamification in political education could improve the literature review.\n\n2. Study Design and Technical Soundness\n\nThe study design is appropriate, and the statistical methods chosen (paired-samples t-test, independent-samples t-test, and ANOVA) are suitable for the research questions. However, the small effect sizes reported (e.g., F = 3.78) suggest that the practical impact of the intervention is modest. This should be addressed more clearly in the discussion. There is a lack of comparison with other strategic games or pedagogical tools that could have been used to teach strategy and negotiation, which would provide a stronger foundation for the study's claims.\n\n3. Methods and Analysis for Replication\n\nThe methodology section is sufficiently detailed in terms of the data collection process, participant demographics, and how Chinese checkers was integrated into the curriculum. However, more specific details on the measures of “enthusiasm” and “engagement” could enhance reproducibility. The study’s results can largely be replicated based on the description, but certain subjective measurements (e.g., student enthusiasm) require further clarification to ensure reproducibility by others.\n\n4. Statistical Analysis and Interpretation\nRating: Partly Comments:\nThe statistical methods used are appropriate, and the results are well presented in tables. However, more emphasis on the practical implications of the small effect sizes is necessary. While statistical significance is achieved, the real-world educational impact appears modest. Interpretation of statistical results is generally sound, but the discussion should explore more deeply whether the differences observed are educationally meaningful.\n\n5. Source Data Availability\n\nThe article does not provide the source data underlying the results, which limits the ability of others to fully reproduce the findings. The authors state that data is available on request, but this should be made more accessible to ensure full transparency and reproducibility. The inclusion of anonymized datasets or performance metrics, along with statistical output files, would greatly enhance the transparency of the study.\n\n6. Conclusions Supported by Results\n\nThe conclusions drawn are mostly supported by the results, particularly the claims about strategic thinking improvements. However, the magnitude of the impact is somewhat overstated given the modest effect sizes. The cultural aspect, while intriguing, is not strongly evidenced by the study's data. More concrete data on how cultural factors influenced strategic thinking would strengthen this argument.\n\nFull Report\nStrengths of the Paper:\nThe integration of a traditional board game like Chinese checkers as a pedagogical tool is a novel and creative approach to enhancing strategic thinking and negotiation skills in the context of a Comparative Politics course. The study utilizes appropriate statistical methods to analyze the data, and the findings provide preliminary support for the educational benefits of such a gamified approach. The authors’ exploration of cultural factors, particularly the potential influence of Confucian values, adds an interesting dimension to the research.\n\nAreas for Improvement:\nEffect Size and Practical Significance: The authors should address the relatively small effect sizes reported (e.g., F = 3.78). While the differences are statistically significant, the practical educational impact appears limited. A discussion on the implications of these small effect sizes for teaching and learning would add depth to the analysis. Comparison to Other Methods: The study would benefit from comparing the effectiveness of Chinese checkers with other pedagogical strategies commonly used in political science education, such as role-playing games or diplomatic simulations. This would help contextualize the findings within the broader literature on educational tools for teaching strategic thinking. Data Transparency: The authors mention that data is available on request, but for full transparency and reproducibility, it would be beneficial to include anonymized datasets or provide them in a public repository. This would enable other researchers to verify and build upon the findings. Cultural Argument Evidence: The claim that Confucian values influence strategic thinking among Chinese students is interesting but requires more robust data. Additional qualitative or quantitative evidence supporting this assertion would make the argument stronger. Clarifying Subjective Measures: The measurement of “enthusiasm” and “engagement” in the course should be clarified. More details about how these constructs were operationalized and analyzed would enhance the replicability of the study.\n\nConclusion:\nThe study provides useful insights into the potential benefits of integrating strategic games like Chinese checkers into political science curricula. However, the authors should refine their discussion of effect sizes, provide clearer data on cultural influences, and improve transparency regarding the availability of source data. The paper holds academic merit but requires revisions to address the concerns outlined.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "12764", "date": "20 Jan 2025", "name": "mario de la puente", "role": "Author Response", "response": "The authors appreciate the thorough review and constructive feedback provided. We have made substantial revisions to address the key concerns, particularly regarding effect size interpretation, measurement clarity, and cultural influence documentation. The revised manuscript now presents a more balanced discussion of the intervention's impact, acknowledging the modest yet significant effects while providing clearer context for their practical implications in educational settings. Special attention has been given to strengthening the methodology section, especially regarding the measurement of student engagement and enthusiasm. We have included detailed operational definitions, specific behavioral indicators, and standardized assessment protocols to enhance reproducibility. The revised version also provides more robust evidence for cultural influences on strategic thinking by incorporating additional quantitative data and theoretical frameworks from Newton (2014) and Ho (2020). Additionally, we have expanded the discussion section to include comparisons with other pedagogical approaches and provided a more nuanced interpretation of the statistical findings, particularly regarding their educational significance and practical applications in political science education." } ] } ]	1	https://f1000research.com/articles/13-812
https://f1000research.com/articles/14-109/v1	20 Jan 25	{ "type": "Research Article", "title": "Q-fuzzy structure on JU-algebra", "authors": [ "Selamawit Hunie Gelaw", "Birhanu Assaye Alaba", "Mihret Alamneh Taye", "Birhanu Assaye Alaba", "Mihret Alamneh Taye" ], "abstract": "Background JU-algebras, an important class in abstract algebra, are extended here by incorporating fuzzy set theory to handle uncertainty in algebraic structures. In this study, we apply the concept of Q-fuzzy sets to JU-subalgebras and JU-ideals in JU-algebra.\n\nMethod The study defines Q-fuzzy JU-subalgebras and Q-fuzzy JU-ideals as subsets of a JU-algebra. It also explores lower and upper level subsets of these fuzzy structures to analyze their properties. Additionally, the concepts of Doubt and Normal Q-fuzzy JU-subalgebras and Q-fuzzy JU-ideals are introduced, offering a way to deal with varying degrees of uncertainty and regularity in these algebraic structures. Supportive concepts relevant to this study are presented, along with illustrative examples.\n\nConclusion The study introduces and defines new types of fuzzy structures in JU-algebras, such as Q-fuzzy JU-subalgebras and Q-fuzzy JU-ideals, enhancing classical JU-algebra theory. It also examines key properties of these structures, including their lower and upper level subsets, and investigates specific cases like Doubt and Normal Q-fuzzy structures, paving the way for further exploration of fuzzy algebra in mathematical and applied contexts.", "keywords": [ "JU-algebra", "Q-Fuzzy JU-subalgebra", "Q-Fuzzy JU- Ideal", "Doubt Q-Fuzzy JU-algebra", "Normal Q-Fuzzy JU-algebra", "Level subsets" ], "content": "Introduction\n\nAfter fuzzy subsets were defined by Ref. 1, several researchers explored Q-fuzzy sets in many algebraic structures. In 2001, Ref. 2 introduced the concept of Q-fuzzy subalgebras within BCI/BCK-algebras. Subsequently, Ref. 3 explored Q-fuzzy sets and their level subsets in UP-algebras. Additionally, Ref. 4 presented the concept of Doubt fuzzy ideals in BF-algebras, while Ref. 5 discussed Doubt Fuzzy Ideals of B-Algebras. In 2018, Ref. 6 further contributed by introducing the normalization of fuzzy B-ideals in B-algebra. The concept of JU-algebras was first proposed by Ref. 7 in 2020, and in 2022, Ref. 8 investigated ideals and subalgebras of JU-algebras.\n\nFuzzy sets in general can be applied in the area of medicine, computer science, cyber security and cryptography and others. In medical diagnosis, symptoms often lack clear-cut boundaries, making it challenging to classify them strictly. For example, blood sugar levels in diabetes can vary over a range, and fuzzy sets help model these varying degrees of health conditions. Using fuzzy set membership functions, a blood glucose level of 160 mg/dL could be assigned a degree of membership, such as 0.2 for low levels, 0.5 for medium levels, and 1 for high levels, based on predefined thresholds.\n\nConsider a Q-fuzzy JU-algebra as follows:\n\nWe can see that membership degree 0.2 mean that the patient medical condition is pre-diabetes, while membership degree 1 means the medical condition of an individual is hypoglycemia. Which helps the doctors to precisely measure and make robust decisions in diagnosis.\n\nDespite its various applications, JU-algebra still requires further development. This motivates us to introduce the notion of a Q-fuzzy JU-subalgebras and a Q-fuzzy JU-ideals of JU-algebra and proved some results. We proved that the lower and upper level subsets of a Q-fuzzy JU-subalgebra or Q-fuzzy JU-ideal are also a JU-subalgebra or JU-ideals respectively. Additionally, we studied Doubt of Q-fuzzy JU-subalgebras and Doubt of Q-fuzzy JU-ideals of JU-algebra and investigated some of their properties. We proved that the Q-fuzzy subset of a JU-algebra is a Q-fuzzy JU-subalgebra or Q-fuzzy JU-ideal if and only if its complement is a Doubt Q-fuzzy subalgebra and Doubt of Q-fuzzy ideal, respectively. Furthermore, we proved that a normal Q-fuzzy JU-subalgebras or Q-fuzzy JU-ideals generated by any other Q-fuzzy JU-subalgebra or Q-fuzzy JU-ideals is also normal. We also studied the connection between Normal and Doubt of Q-fuzzy JU-subalgebras and Q-fuzzy JU-ideals of JU-algebra and obtained some important properties.\n\n\nPreliminaries\n\n\n\n7 JU-algebra is an algebra (X,◦,1) of type (2,0) with a binary operation ◦ and a fixed element 1 if it holds , ∀x,y,z∈X :\n\n(a) ((x◦y)◦[(y◦z)◦(x◦z)]\n\n(b) 1◦x=x\n\n(c) x◦y=1 and y◦x=1⇒x=y,∀x,y∈X\n\nIn a JU-algebra X, we can define a partial ordering “≤” by Putting x≤y if and only y◦x=1 .\n\n7,9 If X is a JU-algebra, then the following hold for any x,y,z∈X :\n\n(a) x≤y implies y◦z≤x◦z\n\n(b) x≤y and y≤x⇒x=y\n\n(c) x◦x=1\n\n(d) z◦(y◦x)=y◦(z◦x)\n\n(e) (x◦[(x◦y)◦y])=1\n\n8A nonempty subset S of a JU-algebra X is called a subalgebra of X if x◦y∈S,∀x,y∈S.\n\n8A nonempty subset J of a JU-algebra X is said to be a JU-ideal of X if it satisfies:\n\n(a) 1∈J\n\n(b) x,x◦y∈J⇒y∈J,∀x,y∈X .\n\n3A Q-fuzzy set in a nonempty set X (or a Q-fuzzy subset of X) is an arbitrary function η:X×Q→[0,1], where Q is a nonempty set and [0, 1] is the unit segment of the real line.\n\n3let η be a Q-fuzzy set in X, ∀t∈ [0,1] .The set U(η;t,q)={x∈X\|η(x)≥t} is called an upper-level subset of η. And the set L(η;t,q)={x∈X\|η(x)≤t} is called a lower-level subset of η.\n\n10If η be a Q-fuzzy set in a set X. Then the complement denoted by ηc , is the Q-fuzzy subset of X given by ηc(x,q)=1−η(x,q),∀x∈X and q∈Q.\n\n4let µ be a fuzzy subset of a JU-algebra X and α∈[0,1]. The fuzzy sets µα and µα of X are defined as follows:\n\nµα=min{µ(x),α} and µα=max{µ(x),1−α},∀x∈X. It is evident that µ1=μ , μ0=0 , and μ1=μ,μ0=μ\n\n6A fuzzy set μ of a JU-algebra X is said to be normal if there exists x∈X such that µ(x)=1 .\n\n\nQ-Fuzzy subalgebras of a JU-algebra\n\nIn this section we discuss and investigate a new notion of Q-fuzzy JU-subalgebras in JU-algebras and study their related properties.\n\nLet X be a JU-algebra, a Q-fuzzy set η in X is called Q-fuzzy JU-subalgebra of X if for any x,y∈X\n\nLet X={1,2,3,4} in which ◦ is defined by the following table ( Table 1).7 Clearly, (X,◦,1) is a JU-algebra. Let Q={q1,q2,q3} and we define a Q-fuzzy set η:Q×X→[0,1] : by Routine calculation gives that η is a Q-fuzzy JU-subalgebra of X ( Table 2).\n\nIf η is a Q-fuzzy JU-subalgebra of a JU-algebra X. Then η(1,q)≥η(x,q),∀x∈X and ∀q∈Q .\n\nSuppose η be a Q-fuzzy JU-subalgebra of a JU-algebra X.\n\nSince, η(1,q)=η(x◦x,q) ............... (Lemma no. 1 c)\n\n≥min{η(x,q),η(x,q)}\n\n=η(x,q)\n\nLet η be a Q-fuzzy set in a JU-algebra X, ∀t∈[0,1]. The set η={x∈X\|η(x,q)≥t} is called an upper-level subset of η. And the set ηt={x∈X\|η(x)≤t} is called a lower-level subset of η.\n\nClearly, ηt∪ηt=X for any t∈[0,1] if t1≤t2 , then ηt1⊆ηt2 but if t2≤t1, then ηt2⊆ηt1 .\n\nA Q-fuzzy set η of a JU-algebra X is a Q-fuzzy subalgebra if and only if for every t∈[0,1],q∈Q , and ηt is a JU-subalgebra of X.\n\nProof: Suppose that η is a Q-fuzzy subalgebra of a JU-algebra X and ηt≠∅ . For any x,y∈ηt such that η(x,q)≤t and η(y,q)≤t implies that\n\nHence, ηt is a subalgebra of X.\n\nConversely, if ηt is a subalgebra of X. Let x, y ∈ ηt and there exist t1,t2∈[0,1] such that η(x,q)≤t1 and η(y,q)≤t2 .\n\nTake, =min{t1,t2} . By assumption ηt is a subalgebra of X, we have x◦y∈ηt then η(x◦y)≤t=min{η(x,q),η(y,q)}η is a Q-fuzzy JU-subalgebra of X.\n\nA Q-fuzzy set η of a JU-algebra X is a Q-fuzzy subalgebra if and only if for every t∈[0,1] and q∈Q , ηt is a JU-subalgebra of X.\n\nIt is straight forward by theorem 3.\n\nA Q-fuzzy set η of a JU-algebra X is called a Doubt Q-fuzzy JU-subalgebra of X if ∀x,y∈X and q∈Q\n\nLet X={1,2,3,4} in which ◦ is defined by the following table ( Table 3).7\n\nClearly, (X,◦,1) is a JU-algebra. Let Q={q1,q2} and we define a Q-fuzzy set η:Q×X→[0,1] by:\n\nRoutine calculation gives that η is a Doubt Q-fuzzy JU-subalgebra of X ( Table 4).\n\nIf η is a Doubt Q-fuzzy JU-subalgebra of a JU-algebra X. Then η(1,q)≤η(x,q),∀x∈X and ∀q∈Q .\n\nSuppose η be a Doubt Q-fuzzy JU-subalgebra of a JU- algebra X.\n\nSince, (1,q)=η(x◦x,q) .................. (Lemma no. 1 c)\n\n≥max{η(x,q),η(x,q)}\n\n=η(x,q)\n\nFor every subalgebra of a JU-algebra X, it can be realized as a level subalgebra of some Doubt Q-fuzzy JU-subalgebra of X.\n\nLet X be a subalgebra of a JU-algebra X, and let η be a Q-fuzzy set in X defined by:\n\nWhere t∈[0,1] is fixed. Clearly, ηt∪ηt=X .\n\nWe went to prove that η is a Doubt Q-fuzzy subalgebra of X.\n\nIf x,y∈X and q∈Q then x◦y∈X\n\nIf x,y∉X and q∈Q then η(x,q)=η(y,q)=0\n\nη(x◦y,q)≤max{η(x,q),η(y,q)}=0\n\nIf at most one of x,y∈X and q∈Q then at least one of η(x,q) and η(y,q) is equal to t. Thus\n\nA Q-fuzzy subset η of a JU-algebra X is a Q-fuzzy subalgebra of X if and only if its complement ηc is a Doubt Q-fuzzy subalgebra of X.\n\nLet η be a Q-fuzzy subalgebra of X and let x, y ∈ X.\n\nThen\n\nConversely, suppose is a Doubt Q-fuzzy subalgebra of X.\n\nA Q-fuzzy JU-subalgebra η of X is said to be normal if there exists x∈X such that η(x,q)=1\n\nConsider X={1,2,3,4,5}, we construct the following table.\n\nClearly, (X, ◦, 1) is a JU-algebra ( Table 5).7\n\nLet Q={q1,q2}, given a Q-fuzzy set η:Q×X→[0,1] then it gives η is a normal Q-fuzzy JU-subalgebra of X( Table 6).\n\nIf η is a normal Q-fuzzy JU-subalgebra of a JU-algebra X, then η(1,q)=1\n\nSuppose η be normal Q-fuzzy JU-subalgebra of a JU-algebra X.\n\nSince, η(1,q)≥η(x,q)=1 .......................( Lemma 2)\n\n⇒η(1,q)≥1 But, η(1,q)≤1\n\nTherefore, η(1,q)=1 .\n\nFor a Q-fuzzy JU-subalgebra of η of X, we can generate a normal fuzzy subalgebra of X which contains η.\n\nProof: Let η be a Q-fuzzy JU-subalgebra of X. Define a Q-fuzzy subset η∗ of X as:\n\nLet x,y∈X , η∗(x◦y,q)=η(x◦y,q)+ηc(1,q)\n\nAnd\n\n⇒ is normal Q-fuzzy JU-algebra of X. Clearly, η⊆η∗ thus η∗ is a normal JU-subalgebra of X which contains η.\n\nIf η itself is normal then η=η∗ If η is a Q-fuzzy JU-subalgebra of X then (η∗)∗=η∗\n\nIt is straight forward by theorem 9.\n\nLet η be a Q-fuzzy JU-subalgebra of X. If η contains a normal Q-fuzzy JU-subalgebra of X generated by any other Q-fuzzy JU-subalgebra of X then η is normal.\n\nLet λ be a Q-fuzzy JU-subalgebra of X. by theorem 9 and λ∗ is a normal Q-fuzzy JU-subalgebra of X. i.e. λ∗=1 by Lemma 8. Then let η is a Q-fuzzy JU-subalgebra of X such that λ∗⊆η then\n\nPut x = 1 ⇒ η (1, q) ≥ λ∗ = 1\n\n⇒η(1,q)≥1 . Hence η is normal.\n\nLet η be a Q-fuzzy JU-subalgebra of X and let f:[1,η(1,q)]→f[0,1] be an increasing function. Define a Q-fuzzy set η:X→[0,1] by η=f(η(x,q)),∀x∈X then\n\ni. ηf is a Q-fuzzy JU-subalgebra of X.\n\nii. If f(η(1,q))=1 then ηf is normal\n\niii. If f(t)≥t,∀t∈[1,η(1,q)] then η⊆ηf\n\n\n\ni.\n\n⇒ηf is a Q-fuzzy subalgebra of X.\n\nii. If f(η(1,q))=1\n\n⇒ηf is normal\n\niii. Let f(t)≥t,∀t∈[1,η(1,q)]\n\nThen\n\nHence η⊆ηf .\n\nLet η be a Doubt Q-fuzzy JU-subalgebra of X and let g:[1,η(1,q)]→[0,1] be a decreasing function. Define a Q-fuzzy set η:X→[0,1] by ηg=g(η(x,q)),∀x∈X then\n\ni. ηg is a Doubt Q-fuzzy JU-subalgebra of X.\n\nii. If g(η(1,q))=1 then ηg is normal\n\niii. If g(t)≤t,∀t∈[1,η(1,q)] then ηg⊆η\n\n\n\ni. Suppose η be a Doubt Q-fuzzy JU-subalgebra of X. Then\n\n⇒ηg is a Doubt Q-fuzzy subalgebra of X.\n\nii. If g(η(1,q))=1\n\n⇒ηg is normal.\n\niii. let g(t)≤t,∀t∈[1,η(1,q)]\n\nThen ηg(x,q)=g(η(x,q))\n\nHence ηg⊆η\n\n\nQ-Fuzzy Ideal of JU-algebras\n\nIn this section we discuss and investigate new notion of Q-fuzzy JU-ideals in JU-algebras and study their related properties.\n\nLet X be a JU-algebra, a Q-fuzzy set η in X is called Q-fuzzy JU-ideal of X if it satisfies the following conditions:\n\n(a) η(1,q)≥η(x,q)\n\n(b) η(y,q)≥min{η(x,q),η(x◦y,q)},∀x,y∈Xand∀q∈Q .\n\n(See table 3.1 from example 3) consider X={1,2,3,4} , and let Q={q1,q2}, given a Q-fuzzy set η:Q×X→[0,1] by Routine calculation gives that η is a Q-fuzzy JU-ideal of X ( Table 7).\n\nEvery Q-fuzzy JU-ideals of a JU-algebra X is order reversing.\n\nLet η be a Q-fuzzy JU-ideals of a JU-algebra X and for any x,y∈X be such that x≤y , then y◦x=1\n\nIf η is a Q-fuzzy JU-ideals of X, then η ((x ◦ y) ◦ y, q) ≥ η(x, q).\n\nSince (x◦ [(x◦y) ◦y]) = 1.......................... (Lemma no.1e)\n\nNow, η((x◦y)◦y,q)≥min{η(x,q),η(x◦[(x◦y)◦y])} , ∀q∈Q=min{η(x,q),η(1,q)}=η(x,q)\n\nA Q-fuzzy ideal of a JU- algebra X is Q-fuzzy JU-subalgebra when η(x◦(x◦y),q)≥η(y,q), for any x,y∈X and ∀q∈Q .\n\nSuppose η is a Q-fuzzy ideal of a JU- algebra X and η(x◦(x◦y),q)≥η(y,q). Then for any x,y∈X and ∀q∈Q .\n\nLet η be a Q-fuzzy set in a JU-algebra X and let t∈[0,1]. Then η is a Q-fuzzy JU-ideal of X if and only if the upper level subset ηt is a JU-ideal of X.\n\nSuppose η be a Q-fuzzy JU-ideal in a JU-algebra X and ηt≠∅\n\nLet x,x◦y∈ηt and ∀q∈Q implies that η(x,q)≥t and η(x◦y,q)≥t then η(y,q)≥min{η(x,q),η(x◦y,q)}≥min{t,t}=t\n\nThis implies that y ∈ηt and hence ηt is a JU-ideal of X.\n\nConversely, assume that the upper level subset ηt is a JU-ideal of X.\n\nFurther, let we assume that there exist some x0 ∈ X such that η(1,q)<η(x0,q)\n\nTake s=12[η(1,q)∗η(x0,q)]\n\nx0∈ηs and 1∉ηs , which is contradict to our assumption that ηs is a JU-ideal of X.\n\nTherefore, η(1,q)≥η(x,q),∀x∈X .\n\nAnd\n\nassume that x0,y0∈X such that\n\nTake s=12[η(y0,q)+min{η(x0,q),η(x0◦y0,q)}]\n\ny0∉ηs , a contradiction, since ηs is a JU-ideal of X. Therefore, η(y0,q)≥min{η(x0,q),η(x0◦y0),q} for any x,y∈X and ∀q∈Q.\n\nFor a Q-fuzzy JU-ideal of η of X, we can generate a normal fuzzy ideal of X which contains η.\n\nLet η be a Q-fuzzy JU-ideal of X. Define a Q-fuzzy subset η∗ of X as:\n\nLet x,y∈X,η∗(1,q)=η(1,q)+ηc(1,q)\n\n≥η(x,q)+ηc(1,q)=η∗(x,q) And\n\n⇒η∗ is normal Q-fuzzy JU-algebra of X.\n\nClearly η⊆η∗ thus η∗ is a normal JU-ideal of X which contains η.\n\nIf η itself is normal then η=η∗ . And if η is a Q-fuzzy JU-ideal of X then (η∗)∗=η∗\n\nIt is straight forward by theorem 22.\n\nLet η is a Q-fuzzy JU-ideal of X. If η contains a normal Q-fuzzy JU-ideal of X generated by any other Q-fuzzy JU- ideal of X then η is normal.\n\nLet λ be a Q-fuzzy JU- ideal of X. By theorem 22 λ∗ is a normal Q-fuzzy JU-ideal of X. i.e., λ∗ = 1 by Lemma 21\n\nLet η is a Q-fuzzy JU-ideal of X such that λ∗⊆η then η(x,q)≥λ∗(x,q),∀x∈X Put x=1\n\n⇒η(1,q)≥1. but, η(1,q)≤1\n\nTherefore, η(1,q)=1.\n\nLet η be a Q-fuzzy JU- ideal of X and let f:[1,η(1,q)]→[0,1] be an increasing function. Define a Q-f fuzzy set ηf:X→[0,1] by η=f(η(x,q)),∀x∈X then\n\ni. ηf is a Q-fuzzy JU- ideal of X.\n\nii. If f(η(1,q))=1 then ηf is normal\n\niii. If f(t)≥t,∀t∈[1,η(1,q)] then η⊆ηf\n\n\n\ni.\n\nAlso ηf(y,q)=f(η(y,q))\n\n⇒ηf is a Q-fuzzy JU-ideal of X.\n\nii. If f(η(1,q))=1\n\n⇒ηf is normal\n\niii. Let f(t)≥t,∀t∈[1,η(1,q)]\n\nThen ηf(x,q)=f(η(x,q))\n\n≥η(x,q),∀x∈X\n\nHence η⊆ηf .\n\nLet η be a Doubt Q-fuzzy JU- ideal of X and let g:[1,η(1,q)]g→[0,1] be a decreasing function. Define g a Q-fuzzy set η:X→[0,1]byη=g(η(x,q)),∀x∈X then\n\ni. ηg is a Doubt Q-fuzzy JU-ideal of X.\n\nii. If g(η(1,q))=1 then ηg is normal\n\niii. g(t)≤t,∀t∈[1,η(1,q)] then ηg⊆η\n\n\n\ni. Suppose η is a Doubt Q-fuzzy JU-ideal of X. Then\n\nAlso\n\n⇒ηg is a Doubt Q-fuzzy ideal of X.\n\nii. If g(η(1,q))=1\n\n⇒ηg is normal\n\niii. let g(t)≤t,∀t∈[1,η(1,q)] then\n\nHenceηg⊆η\n\n\nConclusions\n\nIn this study, we discussed the Q-fuzzy JU-subalgebras and Q-fuzzy JU-ideals of JU-algebra and investigated several related properties. We proved that the lower and upper level subsets of a Q-fuzzy JU-subalgebra or Q-fuzzy JU-ideal are also a JU-subalgebra or JU-ideals. Additionally, we studied Doubt of Q-fuzzy JU-subalgebras and Doubt of Q-fuzzy JU-ideals of JU-algebra and investigated some of their properties. We proved that the Q-fuzzy subset of a JU-algebra is a Q-fuzzy JU-subalgebra or Q-fuzzy JU-ideal if and only if its complement is a Doubt Q-fuzzy subalgebra and Doubt of Q-fuzzy ideal, respectively. Furthermore, we proved that a normal Q-fuzzy JU-subalgebras or Q-fuzzy JU-ideals generated by any other Q-fuzzy JU-subalgebra or Q-fuzzy JU-ideals is also normal. We also studied the connection between Normal and Doubt of Q-fuzzy JU-subalgebras and Q-fuzzy JU-ideals of JU-algebra and obtained some important properties. The findings of this research are expected to enrich the theory of Q-fuzzy JU-subalgebras and Q-fuzzy JU-ideals, based on Q-fuzzy sets, and will serve as a base for further study on this concept.\n\n\nAuthor contributions\n\nSelamawit Hunie Gelaw: Conceptualization, data curation, formal analysis, Investigation, Methodology, and original draft preparation. Birhanu Assaye Alaba and Mihret Alamneh Taye: Conceptualization, Methodology, supervision, Validation, writing review and editing. All authors have read and agreed to the published version of the manuscript.\n\n\nEthics approval and consent to participate\n\nNot applicable.\n\n\nConsent for publication\n\nNot applicable.", "appendix": "Data availability\n\nNo data is associated with this article.\n\n\nReferences\n\nZadeh LA: Fuzzy sets. Inf. Control. 1965; 8: 338–353. Publisher Full Text\n\nÂùò Ó: É-FUZZY SUBALGEBRAS OF BCK/BCI-ALGEBRAS.2001.\n\nTanamoon K, Sripaeng S, Iampan A: Q-fuzzy sets in UP-algebras. Songklanakarin J. Sci. Technol. 2018; 40(1): 9–29.\n\nBarbhuiya S: Doubt fuzzy ideals of BF-algebra. IOSR J. Mathe. (IOSR-JM). 2014; 10(2): 65–70. Publisher Full Text\n\nPrabpayak C: Doubt Fuzzy Ideals of B-Algebras. Appl. Mech. Mater. 2017; 866: 410–413. Publisher Full Text\n\nPrasanna APM, Ismail Mohideen S: Doubt Fuzzy B-Ideals in B-Algebra. Proceedings in International Conference on Mathematical Computer Engineering. Nov-2018.\n\nAnsari MA, Haider A, Koam A: On JU-algebras and p-closure ideals. Int. J. Math. Comput. Sci. 2020; 15(1): 135–154.\n\nDa R: CONCEPT OF FILTERS IN JU-ALGEBRAS. Annals of Oradea University-Mathematics Fascicola. 2022 Jan 1; 19(1).\n\nRal RIVFA: A Binary Block Code Generated by JU-Algebras. Asian Res. J. Math. 2023 Jun 30; 19(9): 58–67. Publisher Full Text\n\nMuthuraj RSM, Muthuraman MS, Sitharselvam PM: Anti Q-Fuzzy BG–Ideals in BG–Algebra. Int. J. Comput. Appl. 2010 Aug; 4(11): 27–31. Publisher Full Text" }	[ { "id": "361133", "date": "05 Feb 2025", "name": "İbrahim Şanlıbaba", "expertise": [ "Reviewer Expertise Fuzzy set", "fuzzy logic", "Decision makin support", "Artificial intelligient", "Fuzzy soft set." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReview Report on the paper:\n\"Q-fuzzy structure on JU-algebra\"\nI gave the manuscript a thorough reading. The paper presents and specifies new kinds of fuzzy structures, in JU - algebras, to improve on classical JU-algebra theory, such as Q-fuzzy JU - subalgebras and Q-fuzzy JU-ideals. In order to open the door for more research into fuzzy algebra in mathematical and applied contexts, it also looks at important characteristics of these structures, such as their lower and upper level subsets, and looks at particular cases like Doubt and Normal Q-fuzzy structures. The outcomes are positive and satisfying, and the study appears to follow accepted scientific practices. The argument in the paper was constructed on a solid foundation of theory, concept, or other ideas. Additionally, the study or intellectual effort equivalent on which the publication is based was well planned. The technique is correctly applied. The article's substance is accurately and succinctly described in the abstract, and the conclusions and interpretations are supported by the data. But I wish to draw attention to these problems in the manuscript:\n\nThe motivation and originality of the article should be mentioned in the introduction section. The novelty of the paper should be better emphasized in the introduction section. Authors should better explain the advantages of the present method over the other numerical methods. Conclusion part of the manuscript can be developed and more explanation about the results of the examples can be added. (Maybe the advantages of the present methods could be given in this section). Please check entire manuscript carefully for grammatical errors and typos. The importance of the design carried out in this manuscript can be explained better than other important studies published in this field. I recommend the authors to review other recently developed works. Şanlıbaba İ, et al., 2024 (Ref 1) and Şanlıbaba İ., 2025 (Ref 2), Şanlıbaba İ., 2022 (Ref 3) Finally, please check the entire manuscript carefully about the above mentioned suggestions.\n\nLast of all, this manuscript does have significant numerical methods content. The topic content of this paper is consistent with the goals of your journal. So my recommendation is acceptance of the manuscript after the major changes. It will hopefully add value to the existing literature.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13283", "date": "07 Feb 2025", "name": "Selamawit Gelaw", "role": "Author Response", "response": "I sincerely appreciate and thank you for your insightful suggestions and constructive comments, which have been invaluable in improving the quality of our work. Herewith below my response to reviewer comments 1.The motivation and originality of the article should be mentioned in the introduction section In the introduction, the motivation and originality is presented under the last paragraph. To explain clearly, JU-algebras have not been thoroughly explored in the context of Q-fuzzy sets, specifically with respect to JU-subalgebras and JU-ideals. This gap motivates us to conduct this study, where we introduce the novel concepts of Q-fuzzy JU-subalgebras and Q-fuzzy JU-ideals to extend the theoretical understanding and practical applications of JU-algebras. 2. The novelty of the paper should be better emphasized in the introduction section. The novelty of the paper is mentioned in the introduction, basically we extends Q-fuzzy sets to JU-algebras, offering new insights and algebraic properties that were previously unexplored. NOTE: JU- algebra is a crisp set. 3. Authors should better explain the advantages of the present method over the other numerical methods. The advantages of the present method is explained in the introduction with example how Q-fuzzy JU-subalgebras and Q-fuzzy JU-ideals allow for a more nuanced representation of fuzzy relationships, making them particularly well-suited for applications in fields like medicine, where conditions often do not have clear-cut boundaries. Furthermore, the inclusion of Doubt fuzzy sets enhances the robustness of the method, allowing for better handling of uncertain data. 4. Conclusion part of the manuscript can be developed and more explanation about the results of the examples can be added. (Maybe the advantages of the present methods could be given in this section). Yes we can explain more and our examples demonstrate how the method can be applied to real-world scenarios, but our focus is to highlight the theoretical concepts of Q-fuzzy JU- sub algebra and Q- fuzzy JU- ideals of JU-algebra . Since we present examples for the theoretical illustration purpose only so that adding results under conclusion is not as such important 6.The importance of the design carried out in this manuscript can be explained better than other important studies published in this field. I recommend the authors to review other recently developed works. Şanlıbaba İ, et al., 2024 (Ref 1) and Şanlıbaba İ., 2025 (Ref 2), Şanlıbaba İ., 2022 (Ref 3)\" I appreciate your nice work and the material you shared. Yes this novel concepts of Q-fuzzy JU-sub algebras and Q-fuzzy JU-ideals demonstrates not only extends the theoretical frameworks of JU-algebras but also insights and invites other researchers work on practical applications in area like medical diagnostics, where precise and adaptable fuzzy models are critical for robust decision-making. However, at this time bringing and introducing this new theoretical concepts should come first." } ] } ]	1	https://f1000research.com/articles/14-109
https://f1000research.com/articles/13-969/v1	27 Aug 24	{ "type": "Systematic Review", "title": "Factors influencing patient satisfaction in home care services: A systematic review", "authors": [ "Deby Zulkarnain Rahadian Syah", "Krisna Yetti", "Enie Novieastari", "Dewi Gayatri", "Sri Nining", "Krisna Yetti", "Enie Novieastari", "Dewi Gayatri", "Sri Nining" ], "abstract": "Background Home care services are an extension of hospital services provided by hospital staff. The hospital must conduct evaluation, coordination, and education for home care patients to ensure proper care and expedite their recovery. This service also introduces a new concept to the community, as it can help save on costs and equipment\n\nMethods A systematic review examined the factors influencing patient satisfaction using home care services by following the PRISMA guidelines. PROSPERO submitted and approved the study protocol with the following numbers: CRD42023482315.\n\nResult Researchers have searched articles through the ScienceDirect, Scopus, and Google Scholar databases. Two hundred eighty-eight articles were selected, but 10 met the inclusion criteria. It was found that factors influenced patient satisfaction with home care services and two things that did not affect them: financial aspects and working time.\n\nConclusion Fifteen aspects influence patient satisfaction and two aspects that do not influence patient satisfaction.", "keywords": [ "Supporting factors", "home care services", "patient satisfaction" ], "content": "Introduction\n\nThe nursing profession is experiencing a paradigm shift, jobs initially classified as vocational have been transformed into professional. Previously seen as an extension or assistant to doctors, nurses are now seen as equal partners with doctors in developed countries. The nursing service is a method of implementing nursing practice for individual patients, families, and communities to promote health, well-being, and maintaining and recovering from disease. Nurses must be able to take the opportunity to be at the policy-making table with a unified voice to support each other from the scope of nursing practice for health equity.1,2\n\nPatients admitted to the hospital already have follow-up care plans at home. Nurses are responsible for educating patients and their families to make patients independent so that they can reduce hospitalization, which reduces costs and time.3,4 In general, home care services are a continuation of hospital services and are carried out by hospital staff, but in evaluation, education and coordination between patients and home care staff are needed to speed up their recovery. It is also a new orientation for the community because it can save costs and equipment.5–7 Home care services require a formal method to measure quality and allocate health services that impact individual patients’ health, so further research is needed on home care and the progress of health services that continue to develop.8,9\n\nProviding nursing services in home care services does not reflect fair, safe and cultural aspects. Barriers are still found such as communication, prejudice, ethnocentrism, lack of education, lack of support from health services.10 The research results show that implementing culturally sensitive nursing care training can increase motivation to interact with patients, even a nurse who was previously reluctant to interact because it was difficult to communicate can finally interact well.11\n\nOne home care model that uses an innovative approach offers the potential to improve quality and address home care challenges. These challenges are resources, time and task rules, health and social care. The form of innovation shows a move from transactional to care that builds trust and relationships between service users, moving towards a proactive and preventive care model. Involve individual care teams and technology as part of the way of working rather than just a care solution.12\n\nQuality home care services in the aspects of reliability, guarantee, direct evidence, empathy and responsiveness are related to patient family satisfaction.13 Health is synonymous with well-being, happiness and life satisfaction which is the level of physical, emotional, intellectual, social, moral and spiritual strength. Human health is a state of satisfaction or happiness and well-being that reflects the level of fulfillment of physical, psychological, spiritual, social, aesthetic and material needs and desires that are felt.14\n\n\nMethods\n\nA systematic review was conducted to examine the factors influencing patient satisfaction using home care services by following the PRISMA guidelines. Eligibility criteria included human subjects of all ages, genders, and with or without disease, interventions with actions that can increase satisfaction, results of qualitative and quantitative research that state the influence on happiness, and literature review of home care patient satisfaction.\n\nReport characteristics are all studies written in English and published from 2012 to 2022. Researchers searched articles through the ScienceDirect, Scopus, and Google Scholar databases. Researchers have checked out article references from database searches to find additional relevant articles. We used Boolean operators to search for the following terms: (Home Care Services) AND Satisfaction and derivatives of these terms, full-text article type, English—subject nursing and health professions, with open access.\n\nIn the data extraction process, irrelevant articles, such as articles about patient satisfaction in nursing homes and outside home care, were removed, resulting in 228 relevant articles based on title and abstract. These articles were screened, and 31 were removed due to duplication, leaving 197 relevant articles based on title and abstract. Next, variables that met the inclusion criteria were selected, namely variables that influenced home care patient satisfaction, leaving 73 pieces. Next, the selection was carried out by rereading the suitability of the variables, leaving ten complete articles that met the inclusion criteria.\n\nCritical appraisal is carried out to identify the quality of the research included in it. The author carries out the process. Four research articles used a list of qualitative studies, five studies used quantitative research checklists, and one used a mixed methods study.\n\nThe nine synthesis steps without meta-analysis (SWiM) in systematic reviews guided data analysis.15 In the first group, the studies are to be synthesized. Grouping populations, interventions, outcomes, and research design. Next, in stages 2–6, answer review questions. Similarities and differences mainly related to assessment methods, assessment tools, assessors involved, and acquired competencies were identified. Findings are formulated based on keywords for categorized. The findings are categorised into two major themes: the assessment process and the competencies obtained. The findings are then entered into tables, indicating study groups and themes, presenting and discussing results, and identifying limitations.\n\n\nResults\n\nAfter selecting and using the Prisma chart (Figure 1), ten articles were obtained that were the aim of this research, namely identifying factors that influence satisfaction with home care services. The first journal’s influencing factor is respecting patients and maintaining their dignity.16 Furthermore, the second journal states that nurses must understand the patient’s illness and establish a relationship of mutual trust.17 The third journal shows the opposite: economic factors and working hours do not affect home care patient satisfaction.18 Furthermore, the four can coordinate in a comprehensive, continuous assessment of service and collaborate with multidisciplinary science.19 Fifth, sixth, and seven, well-prepared routines, language and communication, and empathy.20–22 Eighth, nine, and ten, namely quality nursing services, a combination of competence and professional skills in wound management, continuity of care, and training and experience of nurses.23–25\n\n\nDiscussion\n\nNurses can start home care services with a humble attitude and have an attitude of respecting their clients and listening to them. This attitude is very important because it is related to making decisions for clients to suit their needs.26 The attitude and responsibility of nurses show that nursing actions are not just technical actions, but require a process of change and dynamic organization.27 Nurses maintain a person’s dignity, which is one of the fundamental actions and rights of every human being since birth to have the same dignity. Respectful attitudes to anyone must be carried out by nurses because it is the core concept that is guaranteed for every human being.28\n\nA nurse when caring for a home care patient must be flexible, be able to trust each other and be able to approach the patient. Meeting after meeting will describe the positive aspects that are assessed by the client. Nurses must be able to explain the importance of mutual trust, and the need to create a sense of trust.29 Nurses must be able to understand their clients’ conditions, because they will seek a deep understanding of their illness, the causes of their illness, and prevention of complications.30\n\nNurses contribute to coordinating with the health team, to support the interventions provided. Good coordination also has an impact on meeting the complex needs of clients.31 Collaboration with other nurses needs to be improved, and made systematic by nurse managers, because it can improve patient safety culture.32 Nurses strive for continuous professional development and undertake lifelong learning to improve standards of care. Nurses are also motivated to improve their knowledge, skills and follow the latest scientific developments.33\n\nNurses can provide empathy, namely being able to understand the client’s personal experience without being tied down, and being able to communicate well including emotional, cognitive and behavioral aspects. A health professional can provide empathy well which can influence therapeutic changes in their clients. Clients will feel safe to convey their problems in order to be able to provide services according to their needs.34 Understanding empathy towards patients can improve nursing communication skills.35\n\nHome care nurses can provide continuous professional nursing services by involving their families. Nurses need home care guidelines as a reference to provide the best quality of care to patients.36 Professional skills are also needed such as wound care. Registered nurses are required to have diverse competencies and perform good quality evidence-based actions. Consistent and structured areas of competency such as wound care can be improved and developed to produce services according to client expectations.37 Optimal home care depends on collaborative action and dialogue between the client, family, home care nurse, and general practitioner. A good starting point is when the interdisciplinary collaboration meeting is held for good results in home care services.38\n\nRespect and maintaining dignity are supporting factors that influence patient satisfaction found in nurses or home care teams. Meanwhile, what can be learned and trained is understanding the client’s illness, establishing a relationship of trust, assessing services, collaboration, language, communication, empathy, and quality of service. Aspects that must be possessed include experience and training. The limitation of this research is that home care services are not specific to specific cases or are general. The articles reviewed also vary between qualitative, quantitative and mixed research.\n\n\nConclusion\n\nFactors that influence patient satisfaction using home care services become input for the provider’s management. Nurses and teams can pay attention to factors that can affect patient satisfaction. There are two factors that do not influence patient satisfaction, namely finances and working time. This will be an evaluation for subsequent research.\n\n\nEthics and consent\n\nEthical approval and consent were not required.", "appendix": "Data availability\n\nNo data are associated with this article.\n\nFigshare: Factors Influencing Patient Satisfaction in Home Care Services: A Systematic Review. https://doi.org/10.6084/M9.FIGSHARE.26489203.V1. 39\n\nThis project contains the following underlying data:\n\n1. PRISMA flow diagram: the number of records identified, included and excluded and the reasons for exclusions in this review.\n\n2. Summary review: The summary review contains an analysis of the selected articles in this review.\n\nData are available under the terms of the Creative Commons Zero “Universal” data waiver (CC0 1.0 Public domain dedication).\n\nFigshare: Factors Influencing Patient Satisfaction in Home Care Services: A Systematic Review. https://doi.org/10.6084/M9.FIGSHARE.26489203.V1 39\n\nThis project contains the following extended data:\n\n1. PRISMA checklist: a critical tool in the field of systematic reviews\n\n2. PRISMA flow diagram: the number of records identified, included and excluded and the reasons for exclusions in this review.\n\nData are available under the terms of the Creative Commons Zero “Universal” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgments\n\nWe thank The Center for Higher Education (BPPT) and the Lembaga Pengelola Dana Pendidikan (LPDP) for the significant support in the development of this article.\n\n\nReferences\n\nAdams S: Politics and paradigms in healthcare: Challenging the status quo. Nurs Prax Aotearoa New Zeal. 2021 Mar [cited 2022 Nov 30]; 37(1): s16–s16. Publisher Full Text\n\nSylvana Y, Utomo SL: Legal aspects of patient care with homecare services based on pratama clinical practices. Budapest Int Res Critics Institute-Journal. 2021 Dec 23 [cited 2022 Nov 10]; 4(4). Publisher Full Text\n\nDeLaune SC, Ladner PK: Fundamentals of nursing: standards & practice. illustrate. DeLaune SC, Ladner PK, editors. 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PubMed Abstract \| Publisher Full Text\n\nLumillo-Gutierrez I, Salto GE: Buurtzorg Nederland, a proposal for nurse-led home care. Enferm Clin (English Ed.). 2021 Sep 1 [cited 2023 Sep 14]; 31(5): 323–327. PubMed Abstract \| Publisher Full Text\n\nHuang J, Pacheco Barzallo D, Rubinelli S, et al.: Professional home care and the objective care burden for family caregivers of persons with spinal cord injury: Cross sectional survey. Int J Nurs Stud Adv. 2021 [cited 2023 Sep 19]; 3: 100014. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nNg AYM, Wong FKY: Effects of a home based palliative heart failure program on quality of life, symptom burden, satisfaction and caregiver burden: A randomized controlled trial. J Pain Symptom Manag. 2018 Jan [cited 2023 Sep 14]; 55(1): 1–11. PubMed Abstract \| Publisher Full Text\n\nCastor C, Hallstrom I, Hansson H, et al.: Home care services for sick children: Healthcare professionals conceptions of challenges and facilitators. J Clin Nurs. 2017 Sep 3 [cited 2023 Sep 29]; 26(17–18): 2784–2793. PubMed Abstract \| Publisher Full Text\n\nSuurmond J, Rosenmoller DL, El Mesbahi H, et al.: Barriers in access to home care services among ethnic minority and Dutch elderly: A qualitative study. Int J Nurs Stud. 2016 [cited 2023 Sep 14]; 54: 23–35. PubMed Abstract \| Publisher Full Text\n\nCaro MM, San-Martin M, Delgado-Bolton R, et al.: Empathy, loneliness, burnout, and life satisfaction in Chilean nurses of palliative care and homecare services. Enferm Clin. 2017 [cited 2023 Sep 29]; 27(6): 379–386. PubMed Abstract \| Publisher Full Text\n\nMing HC, Kenagy GP: Exploring the association between quality of homecare services and older adults well-being. Home Health Care Serv Q. 2020 Apr 2 [cited 2023 Sep 27]; 39(2): 65–79. PubMed Abstract \| Publisher Full Text\n\nSmith-Strom H, Iversen MM, Graue M, et al.: An integrated wound-care pathway, supported by telemedicine, and competent wound management: Essential in follow-up care of adults with diabetic foot ulcers. Int J Med Inform. 2016 [cited 2023 Sep 15]; 94: 59–66. PubMed Abstract \| Publisher Full Text\n\nDostalova V, Bartova A, Blahova H, et al.: The experiences and needs of frail older people receiving home health care: A qualitative study. Int J Older People Nursing. 2022 Jan 1 [cited 2023 Sep 29]; 17(1): e12418. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMartinsen B, Mortensen AS, Norlyk A: Nordic homecare nursing from the perspective of homecare nurses: A meta ethnography. Br J Community Nurs. 2018 Dec 2 [cited 2022 Oct 3]; 23(12): 597–604. PubMed Abstract \| Publisher Full Text\n\nKahouei M, Soleimani M, Mirmohammadkhani M, et al.: Nurses attitudes of a web patient portal prior to its implementation in home health care nursing. Heal Policy Technol. 2021 Sep 1 [cited 2023 Nov 12]; 10(3): 100524. Publisher Full Text\n\nWachholz P, Giacomin K, Chadborn NH, et al.: Dignity in the care of older adults living in nursing homes and long-term care facilities (revised). F1000Res. 2023 [cited 2024 Aug 7]; 11: 1208. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLarsson Gerdin A, Hellzen O, Kjallman Alm A, et al.: Encountering patients in their homes: A qualitative study of home care nurses experiences. Nord J Nurs Res. 2023 Jan 1 [cited 2024 Aug 7]; 43(1): 205715852311589. Publisher Full Text\n\nNunstedt H, Rudolfsson G, Alsen P, et al.: Patients variations of reflection about and understanding of long-term illness- impact of Illness perception on trust in oneself or others. Open Nurs J. 2017 Apr 17 [cited 2024 Aug 8]; 11(1): 43–53. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKaram M, Chouinard M-C, Poitras M-E, et al.: Nursing care coordination for patients with complex needs in primary healthcare: A scoping review. Int J Integr Care. 2021 Mar 19 [cited 2024 Aug 8]; 21(1): 16. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCelik Durmus S, Gezer MF: Relationship between nurse-nurse collaboration and patient safety culture. J Heal Nurs Manag. 2022 [cited 2024 Aug 8]; 9(3): 363–370. Publisher Full Text\n\nRouleau G, Gagnon M-P, Cote J, et al.: Effects of e-learning in a continuing education context on nursing care: Systematic review of systematic qualitative, quantitative, and mixed-studies reviews. J Med Internet Res. 2019 Oct 2 [cited 2020 Oct 12]; 21(10): e15118. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMoudatsou M, Stavropoulou A, Philalithis A, et al.: The role of empathy in health and social care professionals. Healthcare. 2020 Jan 30 [cited 2024 Aug 13]; 8(1): 26. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWu Y: Empathy in nurse patient interaction: A conversation analysis. BMC Nurs. 2021 Dec 1 [cited 2024 Aug 13]; 20(1): 16–18. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLigita T: Home care nurses roles in enhancing quality of nursing care for patients at home: A phenomenological study. Belitung Nurs J. 2017 Aug 31 [cited 2023 Sep 19]; 3(4): 345–351. Publisher Full Text\n\nKielo-Viljamaa E, Suhonen R, Jalonen L, et al.: Areas of nursing competence in acute wound care: A focus group study. Collegian. 2022 Feb 1 [cited 2024 Aug 13]; 29(1): 44–53. Publisher Full Text\n\nDanielsen BV, Sand AM, Rosland JH, et al.: Experiences and challenges of home care nurses and general practitioners in home-based palliative care: A qualitative study. BMC Palliat Care. 2018 Jul 18 [cited 2024 Aug 13]; 17(1): 95. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nRahadian Syah DZ: Factors influencing patient satisfaction in home care services: A systematic review.2024 Aug 3 [cited 2024 Aug 3]. Publisher Full Text" }	[ { "id": "334099", "date": "09 Nov 2024", "name": "Kallol Kumar Bhattacharyya", "expertise": [ "Reviewer Expertise Long-term care", "Dementia", "Late life cognitive impairment", "Quality of life and quality of care in long-term care." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nComments to the Author\nI am pleased to review the manuscript “Factors influencing patient satisfaction in home care services: A systematic review.” The study is important in evaluating the factors influencing the satisfaction of home care patients to ensure proper care and expedite their recovery. Although the article is well-written, and the findings likely benefit future researchers, some fundamental issues dampen my enthusiasm.\nMajor Issues.\nAbstract: The first sentence of the Result section, “Researchers have searched …databases,” should go to the Methods section. Also, a purpose statement for this study should be added in the Background section.\n\nThe Introduction section needs more work highlighting the purpose of the current study. The ideas jumped from one to another; there should be more transition sentences, and more importantly, it needs to be more focused to highlight the novelty or strengths of the current research, i.e., what this paper adds to the literature. Further, the authors need to build a robust theoretical base in the Introduction.\n\nSearch Methods: “…published from 2012 to 2022. Researchers searched articles through the ScienceDirect, Scopus, and Google Scholar databases.” Why were these specific electronic databases chosen? Was there any rationale behind choosing a specific timeframe?\n\nIn Figure 1, the PRISMA flowchart should include reasons for excluding studies in both steps of the screening section (full reasons for n=197 to n=73).\n\nQuality appraisal needs more details.\n\nData Analysis: Regarding the reliability checks, the authors should provide more clarity to ensure accuracy. I am curious to see what methodology they followed (including citation): having fuller information about how these categorization decisions were made and agreed upon would convince me that these categories fully and reliably reflect the appropriate methodology.\n\nThe authors provide a systematic review of 10 studies. The included studies have a heterogeneity of design, sample, and variables. I recommend pointing out the heterogeneity of the included studies as one of the main limitations of this study.\nThe Implication and Conclusion sections need more work from a policy perspective.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Partly\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Partly\n\nIs the statistical analysis and its interpretation appropriate? Partly\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable", "responses": [ { "c_id": "12822", "date": "15 Nov 2024", "name": "Deby Zulkarnain Rahadian Syah", "role": "Author Response", "response": "Thank you to Mr. Kallol Kumar Bhattacharyya for reviewing our article in detail. You are an expert in Gerontology, Dementia, Long-term that I admire. We are happy for the inputs that are very constructive in order to achieve good quality of the article. We will immediately improve it according to the inputs and suggestions. May Mr. Kallol Kumar Bhattacharyya always be in good health and happy. Warm regards Deby Zulkarnain Rahadian Syah" }, { "c_id": "12834", "date": "25 Nov 2024", "name": "Deby Zulkarnain Rahadian Syah", "role": "Author Response", "response": "Abstract: The first sentence of the Result section, “Researchers have searched …databases,” should go to the Methods section. Also, a purpose statement for this study should be added in the Background section. Response: The literature search database has been included in the Method section. The purpose of this study has been added to the background, namely to determine what factors can influence patient satisfaction with home care services from previously published literature. The Introduction section needs more work highlighting the purpose of the current study. The ideas jumped from one to another; there should be more transition sentences, and more importantly, it needs to be more focused to highlight the novelty or strengths of the current research, i.e., what this paper adds to the literature. Further, the authors need to build a robust theoretical base in the Introduction. Response: The paragraphs in the Introduction have been arranged according to the research objectives starting from paragraph one describing the issue of the professional nurse paradigm. Paragraph two describing the need for post-hospitalization care in hospitals. Paragraph three several obstacles to home care services. Paragraph four the importance of innovation in home care services that can increase patient satisfaction. The objectives of this literature review have been added. Search Methods: “…published from 2012 to 2022. Researchers searched articles through the ScienceDirect, Scopus, and Google Scholar databases.” Why were these specific electronic databases chosen? Was there any rationale behind choosing a specific timeframe? Response: The researcher chose the three databases that are open access providers. Including Scopus and ScienceDirect are article search databases that can be accessed directly in the electronic resources of the University of Indonesia Library. The 10-year time span is considered as a source of literature that is still relevant to be used as a reference in evaluating home care service satisfaction. In Figure 1, the PRISMA flowchart should include reasons for excluding studies in both steps of the screening section (full reasons for n=197 to n=73). Response: In the data extraction process, irrelevant articles such as articles on patient satisfaction in nursing homes and out-of-home care were removed resulting in 228 relevant articles based on the title and abstract in English. The articles were filtered and 31 articles were removed due to duplication in the Google Scholar database search leaving 197 relevant articles based on the title and abstract. Furthermore, variables that met the inclusion criteria were selected, namely variables that affect patient satisfaction with home care leaving 73 articles. Furthermore, the selection was carried out by re-reading the suitability of the variables leaving ten complete articles that met the inclusion criteria. Quality appraisal needs more details. Response: Critical appraisal was conducted to identify the quality of the included studies. The author conducted the process. Four research articles used a qualitative study checklist, five studies used a quantitative research checklist, and one used a mixed methods study. The data showed high heterogeneity in terms of research methods. The researcher conducted a quality assessment with one research member, and if there was disagreement on the review results, the researcher asked the other research members for the review results. The results are presented in a table showing a summary of the variables that affect satisfaction. Data Analysis: Regarding the reliability checks, the authors should provide more clarity to ensure accuracy. I am curious to see what methodology they followed (including citation): having fuller information about how these categorization decisions were made and agreed upon would convince me that these categories fully and reliably reflect the appropriate methodology. Response: The nine steps of synthesis without meta-analysis (SWiM) in systematic reviews guide the analysis of data in articles using quantitative methods to complement and extend PRISMA. In the first step, studies should be synthesized, grouping populations, interventions, outcomes, and study designs. Next, in steps 2–7, answer the review question. Similarities and differences that are primarily related to assessment methods, assessment tools, assessors involved, and competencies acquired are identified. In steps 8–10, results are formulated based on keywords for categorization. Results are synthesized and the certainty of findings is made in consistent language. Results are then presented in tables, indicating study groups and objectives, presenting and discussing results, and identifying limitations. The authors provide a systematic review of 10 studies. The included studies have a heterogeneity of design, sample, and variables. I recommend pointing out the heterogeneity of the included studies as one of the main limitations of this study. Response: The author admits that in conducting the analysis of the 10 literatures, there are limitations, namely three different research designs obtained. However, the variables that influence home care patient satisfaction from the 10 literatures can be used as an evaluation for the development of home care services that prioritize patient satisfaction aspects." } ] } ]	1	https://f1000research.com/articles/13-969
https://f1000research.com/articles/14-17/v1	03 Jan 25	{ "type": "Research Article", "title": "Trends, key contributors, and emerging issues in honey and breast cancer: A bibliometric analysis from 2014 to 2024", "authors": [ "Andi Nilawati Usman", "Fendi Fendi", "Zafitri Nulandari", "Dinah Inrawati Agustin", "Fendi Fendi", "Zafitri Nulandari", "Dinah Inrawati Agustin" ], "abstract": "Background Honey, a natural product with diverse bioactive compounds, has been increasingly explored for its potential anticancer properties. This study aims to comprehensively analyze the scientific literature on the relationship between honey and breast cancer.\n\nMethods A bibliometric analysis was conducted using the ScienceDirect database to identify publications from 2014 to 2024. Data on publication trends, author collaboration, and keyword analysis were extracted to gain insight into the research landscape. Keyword analysis identified nine distinct clusters, indicating diverse research directions regarding the role of honey in breast cancer treatment.\n\nResults Key journals such as the Journal of Ethnopharmacology and Food Chemistry have been at the forefront of disseminating research findings in this domain, demonstrating a strong interdisciplinary approach that bridges traditional medicine and modern scientific inquiry. The increasing interest in the anticancer properties of honey, as evidenced by the growing number of studies, underlines its potential as a promising natural agent for breast cancer prevention and treatment. Recent advances in the synthesis and theranostic paradigms of cerium oxide nanoparticles (CeONPs) have been highlighted, as well as the potential for selenium nanoconstructs. The toxicity and quality control of Perillae Fructus have also been highlighted.\n\nConclusions This study provides a comprehensive overview of the current state of knowledge and uncovers emerging issues that require further investigation.", "keywords": [ "honey", "breast cancer", "ScienceDirect", "bibliometric analysis", "VOSviewer" ], "content": "Introduction\n\nBreast cancer is the type of cancer that most frequently affects women and has a rather high death rate. Particularly in developing nations, the prevalence rate tends to rise annually, which frequently leads to deaths from delayed identification and treatment, which frequently detects the disease in its terminal stages.1 The malignant growth known as breast cancer (carcinoma mammae) develops in the breast tissue. This cancer starts to spread across the breast’s connective tissue, fatty tissue, and mammary glands.2\n\nBreast cancer is the most often diagnosed disease and the fifth largest cause of cancer mortality worldwide, with a projected 2.3 million diagnoses and 685,000 deaths in 2020, rising to 4.4 million by 2070. Breast cancer accounts for roughly 24.5% of all cancer cases and 15.5% of cancer deaths in women, making it the leading cause of death and incidence in the majority of countries by 2020.3 Approximately half of all breast cancers arise in women who have no known risk factors other than gender and age. Breast cancer will be the most frequent cancer among women in 157 of 185 nations by 2022. Breast cancer affects every country in the world. Men account for around 0.5-1% of all breast cancer cases.4\n\nOne of the reasons for the increasing number of cancer cases in Indonesia is that environmental circumstances continue to create harmful substances, such as air, soil, and air pollution, as well as the effects of cigarettes and fast food.5,6 Other factors that influence this include sleeping too late, a lack of physical activity, and consuming fast food.7–9\n\nIn recent years, numerous items made from different plants, consumables (including fruits, vegetables, and herbs), marine life, and microorganisms have been discovered to be effective in treating a range of human illnesses.10 It has been demonstrated that the efficacy of conventional therapy is increased when they are combined with natural items.11\n\nTraditionally, honey has been used for ages to heal various illnesses. Honey is one of these substances that has gained more attention recently because of its abundance of bioactive chemicals, which are thought to offer several health advantages, including anticancer effects.12 Honey has been discovered to have biological properties such as antioxidant, antibacterial, anticancer, and antiproliferative properties.13 The study of natural substances as potential therapeutic agents in the treatment of cancer has gained significant traction, particularly in the case of breast cancer.14\n\nBibliometric analysis provides a quantitative and qualitative overview of the scientific literature.15 Through this analysis, we will explore key trends in research by focusing on publications from 2014 to 2024, identify leading contributors in the field, and uncover emerging issues that require further investigation. By systematically examining published research, we seek to provide a comprehensive overview of the current state of knowledge and identify areas that require additional research to fully understand the potential role of honey in breast cancer prevention and treatment.\n\n\nMethods\n\nBibliometric analysis is a quantitative methodology that facilitates in-depth mapping, analysis, and interpretation of scientific literature.15,16 Through this approach, we can identify research trends over time, reveal collaborative networks between researchers, and identify key topics of research focus. Thus, bibliometric analysis provides a comprehensive picture of the research landscape of a field, including the most dominant journals and the most frequently occurring keywords in the related literature.\n\nData collection Data was retrieved from the Science Direct database on November 10, 2024. Science Direct was chosen because it is one of the largest searchable databases of abstracts and citations of academic publications compared to other databases, such as Web of Science and Google Scholar, and is continuously expanded and updated. Over 4111 source titles are from over 700 publishers in the Science Direct database. The search terms “honey” and “breast cancer” in the article title were used to search for relevant articles. We refined the search for publication years from 2014 to 2024 to capture current honey and breast cancer research trends. We included published and reviewed articles in English that have appeared in journals, as this visualizes and maps the honey and breast cancer research literature over a decade ( Figure 1).\n\n\nResults\n\nTotal of publications\n\nBased on Figure 2 there is a significant increase in the number of publications from year to year. Starting from 2014 to 2024, there is a consistent upward trend. The most drastic increase occurred in 2023, with the number of publications reaching 121, an increase of more than three times compared to 2014.\n\nThe journal that publishes most frequently\n\nThe Journal of Ethnopharmacology is the most frequently published journal, with 51 publications. This journal is very relevant because it often publishes research on traditional medicines, including honey, which has potential as an alternative or complementary treatment for various diseases, including cancer. Food Chemistry occupies the second position with several publications 36. This journal is relevant because honey is a natural product with complex chemical content. Research in this field can reveal honey components with antioxidant or antitumor activity. Food Research International is in third place with 17 publications, followed by Food and Chemical Toxicology with 14 publications; both journals focus on food research in general, including functional foods such as honey that have potential health benefits. In seventh place is the Journal of Ayurveda and Integrative Medicine, which is particularly relevant as Ayurveda, the traditional Indian system of medicine, often uses honey to treat various diseases, including cancer. This can also be seen in Table 1.\n\nBased on the data presented in Table 1, the Journal of Ethnopharmacology emerged as the most productive journal in publishing research related to traditional and natural medicines such as honey and breast cancer. This indicates that ethnopharmacology is undergoing rapid development and attracting the interest of many researchers.\n\nIn addition, the high number of publications in food-related journals, such as Food Chemistry and Food Research International, indicates that research in the field of food is also very active.\n\nCo-authorship\n\nBased on Figure 4, authors Battino, Maurizio, and Giampieri, Francesca appear to be two authors with a total link strength of 44. Their high link strength indicates that they have produced many honey and breast cancer publications and have a wide collaboration network in their research field.\n\nPublishing co-authors who published honey and breast cancer from 2014 to 2024 resulted in 4514 authors. We removed articles with more than 4000 co-authors to avoid considering negligible contributions in the network map. By applying a minimum threshold of 2 published articles per author, 30 authors were identified. Still, only 10 authors were visually mapped in the Figure because some were disconnected.\n\nIn Figure 4, the lines between authors represent their collaborative relationships, while 3 different colors represent the authors’ collaboration groups. Although all the top 10 authors listed in Table 2 belong to different groups, their close and strong interconnections indicate a fairly strong research relationship relating to honey and breast cancer. For example, Arifin, Sadia. Alvarez-Suarez, Jose m. Battino, Maurizio. Cianciosi, Danila. Giampieri, Francesca in Cluster 1 (Red), Xiao, Jianbo. Rashid, Summya. Fraga-corral, m. (Green), and Nafees, Sana. Qamar and Wajhul in Cluster 3 (Blue) are closely interlinked, as shown in Figure 3.\n\nThe network appears dense and interconnected, with several clusters forming around the center. This suggests a complex relationship between honey and breast cancer, with many factors contributing to the overall understanding. This co-occurrence network map provides a valuable overview of the current research landscape on honey and breast cancer. The map highlights the potential of honey as a natural remedy for cancer prevention and treatment. The Table 3 shows the Key Clusters and Connections.\n\n\n\n• Traditional knowledge: This cluster highlights the importance of traditional knowledge in understanding and utilizing plants for medicinal purposes. It connects to ethnobotany, medicinal plants, and traditional medicine.\n\n• Ethnobotany: This cluster focuses on the scientific study of traditional knowledge related to plants, particularly their use in medicine. It links to medicinal plants, human health, ethnomedicine, and ethnopharmacology.\n\n• Medicinal plants: This cluster represents the core focus of the map, emphasizing the role of plants in traditional and modern medicine. It connects to traditional knowledge, ethnobotany, human health, and ethnomedicine.\n\n• Traditional medicine: This cluster highlights the use of traditional practices and remedies in healthcare. It connects to medicinal plants, human health, and ethnomedicine.\n\n\n\n• Human health: This cluster emphasizes the broader context of human health, including the role of plants in preventing and treating diseases. It connects to medicinal plants, ethnomedicine, ethnopharmacology, and cancer.\n\n• Cancer: This cluster focuses on cancer, a major health concern. It connects to human health, ethnomedicine, ethnopharmacology, and various plant-based compounds with potential anticancer properties.\n\n• Ethnomedicine: This cluster explores the use of traditional medical practices and remedies in different cultures. It connects to human health, cancer, and medicinal plants.\n\n• Ethnopharmacology: This cluster focuses on the scientific study of traditional medicine and its potential applications in modern healthcare. It connects to human health, cancer, and medicinal plants.\n\n\n\n• Quercetin, Pyrrolizidine alkaloids, Rutin, Flavonoids: These clusters represent various plant-based compounds with potential health benefits, particularly in cancer prevention and treatment. They connect to cancer, antioxidants, inflammation, and apoptosis.\n\n• Antioxidant, Inflammation, Apoptosis: These clusters represent biological processes targeted by plant-based compounds. They connect to cancer and various plant-based compounds.\n\n• Honey, Food safety, Heterocyclic amines: This cluster highlights the potential of honey as a food source and its safety concerns related to contaminants. It connects to food safety and heterocyclic amines.\n\nThe co-occurrence analysis of author keywords was conducted from 2014 to 2024 ( Table 4). For the analysis, a threshold of a minimum number of 5 keyword occurrences was set. The analysis yielded 2818 keywords out of 68. The results showed 9 distinct clusters ( Figure 5). Each cluster or combination of clusters represents a subfield of honey and breast cancer research. In particular, as shown in the green, yellow, red, blue, and light blue clusters, keywords such as “Anti-cancer,” “Apoptosis,” and “Inflammation.” “Oxidative stress” is related to Honey as a Cancer Agent. Next, in the green cluster, there are keywords such as “Anti-inflammatory,” “Antimicrobial,” “Antioxidant,” “Honey,” and “Propolis,” which are associated with the antimicrobial effects of honey. in the light blue cluster, the respective keywords are related to the nature of cancer treatment. in the yellow cluster, the respective keys are related to the types of treatment. in the light blue cluster, the respective keys are related to drug development.\n\nThis visualization presents a comprehensive overview of research topics related to natural products and their health benefits. The network structure, with nodes representing keywords and edges indicating co-occurrence, reveals the interconnectedness of these concepts. Overall, the VOSviewer visualization provides a valuable overview of current research trends in natural products and their health benefits. It highlights the potential of these compounds to address various health challenges and underlines the need for further research to unlock their full potential ( Table 5).\n\nThe following table describes the VOSviewer visualization, which provides a valuable overview of research trends and potential future directions in natural products and their health benefits.\n\n\nDiscussion\n\nThe findings indicate a robust interest in exploring honey as a complementary treatment for breast cancer. The increase in publications suggests that researchers increasingly recognize honey’s potential benefits due to its antioxidant and anti-inflammatory properties. The dominance of specific journals indicates a focused interest in ethnopharmacology and food science disciplines. Collaborative networks among top authors demonstrate an active community engaged in this research area, which may lead to more comprehensive studies and innovative therapeutic strategies.\n\nThe last decade has witnessed significant evolution in cancer research, particularly in the exploration of natural products as potential therapeutic agents.94 The rich biodiversity in nature provides a variety of unique chemical compounds with promising biological activities.95 In addition, the long history of the use of medicinal plants and the assumption that natural products are safer with fewer side effects further encourage research.96 The active compounds in natural products also serve as inspiration for the development of new synthetic drugs while supporting the principle of cessation.97 Thus, exploring natural products offers new hope in the pharmaceutical world. Among others, honey has attracted attention due to its rich composition of bioactive compounds, which are believed to provide a variety of health benefits.98 According to a growing body of research, honey is not cytotoxic to normal cells but is highly and particularly cytotoxic to tumor cells, suggesting that honey may exhibit anticancer effects.99 From 2014 to 2024, the scientific community is increasingly focused on understanding the essence of honey in breast cancer treatment, reflecting a broader trend towards integrating traditional medicine with modern medical practice.\n\nIn 2014, research on honey and its effects on cancer was still emerging, with only a handful of studies investigating its therapeutic potential. However, as awareness of the adverse side effects associated with conventional cancer treatments grew, so did interest in alternative therapies. In 2023, this interest culminated in a marked surge in publications, indicating a paradigm shift toward exploring natural substances such as honey as adjuncts to conventional cancer therapies.\n\nThis analytical period highlights the increase in published research and the diversification of study methodologies and interdisciplinary collaborations. Researchers from diverse fields-from pharmacology to nutrition, have begun to converge on this topic, fostering a rich environment for innovation and discovery. This ten-year analysis of publications reveals key trends in authorship, journal contributions, and thematic focus areas, providing insight into how Honey is positioned within the broader context of breast cancer research.100–102 As we delve deeper into this analysis, it becomes clear that the intersection of traditional knowledge and scientific inquiry is paving the way for new therapeutic approaches.103 The growing body of literature underscores honey’s potential role as a valuable resource in breast cancer treatment strategies and emphasizes the need for continued research to elucidate its mechanisms and efficacy fully.104,105\n\nThe period from 2014 to 2024 has witnessed a tremendous increase in publications related to honey and breast cancer. Initially, research in this field was still limited, but a significant surge in interest became apparent in 2023 when the number of publications jumped to 121- more than three times the 2014 results. the 2014 results trend reflects the growing recognition of the potential therapeutic properties of honey, including its antioxidant and anti-inflammatory effects, which are particularly important in the fight against cancer. This analysis highlights that key journals such as the Journal of Ethnopharmacology and Food Chemistry have been at the forefront of disseminating findings in this domain, indicating the involvement of the findings in this domain and indicating a strong engagement from ethnopharmacology and food science perspectives.\n\nThe co-authorship network identifies key contributors to this field, highlighting leading researchers such as Maurizio Battino and Francesca Giampieri. Their collaboration and extensive publication record underscore the importance of collective efforts in advancing knowledge on the therapeutic effects of honey. The analysis also reveals that leading journals such as the Journal of Ethnopharmacology and Food Chemistry have played an important role in disseminating research findings, demonstrating a strong interdisciplinary approach that bridges traditional medicine and modern scientific inquiry.\n\nFurthermore, this bibliometric analysis investigates emerging issues in the research landscape, identifying important themes through keyword co-occurrence analysis. Key terms such as “anticancer,” “apoptosis,” “inflammation,” and “oxidative stress” reflect the multifaceted nature of honey’s role in cancer treatment. Identifying different research groups suggests that research increasingly focuses on different aspects of honey’s biological activity, including its antimicrobial properties and potential applications in drug development.\n\n\nConclusion\n\nThis bibliometric analysis highlights the growing interest in honey as a potential adjunctive therapy for breast cancer. The increasing number of publications indicates a promising future for honey research. Moreover, this analysis emphasizes the potential of plant-based compounds, especially those derived from honey, as promising therapeutic agents for cancer. Integrating traditional knowledge with modern scientific methods is essential to unlock the full potential of these compounds. Further research is needed to elucidate their mechanism of action, assess their safety and efficacy, and develop evidence-based interventions. By bridging the gap between traditional knowledge and scientific research, we can harness the power of nature to improve human health.\n\n\nAuthor contributions\n\nANU, FF, ZN, and DIA contributed to the literature review, data extraction from various databases, conceptualization, development of the economic models on Microsoft Excel Software, formal analysis, findings interpretation, and manuscript writing. All authors approved the final version of the paper.\n\n\nEthic and consent\n\nEthical approval and consent were not required.", "appendix": "Data availability\n\nFigshare:Trends, key contributors, and emerging issues in honey and breast cancer: A bibliometric analysis from 2014 to 2024, Doi: https://doi.org/10.6084/m9.figshare.28013666.106\n\nThe project contains the following underlying data:\n\n- data figshare_bibliomettik_F1000.xlsx (This study examined the relationship between honey and breast cancer. The researchers analyzed scientific publications from 2014 to 2024 to understand research trends, researcher collaborations, and key topics studied).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nFigshare: PRISMA 2020 checklist for the article “Trends, key contributors, and emerging issues in honey and breast cancer: A bibliometric analysis from 2014 to 2024” has been uploaded to Figshare and is available at the following DOI: https://doi.org/10.6084/m9.figshare.28041074.107\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAmens JN, Bahçecioglu G, Zorlutuna P: Immune System Effects on Breast Cancer. Cell. Mol. Bioeng. 2021; 14(4): 279–292. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBarzaman K, Moradi-Kalbolandi S, Hosseinzadeh A, et al.: Breast cancer immunotherapy: Current and novel approaches. Int. 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Publisher Full Text\n\nRanneh Y, Akim A, Hamid HA, et al.: Honey and its nutritional and anti- inflammatory value.2021; 5: 1–17.\n\nUsman AN, Fendi F, Nulandari Z, et al.: Trends, key contributors, and emerging issues in honey and breast cancer: A bibliometric analysis from 2014 to 2024 (Version 1). 2024. figshare. Publisher Full Text\n\nUsman AN, Fendi F, Nulandari Z, et al.: Checklist for Trends, key contributors, and emerging issues in honey and breast cancer: A bibliometric analysis from 2014 to 2024. figshare. 2024. Preprint. Publisher Full Text Publisher Full Text" }	[ { "id": "355982", "date": "10 Jan 2025", "name": "Mogana Das Murtey", "expertise": [ "Reviewer Expertise Cancer Biology" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article is well-structured, provides a thorough bibliometric analysis, and appropriately cites current literature from 2014 to 2024. However, some minor details in the keyword co-occurrence analysis could be expanded for clarity. The methodology, using bibliometric analysis via ScienceDirect, is appropriate and robust. The analysis tools, such as VOSviewer, were suitably employed to map research trends. The methods section provides adequate detail about data collection, inclusion criteria, and analytical tools, enabling replication. The bibliometric statistics and visualization interpretations are appropriate and effectively highlight trends and clusters. The authors have deposited the data in a public repository (Figshare) and described it adequately. The conclusions align with the results, highlighting honey's therapeutic potential in breast cancer, but a discussion of clinical trial needs could be elaborated.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] } ]	1	https://f1000research.com/articles/14-17
https://f1000research.com/articles/13-429/v1	30 Apr 24	{ "type": "Research Article", "title": "Influencing factors of health-related quality-of-life perceived by both children/adolescents patients with type-1 diabetes mellitus and their parents: A North-African study", "authors": [ "Imen Ben Abdesselem", "Raoudha Kebeili", "Khansa Derbel", "Hichem Ben Said", "Lamia Boughamoura", "Jihene Bouguila", "Helmi Ben Saad", "Raoudha Kebeili", "Khansa Derbel", "Hichem Ben Said", "Lamia Boughamoura", "Jihene Bouguila", "Helmi Ben Saad" ], "abstract": "Aim To determine the influencing factors of health-related quality-of-life (HRQoL) perceived by North-African children/adolescents with type-1 diabetes-mellitus (T1DM) and their parents.\n\nMethods It was a cross sectional study conducted in Tunisia. A total of 116 patients ( ie ; 43 children and 73 adolescents) and their parents were included. The Arabic validated version of the Pediatric Generic Core Quality-of-Life Inventory 4.0-Scale (PedsQL4.0) was used to evaluate the HRQoL of children/adolescents as perceived by patients and parents. The dependent data were the patients’ self-report and the parents’ proxy-report of the PedsQL4.0 total scores, and the independent data were the patients and parents characteristics.\n\nResults Patients’ PedsQL4.0 total score was influenced significantly by siblings in the family > 2; lipodystrophy, and glycosylated hemoglobin (HbA1C). The combination of these factors explained 34.84% of the PedsQL4.0 total score variability. Parents’ PedsQL4.0 total score was influenced significantly by lipodystrophy, siblings; body mass index (BMI), hypoglycemia episodes, and HbA1C. The combination of these factors explained 56.92% of the PedsQL4.0 total score variability.\n\nConclusion T1DM patients self-reported HRQoL was influenced by siblings in the family > 2; lipodystrophy, and HbA1C. The parents’ proxy-report HRQoL was influenced by lipodystrophy, siblings, BMI, hypoglycemia episodes, and HbA1C.", "keywords": [ "Adolescent", "Child", "Diabetes mellitus type 1", "Parents", "HRQoL", "North Africa" ], "content": "Introduction\n\nType 1 diabetes mellitus (T1DM) is a major public health problem.1 It is one of the most common chronic childhood diseases, with approximately 208000 children/adolescents worldwide affected in 2017.2 The 2010-2020 decades have seen a significant increase in the incidence of T1DM worldwide.3 This corresponds to an increase of more than 120000 new cases of T1DM per year in children/adolescents.2 Between 2011 and 2021, and according to the 2022-report of the world health organization, the number of cases of T1DM in African children/adolescents increased fivefold (ie; from 4 to 20 cases per 1000 children/adolescents).4 In low and middle- incomes countries, an increase of the incidence of T1DM was also observed.5–7 T1DM influences negatively the physical and mental health, emotional development and vital prognosis of children/adolescents.2,5,8 Traditionally, the management of T1DM has focused on achieving an optimal glycemic control in order to prevent long-term complications.6 In addition to technological advances in the treatment of T1DM, more and more attention is being paid to the psychosocial component, and the family dynamics of the diabetic patient.9 In fact, the complexity of the daily care plan, which continues throughout life, can affect negatively health-related quality of life (HRQoL) in children/adolescents with T1DM.2,6–16 According to the Erikson's developmental theory, the disease brings significant changes to the development of the children/adolescents, and when the latter experience long-term treatment with painful injections, their normal mental development process is interrupted, and their self-esteem can be affected.17 Every day, these children/adolescents live with the burden of this disease.17 HRQoL, which is a concept, formed from the physical environment and a combination of social, emotional and school functions,11,16,18,19 has become an important issue in the health field.\n\nGeneric and diabetes-specific HRQoL assessments are often advocated and have been shown to be useful in research.12 For this reason, and in order to take decisions about the management of T1DM, approaches that focus on the triad ‘child-family-disease’ are needed.20 Improving the HRQoL and the well-being of children/adolescents with T1DM is as important as metabolic control to prevent secondary morbidity.20–22 Consequently, ‘modern’ diabetes care for children/adolescents has shifted from a purely medical approach to one that aims at optimal glycemic control and maximum HRQoL.21 Despite the large number of international scientific studies examining HRQoL of diabetic children/adolescents,2,5–24 only one Egyptian study were performed in North-Africa.5 The Egyptian authors evaluated the HRQoL of 72 children with T1DM, tested how much it could be affected by their mood and family attitudes, and studied the relationship between these variables and the metabolic control of the patients.5 They have included a control group of 72 children apparently healthy, non-diabetic, age and sex matched and siblings of the diabetic patients were included as a control group.5 The authors have applied the Pediatric Generic core Quality of life Inventory 3.0 Scale (PedsQL3.0), parent stress index (PSI) questionnaire and glycosylated hemoglobin (HbA1C, %).5 The authors reported i) significant positive fair correlations between the age, weight and body mass index (BMI) of diabetic children with the children and parent’ PedsQL; and ii) significant negative weak correlations between PSI score and children and parent’ PedsQL (ie; the higher parental stress, the lower HRQoL of the diabetic child (reported by both child and parent).5\n\nThe results of the studies to examine the HRQoL of diabetic children/adolescents2,5,6,8,9,12,20,23,24 can contribute to the evolution of professional practices and lead to the improvement of the delivery of health services to children/adolescents with T1DM in low- or middle- income countries, such as Tunisia. Therefore, the objectives of this study were to i) assess the HRQoL of Tunisian children/adolescents with T1DM as perceived by both patients (self-reported) and parents (proxy-reported); and ii) determine the influencing factors of the self-reported and proxy-reported HRQoL perceived by patients and their parents, respectively.\n\n\nMethods\n\nIt was a cross-sectional study performed between January 2019 and February 2022 in the pediatric department of the Farhat HACHED Sousse university hospital, Tunisia. The study’s ethical approval was obtained from the ethics committee of the faculty of medicine of Sousse (Reference: CEFMS 61/2021). After obtaining their agreement, the parents of the children/adolescents signed a consent form. In addition, adolescents over 13 years old signed the consent form. The children/adolescents and their parents were informed about the i) study protocol and its aims, and ii) possibility of withdrawal from the research project at any time. During the period between June 2020 and February 2022, all recommended preventive measures to fight against the transmission of the severe acute respiratory syndrome coronavirus 2 were applied (eg; physical distancing of at least one meter, wearing a fitted facemask properly and cleaning hands frequently with alcohol-based hand rub or soap and water), During each study step, all recommended preventive measures to fight against COVID-19 transmission were applied. The study was conducted following the guidelines established by the STROBE statement.25 In order to respect the anonymity and confidentiality of the data, a code was assigned to each patient.\n\nThe source population was the children/adolescents (and their parents) attending pediatric outpatient consultations at the above cited hospital. The target population was the children/adolescents with T1DM who were consulted during the study period. Only children/adolescents aged 8 to 18 years, who were accompanied by their parents, who had a medical diagnosis of T1DM at least one year before the inclusion in the study, and who received only insulin analogues for at least three months were included in the study. Children/adolescents who had a mental retardation, a sensor neural disorder that interferes with normal communication; or another chronic disease, such as celiac disease, were not included in this study. Children/adolescents who participated in another experimental survey during the study period were excluded from the statistical analysis. Figure 1 exposes the study flow chart.\n\nThe sample size was appraised according to the following formula26: N = (Zα)2 s2/d2, where “s” is the standard deviation (SD= 9.79) and “d” is the accuracy of estimate or how close it is to the true mean (= 76.51). Given the pioneering nature of this study, the above “s” and “d” data were collected from a previous work including 503 adolescents with T1DM,27 aiming to evaluate the HRQoL via the diabetes quality of life instrument for youth.28 In the aforementioned study, the percentage mean score of the total HRQoL for all adolescents was 76.51±9.79. “Zα” is the normal deviate for a one-tailed alternative hypothesis at a level of significance (Zα equal to 1.28 at an error rate of 0.10%). The appraised sample size gives a sample of 116 patients. The assumption of 25% for the non-inclusion and exclusion criteria gives a revised sample of 154 patients (154 =116/ (1.0-0.25)).\n\nOne investigator (IBA in the authors’ list) was in charge of administering and explaining the different components of the questionnaire to children/adolescents and their parents. On the beginning of the consultation day, the questionnaire was given to patients and parents independently in order to improve the response rate. The questionnaire was then collected at the end of the morning of the same day. The questionnaire included two parts and the time taken to complete it was 15 minutes.\n\nThe first part of the questionnaire, which was written in Arabic, was pretested, structured, and self-administered by the researcher (IBA in the authors’ list). It was related to personal data of both diabetic patients and their parents. For parents, the following data were collected: accompanying tutor (ie; mother; father), marital status (ie; married; divorced), schooling-level (ie; illiterate or primary or secondary school; university), and socio-economic level [ie; low (eg; unskilled worker, jobless); high (eg; skilled worker, farmer, manager)]. For patients, the following data were collected: sex (ie; male; female), age (ie; years, children (8 to 12 years), adolescents (13 to 18 years)); BMI (kg/m2), corpulence status (ie; normal weight; overweight or obese),29 siblings in the family (ie; number sibling > 2), schooling-level [ie; low (primary or preparatory school) and high (secondary school)], schooling-performance (ie; normal; repeating or stop); family history of diabetes mellitus (ie; yes, no), onset age and seniority of T1DM (ie; year), person in charge of insulin injection (ie; patient, parents), dietetic education (ie; yes, no), diet (ie; yes, no), hypoglycemia episodes during the last three months before the inclusion in the study (ie; number, yes, no), average glycaemia during the hypoglycemia episodes (ie; g/l), home self-monitoring (ie; yes, no), home self-monitoring frequency (ie; never, > 1), most recent HbA1C level (ie; %), duration of HbA1C control (ie; control < 3 months, control > 6 months), lipodystrophy (ie; yes, no), previous hospitalization (ie; yes, no), and etiologies of hypoglycemia (ie; lipodystrophy, diet, stop insulin). Two subgroups of patients (ie; non-active; active) were formed according to regular sports activity based on the response to the following question30: do you practice any sports activities outside of school? Some data (eg; family history of T1DM, HbA1C levels and potential previous hospitalizations) were extracted from the patients’ medical records.\n\nThe second part of the questionnaire was reserved to the PedsQL4.0.10,31 The latter was developed to assess the HRQoL of children/adolescents (self-reported) as well as their parents’ (proxy-report).10,31 HRQoL is assessed in four domains: physical function (8 items), emotional function (5 items), social function (5 items), and school function (5 items).10,31 The following three scores are determined: total score, physical health score, and psychosocial health score (covering emotional, social and academic function).10,31 Total scores are obtained by adding the scores and dividing them by the total number of items completed. Patients and parents were asked to rate the ‘problem in the past three months’ on 5 Likert scales from 0 to 4 (0 = never a problem; 1 = almost never a problem; 2 = sometimes a problem; 3 = often a problem, 4 = almost always a problem). Then each item was scored backwards and linearly transformed on a scale of 0 to 100 (0 = 100, 1 = 75, 2 =50, 3 = 25, 4 = 0), so that the highest score indicates better HRQoL.10,31 The PedsQL4.0 has appropriate forms for child self-assessments and parent proxy reports,31 and has shown good internal consistency, reliability and validity.10 The validated Arabic version of the PedsQL4.0 was applied.15 Permission to use the PedsQL 4.0 was obtained from the authors.\n\nData expression. The Kolmogorov Smirnov test was used to analyze quantitative data’s distribution. All quantitative data have a normal distribution, and therefore were expressed as means ± standard deviation. Categorical data were expressed as number (frequency).\n\nComparisons parents vs. patients. Comparisons of the PedsQL4.0 scores between parents and patients were performed by the Student-T test.\n\nUnivariate and multiple regression analysis (influencing factors). The dependent variable (ie; PedsQL4.0 total scores of patients and parents) was normally distributed. Student-T test were used to evaluate the associations between the PedsQL4.0 total score and categorical data [ie, parents’ data (accompanying tutor, marital status, schooling-level, and socio-economic-level); patients’ data (sex, age range, siblings in the family, schooling-level, schooling-performance, corpulence status, charge of injections, dietetic education, diet, regular physical activity, hypoglycemia, home self-monitoring, frequency of home self-monitoring, duration of the control of HbA1C, lipodystrophy, previous hospitalizations, and family history of diabetes mellitus)]. The Pearson product-moment correlation coefficients (r) evaluated the associations between the PedsQL4.0 total score and continuous data [ie; age, siblings, BMI, hypoglycemia episodes, average glycaemia during hypoglycemia episodes, HbA1C, onset age of T1DM, and seniority of T1DM]. The linearity of the association between the PedsQL4.0 total scores and the continuous data was checked graphically by plotting each regressor against the PedsQL4.0 total scores. Only significantly and linearly associated data were entered into the model.\n\nLinear regression models were used to evaluate the independent data explaining the variance in PedsQL4.0 total scores. Candidate data were put into the model with a stepwise selection method. To determine entry and removal from the model, significant levels of 0.15 and 0.05 were used, respectively. No colinearity between predictors was detected with variance inflation factors. The linear regression models were evaluated by the (r) and the standard error. All statistical procedures were performed using a statistical software (StatSoft, Inc. (2014). STATISTICA (data analysis software system), version 12. www.statsoft.com, RRID: SCR_014213). The significance level was set at p<0.05.\n\n\nResults\n\nAmong the 154 patients assessed for eligibility, and after applying the inclusion, non-inclusion, and exclusion criteria, 116 diabetic patients aged 8 to 18 years and 116 parents were included in the study (Figure 1).\n\nTable 1 illustrates the parents’ and patients characteristics, respectively. Its main conclusions were: i) almost 92% of parents have a low socio-economic-level; ii) there was a predominance of adolescents and females (63% and 64%, respectively), iii) 56% of patients have normal weight, iv) the mean of siblings was 3±1, and 71% of patients had more than 2 siblings in the family, v) the means of hypoglycemia episodes and HbA1C were 4.3±1.5, and 10±1, respectively, and vi) 69% of patients have lipodystrophy.\n\na Mean±standard deviation.\n\nb Number (%).\n\nPatients and parents had comparable scores of physical health (67±20 vs. 70±21, p=0.271, respectively), emotional function (53±20 vs. 57±21, p=0.074, respectively), social function (81±18 vs. 83±18, p=0.502, respectively), academic function (70±21 vs. 70±21, p=0.886, respectively), and total score (68±13 vs. 70±14, p=0.180, respectively).\n\nTables 2 and 3 expose the univariate analysis between PedsQL4.0 total scores of patients and parents and categorical and quantitative data, respectively. Among patients, the following four data influence the PedsQL4.0 total score: siblings in the family, dietetic education, lipodystrophy, and HbA1C. In parents, the following eight data influence the PedsQL4.0 total score: siblings in the family, corpulence status, dietetic education, lipodystrophy, siblings, BMI, hypoglycemia episodes, and HbA1C.\n\n* P-value (Student T test) < 0.05: comparison between 2 categories for the same group (patients or parents).\n\n* p-value < 0.05.\n\nTable 4 exposes the multivariate linear regression analysis. Among patients, only three data influence the PedsQL4.0 total score: siblings in the family, lipodystrophy and HbA1C. Altogether, they explain 34.84% of the PedsQL4.0 total score variance. In parents, only five data influence the PedsQL4.0 total score: lipodystrophy, siblings, BMI, hypoglycemia episodes, and HbA1C. Altogether, they explain 56.92% of the PedsQL4.0 total score variance.\n\n\nDiscussion\n\nThe main results of the present study including 116 diabetic children with T1DM (and their parents) were that the diabetic patients self-reported HRQoL was influenced by siblings in the family >2; lipodystrophy, and HbA1C, and that the parents’ proxy-report HRQoL was influenced by lipodystrophy, siblings; BMI, hypoglycemia episodes, and HbA1C.\n\nPatients living with T1DM experience various challenges, related mainly to a restrictive lifestyle, multiple daily insulin injections, and monitoring of blood glucose levels.6 The process to manage this chronic disease impacts the HRQoL of the children/adolescents, and interferes also with the familial dynamics and the parents’ HRQoL.32 This study provides results useful for assessing HRQoL in patients with chronic diseases living in Tunisia, and North Africa. To the best of the authors’ knowledge, this is the first North-African study that evaluates the influencing factors of the HRQoL of children/adolescents with T1DM as perceived by patients and parents.\n\nThe Arabic version of PedsQL4.0 is understandable and usable in Tunisia.15 It has a high validity and reliability.15 Table 5 exposes the PedsQL4.0 scores among different populations of diabetic children/adolescents with TIDM.2,6,8,10–16\n\na Minimum-maximum.\n\nb Mean.\n\nc Mean±standard deviation.\n\nIn this study, the patients’ total score was 68±13 (Table 5). In the one hand, it was comparable to the one of the Iranian population of patients aged 8 to 18 years13 who has a score of 68±14 (Table 5). In the other hand, our score was lower than the ones reported in similar studies [ie, score ranging from 76±1116 to 88±118]. In this study, while the patients’ social function score was high at 81±18, this of the emotional function was low at 53±20. Our results are intermediate with those reported in literature (Table 5). First, almost all previous studies2,6,8,10–16 reported that the social function score was the highest [ie; ranging from 77±1813 to 95±108 (Table 5)]. Second, while some previous studies,2,10,11,13–16 reported that the emotional function score was the lowest [ie; ranging from 60±2013 to 76±1611 (Table 5)], three studies6,12,13 identified that the academic function score was the lowest [ie; ranging from 67±1813 to 72±166 (Table 5)].\n\nThe discrepancy between results could be explained partly by the age of included patients ranging from 2-18 years11,15,16 to 8-18 years.2,6,13 In addition, according to Abderrassoul et al.,16 impaired emotional function may be explained by the lack of autonomy and preoccupation with chronic complications. In order to increase the emotional function score, and to early detect and solve problems that children/adolescents may encounter, we recommend that HRQoL assessment after T1DM diagnosis should be a routine practice.\n\nThe PedsQL4.0 scores of diabetic patients were comparable with those of their parents. This result is inconsistent with previous studies, which reported a significant difference between patients and their parents’ subjective perception of T1DM and the impact of the disease on their daily life.2,6,16,27 The concordance between patient and parents results observed in this study can be explained by different factors, such as the presence of communication between parents and their children/adolescents, especially among children, who do not present generally a withdrawal and oppositional behavior before the pubertal period.2,14 Moreover, parents seem to have more concern about their children/adolescents health when they reach school age, given the fact that kids haven’t yet developed an independent personality and weren’t became self-sufficient around this range of age.\n\nTable 5 exposes the influencing factor of the patients’ PedsQL4.0 scores among different populations of diabetic children/adolescents with TIDM. It appears that the following factors are independent predictors of HRQoL as perceived by diabetic patients: HbA1C,2,6,12,14,16 age,2,14,16 sex,6,14,16 siblings,2,6 depression,12 adherence to treatment,12 hypoglycemia,14 hyperglycemia,14 onset of T1DM,14 duration of T1DM,16 socioeconomic level,6 therapeutic education,6 hospitalization,6 mothers’ and fathers’ educational status,8 fathers’ occupation,8 monitoring blood glucose.8 In the present study, among all studies data, siblings in the family, lipodystrophy and HbA1C were independent predictors of HRQoL as perceived by diabetic patients, and lipodystrophy, siblings, BMI, hypoglycemia episodes, and HbA1C were independent predictors of HRQoL as perceived by parents (Table 4). The following sentences will discuss the aforementioned factors.\n\nAn increase in the number of children in the family had a statistically significant effect on the HRQoL of children/adolescents as well as their parents (Table 4). A number of “siblings higher than 2” reduces the patients’ HRQol total score by 6.84, and one unit of sibling reduced the parents’ HRQoL total score by 3.73 (Table 4). Our results, which are in line with the findings of some studies from Turkey2 and Ethiopia,6 could be explained by the fact that increasing number of children in family may reduce parental support. Thus, siblings should be included in diabetes health education and diabetic children/adolescents should be supported by all family members.6\n\nLipodystrophy was an independent predictor of HRQoL as perceived by both patients and parents (Table 4). It appears that the presence of lipodystrophy reduces the patients and parents’ HRQoL total scores by 4.29 and 6.97, respectively. Besides, the changes of the skin and the unsightly aspect of lipodystrophy can also perturb the body image, especially among adolescents, and thus decreases the emotional function in HRQoL. To the best of the authors’ knowledge, no previous study has found an association between lipodystrophy and HRQoL (Table 5).\n\nHbA1C level (%) was an independent predictor of HRQoL as perceived by both patients and parents (Table 4). One unit of HbA1C reduces the patients and parents’ HRQoL total scores by 1.20 and 0.96, respectively (Table 4). Our result is in line with the findings of some previous studies reporting an association between lower HRQoL of patients and higher HbA1C levels.2,6,9,12,14,16\n\nBMI (kg/m2) was an independent predictor of HRQoL as perceived by parents (Table 4). In our study, we observed a noteworthy and positive correlation (r = 0.526), one unit of BMI increases the parents’ HRQoL total score by 1.03 (Table 4). This finding aligns with two previous studies conducted in Saudi Arabia33 and in Egypt.5\n\nHypoglycemic episodes was an independent predictor of HRQoL as perceived by parents (Table 4). Each hypoglycemic episode decreases the parents’ HRQoL total score by 1.69 (Table 4). Our finding was consistent with other studies that indicated that treatment ongoing risk of hypoglycemia (especially nocturnal hypoglycemia) negatively affect the HRQOL of patients and their families.20 In fact, hypoglycemia episodes are uncomfortable experiences and could cause an important psychological impact on the children/adolescents. Therefore, assessment of psychosocial burden, including fear of hypoglycemia, should be part of the management of T1DM.20 Our findings suggest that motivating a child/adolescent to achieve optimal glycaemia levels and incorporating routine clinical assessment of HRQoL as an important component of diabetes management are necessary to determine the appropriate intervention to improve HRQoL.20 Contrary to the present study, one Greece study14 identified hypoglycemia as an independent predictor of HRQoL as perceived by diabetic patients (Table 5).\n\nAdditional factors, such as age,2,14,16 sex,6,14,16 and socioeconomic data,6,8 need to be discussed. First, in the present study, and similar to other studies,3,9,34–36 there were no effects of age or sex on HRQoL. However, some previous studies reported that girls have lower total HRQoL scores than boys.6,9,15,16,18,37 In general population, during adolescence, girls tend to have less self-esteem than boys,38 and present more signs of depression,23 which may constitute factors of a lower HRQoL. Moreover, adolescent girls with T1D are reported to be more anxious and less satisfied than boys,16 and experience hormonal changes with an increase of insulin require. In our study, there was no significant association between socioeconomic status and patients’ HRQoL. This is consistent with the finding of a Norwegian study.36 However, some other studies reported that a low socioeconomic level was significantly associated with sub-optimal management of T1DM, and this may negatively affect quality of life.6,8,9,39\n\nThe main two strengths of our study were the high enrolment rate (76%) and its pioneer character. Since it is the first study from the Great Maghreb, which assessed HRQoL and associated factors in a pediatric diabetic population.\n\nOur study has three main limitations. The first limitation is related to the lack of a control group. The second limitation concerns the non-evaluation of some other potential determinant of HRQoL such as family and psychological relationships. The third limitation is related to the recruitment method from one center. Since all our patients were recruited from a single pediatric hospital, our results may not be easily generalized to children/adolescents with T1DM living in other locations in Tunisia or North Africa.\n\nIn clinical practice, providing support to patients with T1DM to guide them in reducing the risk of acute and chronic complications. Involving parents in the management of their children/adolescents’ disease and more particularly encouraging a constant commitment for the potential disease progression would eventually improve the HRQoL of children/adolescents as well as their parents. Therefore, our research emphasizes the significance of adequate management of diabetes for improved HRQoL, and conversely, the importance of good HRQoL for maintaining good diabetic control. To improve the low emotional and school function scores identified in the study, it is advisable to regularly evaluate the HRQoL of these children to detect any significant deterioration early on. This will facilitate the implementation of appropriate interventions that can enhance the overall management of the disease. Additionally, in families with multiple children/adolescents, it is essential to involve the siblings in diabetes education and empower them to take responsibility. Providing families with information on available social support resources can also be helpful.\n\n\nConclusion\n\nThe study indicated that the PedsQL4.0 scores were satisfactory overall, with higher scores on the social function subscale, and lower scores in emotional and school functions. Furthermore, PedsQL4.0 scores for children/adolescents patients, and their parents were comparable. HRQoL of children/adolescents was influence significantly by sibling relationships, lipodystrophy, and HbA1C levels. Therefore, assessing the HRQoL after a diabetes diagnosis can aid in identifying and addressing potential challenges early on for children/adolescents.\n\n\nEthical approval\n\nThe study’s ethical approval was obtained from the ethics committee of the faculty of medicine of Sousse, Tunisia (Reference: CEFMS 61/2021, date: September 7, 2021).\n\n\nInformed consent\n\nWritten informed consent was obtained from all parents of the children/adolescents after receiving an explanation of the study. In addition, adolescents over 13 years old signed the consent form\n\n\nDeclaration\n\nWe have looked for assistance from artificial intelligence (ie; language model, ChatGPT 3.5) in the language editing our scientific paper.40", "appendix": "Data availability\n\nZenodo : Excel data of the 116 Tunisian participants and their parents [Data set]. Zenodo. https://doi.org/10.5281/zenodo.10900075. 41\n\nThe project contains the following underlying data\n\n- [Excel Data of the 116 participants and parents.xls] (Excel file including the numerical data of the 116 patients and their parents).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nZenodo: Influencing factors of health-related quality-of-life perceived by both children/adolescents patients with type-1 diabetes mellitus and their parents: A North-African study\n\nThe project contains the following underlying data:\n\n- [ Appendix A: Copy of the PedsQl4 French questionnaire] (Applied questionnaire). https://doi.org/10.5281/zenodo.10900088. 42\n\n- [ Appendix B : Copy of the translated PedsQl4 Arabic questionnaire] (Translated questionnaire). https://doi.org/10.5281/zenodo.10900100. 43\n\n- [Appendix C: Copy of the translated PedsQl4 English questionnaire] (Translated questionnaire).https://doi.org/10.5281/zenodo.10900109. 44\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nZenodo: STROBE checklist for ‘[Influencing factors of health-related quality-of-life perceived by both children/adolescents patients with type-1 diabetes mellitus and their parents: A North-African study]. https://doi.org/10.5281/zenodo.10900117. 45\n\n\nReferences\n\nNwose EU, Digban KA, Anyasodor AE, et al.: Development of public health program for type 1 diabetes in a university community: preliminary evaluation of behavioural change wheel. 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PubMed Abstract \| Free Full Text\n\nNansel TR, Weisberg-Benchell J, Wysocki T, et al.: Steering committee of the family management of diabetes s. Quality of life in children with type 1 diabetes: a comparison of general and diabetes-specific measures and support for a unitary diabetes quality-of-life construct. Diabet. Med. 2008 Nov; 25(11): 1316–23. Epub 2008/12/03. eng. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nJafari P, Forouzandeh E, Bagheri Z, et al.: Health related quality of life of Iranian children with type 1 diabetes: reliability and validity of the Persian version of the PedsQL Generic Core Scales and Diabetes Module. Health Qual. Life Outcomes. 2011 Nov 23; 9: 104. Epub 20111123. eng. PubMed Abstract \| Publisher Full Text \| Free Full Text ,\n\nKalyva E, Malakonaki E, Eiser C, et al.: Health-related quality of life (HRQoL) of children with type 1 diabetes mellitus (T1DM): self and parental perceptions. Pediatr. Diabetes. 2011 Feb; 12(1): 34–40. Epub 2010/06/16. eng. PubMed Abstract \| Publisher Full Text\n\nAbdul-Rasoul M, AlOtaibi F, AlMahdi M, et al.: Reliability and validity of the Arabic version of the PedsQL TM 3.0 diabetes module. J. Diabetes Mellit. 2012 01/01; 02(03): 301–307. Publisher Full Text\n\nAbdul-Rasoul M, AlOtaibi F, Abdulla A, et al.: Quality of life of children and adolescents with type 1 diabetes in Kuwait. Med. Princ. Pract. 2013; 22(4): 379–84. Epub 20130215. eng. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nErikson EH: Childhood and society. 2nd ed.Erikson-New York: Norton; 1963.\n\nHoey H, Aanstoot HJ, Chiarelli F, et al.: Good metabolic control is associated with better quality of life in 2,101 adolescents with type 1 diabetes. Diabetes Care. 2001 Nov; 24(11): 1923–8. Epub 2001/10/27. eng. PubMed Abstract \| Publisher Full Text\n\nReid AM, Balkhi AM, St. Amant J, et al.: Relations between quality of life, family factors, adherence, and glycemic control in pediatric patients with type 1 diabetes mellitus. Child. Health Care. 2013 2013/10/01; 42(4): 295–310. Publisher Full Text\n\nCaferoglu Z, Inanc N, Hatipoglu N, Kurtoglu S: Health-related quality of life and metabolic control in children and adolescents with type 1 diabetes mellitus. J. Clin. Res. Pediatr. Endocrinol. 2016 Mar 5; 8(1): 67–73. Epub 20151218. eng. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nvon Sengbusch S , Muller-Godeffroy E, Hager S, et al.: Mobile diabetes education and care: intervention for children and young people with Type 1 diabetes in rural areas of northern Germany. Diabet. Med. 2006 Feb; 23(2): 122–7. eng. PubMed Abstract \| Publisher Full Text\n\nBas V, Bideci A, Soysal Acar A, et al.: Evaluation of factors affecting quality of life in children with type 1 diabetes mellitus. J. Diabetes Metab. 2011; 02(8): 154. Publisher Full Text\n\nAlBuhairan F, Nasim M, Al Otaibi A, et al.: Health related quality of life and family impact of type 1 diabetes among adolescents in Saudi Arabia. Diabetes Res. Clin. Pract. 2016 Apr; 114: 173–9. Epub 20160108. eng. PubMed Abstract \| Publisher Full Text\n\nWagner J, Heapy A, James A, et al.: Brief report: glycemic control, quality of life, and school experiences among students with diabetes. J. Pediatr. Psychol. 2006 Sep; 31(8): 764–9. Epub 20050914. eng. PubMed Abstract \| Publisher Full Text\n\nvon Elm E , Altman DG, Egger M, et al.: The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Int. J. Surg. 2014 Dec; 12(12): 1495–9. Epub 20140718. PubMed Abstract \| Publisher Full Text\n\nKang M, Ragan BG, Park JH: Issues in outcomes research: an overview of randomization techniques for clinical trials. J. Athl. Train. 2008 Apr-Jun43(2): 215–21. Epub 2008/03/18. eng. PubMed Abstract \| Free Full Text\n\nAbolfotouh MA, Kamal MM, El-Bourgy MD, et al.: Quality of life and glycemic control in adolescents with type 1 diabetes and the impact of an education intervention. Int. J. Gen. Med. 2011 Feb 20; 4: 141–52. Epub 20110220. eng. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nIngersoll GM, Marrero DG: A modified quality-of-life measure for youths: psychometric properties. Diabetes Educ. 1991 Mar-Apr; 17(2): 114–8. Epub 1991/03/01. eng. PubMed Abstract \| Publisher Full Text\n\nCole TJ, Bellizzi MC, Flegal KM, et al.: Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ (Clinical research ed). 2000 May 6; 320(7244): 1240–3. Epub 2000/05/08. eng. Publisher Full Text \| PubMed Abstract \| Free Full Text\n\nBen Saad H, Prefaut C, Missaoui R, et al.: Reference equation for 6-min walk distance in healthy North African children 6-16 years old. Pediatr. Pulmonol. 2009 Apr; 44(4): 316–324. PubMed Abstract \| Publisher Full Text\n\nVarni JW, Seid M, Kurtin PS: PedsQL 4.0: reliability and validity of the pediatric quality of life inventory version 4.0 generic core scales in healthy and patient populations. Med. Care. 2001 Aug; 39(8): 800–12. Epub 2001/07/27. eng. PubMed Abstract \| Publisher Full Text\n\nGraue M, Wentzel-Larsen T, Bru E, et al.: The coping styles of adolescents with type 1 diabetes are associated with degree of metabolic control. Diabetes Care. 2004 Jun; 27(6): 1313–7. Epub 2004/05/27. eng. PubMed Abstract \| Publisher Full Text\n\nAl-Hayek AA, Robert AA, Abbas HM, et al.: Assessment of health-related quality of life among adolescents with type 1 diabetes mellitus in Saudi Arabia. Saudi Med. J. 2014 Jul; 35(7): 712–7. Epub 2014/07/17. eng. PubMed Abstract\n\nMurillo M, Bel J, Perez J, et al.: Health-related quality of life (HRQOL) and its associated factors in children with Type 1 Diabetes Mellitus (T1DM). BMC Pediatr. 2017 Jan 13; 17(1): 16. Epub 2017/01/13. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLaffel LM, Connell A, Vangsness L, et al.: General quality of life in youth with type 1 diabetes: relationship to patient management and diabetes-specific family conflict. Diabetes Care. 2003 Nov; 26(11): 3067–73. Epub 2003/10/28. eng. PubMed Abstract \| Publisher Full Text\n\nFroisland DH, Graue M, Markestad T, et al.: Health-related quality of life among Norwegian children and adolescents with type 1 diabetes on intensive insulin treatment: a population-based study. Acta Paediatr. 2013 Sep; 102(9): 889–95. Epub 20130716. eng. PubMed Abstract \| Publisher Full Text\n\nBabiker A, Al Aqeel B, Marie S, et al.: Quality of Life and glycemic control in Saudi children with type 1 diabetes at different developmental age groups. Clin. Med. Insights Endocrinol. Diabetes. 2021; 14: 1179551421990678. Epub 20210211. eng. PubMed Abstract \| Free Full Text\n\nRowe ML: Understanding socioeconomic differences in parents’ speech to children. Child Dev. Perspect. 2017 2018/06/01; 12(2): 122–7. Publisher Full Text\n\nHassan K, Loar R, Anderson BJ, et al.: The role of socioeconomic status, depression, quality of life, and glycemic control in type 1 diabetes mellitus. J. Pediatr. 2006 Oct; 149(4): 526–31. Epub 2006/10/03. eng. PubMed Abstract \| Publisher Full Text\n\nDergaa I, Zakhama L, Dziri C, et al.: Enhancing scholarly discourse in the age of artificial intelligence: A guided approach to effective peer review process. Tunis. Med. 2023 Oct 5; 101(10): 721–6. Epub 20231005. eng. PubMed Abstract\n\nBen Saad H, Ben AI: Excel data of the 116 Tunisian participants and their parents. [Data set]. Zenodo. 2024. (Last visit: April 12, 2024). Publisher Full Text\n\nBen Saad H, Ben AI: Copy of the PedsQl4 French questionnaire. Zenodo. 2024. (Last visit: April 12, 2024). Publisher Full Text\n\nBen Saad H, Ben AI: Copy of the translated PedsQl4 Arabic questionnaire. Zenodo. 2024. (Last visit: April 12, 2024). Publisher Full Text\n\nBen Saad H, Ben AI: Copy of the translated PedsQl4 English questionnaire. Zenodo. 2024. (Last visit: April 12, 2024). Publisher Full Text\n\nBen Saad H, Ben AI: STROBE checklist for the original study titled “Influencing factors of health-related quality-of-life perceived by both children/adolescents patients with type-1 diabetes mellitus and their parents: A North-African study”. Zenodo. 2024. (Last visit: April 12, 2024). Publisher Full Text" }	[ { "id": "277117", "date": "17 Dec 2024", "name": "Sameh Mabrouk", "expertise": [ "Reviewer Expertise pediatric nephrology" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article about “Influencing factors of health-related quality-of-life perceived by both children/adolescents patients with type-1 diabetes mellitus and their parents: A North-African study” by Ms Ben Abdesselem, is an original article that accurately evaluates the quality of life of children/adolescents with type diabetes as well as their parents with a particular focus on influencing factors of HRQL. It is it is an unprecedented study in Tunisian as well as north African pediatric settings.\nThis article accurately evaluates the quality of life of children/adolescents with type I diabetes as well as their parents. And focuses on influencing factors of HRQL.\nIt is an unprecedented study in the Tunisian pediatric setting.\nThe introduction is too long and should be shortened. Some of it's parts can be withdrawn.\nThe study design was appropriate to the study objectives, and explained with details, making it reproductible if needed.\nResults were well represented with tables, and accurately interpreted . The results responded to the author's objectives.\nThe discussion part was thorough, with authors' self-criticism. The results were discussed according to literature data on the subject.\nReferences were mostly recent.\nGlobally it is an interesting and good study. The authors, methodically addressed a subject of actuality, in the era of increasing incidence of type I diabetes among children, and integrative medicine focusing on quality of life as a major part of chronic disease management.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13083", "date": "08 Jan 2025", "name": "IMEN BEN ABDESSELEM", "role": "Author Response", "response": "The authors sincerely thank the reviewer for her thorough and insightful feedback on our manuscript. We have carefully considered each comment and made the necessary revisions to address his concerns. We believe these changes have significantly improved the manuscript. Below are our specific responses to the reviewer positive comments/suggestions. COMMENT 1. I. General comment: It’s an interesting article, the author determine the influencing factors of health-related quality-of-life (HRQoL) perceived by North-African children/adolescents with type-1 diabetes-mellitus (T1DM) and their parents. «The aim of this study was To determine the influencing factors of health-related quality-of-life (HRQoL) perceived by North-African children/adolescents with type-1 diabetes-mellitus (T1DM) and their parents». RESPONSE We thank the reviewer for his valuable feedback. COMMENT 2. The methodology section is detailed, the author explains data collection and statistical analysis very well RESPONSE We thank the reviewer for his valuable feedback. COMMENT 3. The “result section” meets the objective of the article and the results are well presented in the text and tables. The “discussion section” the results of the article are well discussed with the literature and the bibliography is recent. RESPONSE We thank the reviewer for his valuable feedback COMMENT 4. Major points are: The subject because Type 1 diabetes mellitus (T1DM) is a major public health problem in north Africa, The study design, It was a cross-sectional study The sample size was appraised according to the following formula26: N = (Zα)2 s2/d2, where “s” is the standard deviation (SD= 9.79) and “d” is the accuracy of estimate or how close it is to the true mean (= 76.51). Given the pioneering nature of this study. Sufficient details of methods and analysis are provided to allow replication by others The work clearly and accurately presented and it cite the current literature the statistical analysis and its interpretation are appropriate All the source data underlying the results are available to ensure full reproducibility The conclusions drawn are adequately supported by the results RESPONSE We thank the reviewer for his valuable feedback." } ] }, { "id": "277118", "date": "19 Dec 2024", "name": "Ihsen Zairi", "expertise": [ "Reviewer Expertise pediatric cardiology" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIt’s an interesting article, the author determine the influencing factors of health-related quality-of-life (HRQoL) perceived by North-African children/adolescents with type-1 diabetes-mellitus (T1DM) and their parents. « The aim of this study was To determine the influencing factors of health-related quality-of-life (HRQoL) perceived by North-African children/adolescents with type-1 diabetes-mellitus (T1DM) and their parents » The methodology section is detailed, the author explains data collection and statistical analysis very well The “result section” meets the objective of the article and the results are well presented in the text and tables The “discussion section” the results of the article are well discussed with the literature and the bibliography is recent.\nMajor points are : -\n\nthe subject because Type 1 diabetes mellitus (T1DM) is a major public health problem in north Africa,\n\n-\n\nthe study design, It was a cross-sectional study -\n\nthe sample size was appraised according to the following formula26: N = (Zα)2 s2/d2, where “s” is the standard deviation (SD= 9.79) and “d” is the accuracy of estimate or how close it is to the true mean (= 76.51). Given the pioneering nature of this study. -\n\nsufficient details of methods and analysis are provided to allow replication by others -\n\nthe work clearly and accurately presented and it cite the current literature -\n\nthe statistical analysis and its interpretation are appropriate -\n\nall the source data underlying the results are available to ensure full reproducibility -\n\nthe conclusions drawn are adequately supported by the results\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] } ]	1	https://f1000research.com/articles/13-429
https://f1000research.com/articles/10-454/v1	08 Jun 21	{ "type": "Brief Report", "title": "Klebsiella pneumoniae with capsule type K64 is overrepresented among invasive disease in Vietnam", "authors": [ "Bich Vu Thi Ngoc", "Sylvain Brisse", "Trinh Dao Tuyet", "Dung Vu Tien Viet", "Kathryn E Holt", "Trung Nguyen Vu", "Huong Tran Thi Kieu", "Diep Nguyen Thi Ngoc", "H Rogier van Doorn", "Heiman F L Wertheim", "Sylvain Brisse", "Trinh Dao Tuyet", "Dung Vu Tien Viet", "Kathryn E Holt", "Trung Nguyen Vu", "Huong Tran Thi Kieu", "Diep Nguyen Thi Ngoc", "H Rogier van Doorn", "Heiman F L Wertheim" ], "abstract": "Introduction: Recent reports indicate the emergence of community-acquired pneumonia associated with K64-Klebsiella pneumoniae. Here, we identify the capsular types and sequence type of invasive and commensal K. pneumoniae isolates from Vietnam. Methods: We included 93 K. pneumoniae isolates from patients hospitalized at the National Hospital for Tropical Diseases, Hanoi between 2007 and 2011; and 110 commensal isolates from throat swabs from healthy volunteers living in rural and urban Hanoi in 2012. We determined sequence types (STs) by multi-locus sequence typing (MLST) and capsule typing for seven K types by PCR. Antibiotic susceptibility testing was performed using disk diffusion. Results: The most common detected capsule types were K1 (39/203, 19.2%, mainly ST23) and K2 (31/203, 15.3%, multiple STs: ST65, ST86, ST380). We found significantly more K2 isolates among invasive in comparison to commensal isolates (22.6% vs 9%, p = 0.01) but no significant difference was observed between invasive and commensal K1 isolates (14.5% vs 24.7%, p = 0.075). K64 with varying sequence types were predominantly seen among invasive K. pneumoniae (8 vs. 3) and were isolated from sepsis and meningitis patients. Among K64 isolates, one was carbapenem-resistant with ST799. Conclusion: Our study confirms that capsule type K64 K. pneumoniae is associated with community-acquired invasive infections in Vietnam. Research is needed to unravel the mechanisms of virulence of capsule type K64 in both community and hospital settings.", "keywords": [ "Klebsiella pneumoniae", "K64", "capsule type", "community-acquired infections", "carbapenem-resistant" ], "content": "Introduction\n\nIn low and middle-income countries in Asia, like Vietnam, Klebsiella pneumoniae is an important cause of severe community-acquired infections, including pneumonia, liver abscesses and sepsis.1 Multidrug-resistance in K. pneumoniae, especially among hospital acquired infections, is an emerging problem associated with high morbidity and mortality.2 A genomic analysis of diversity and population structure of 288 human and animal K. pneumoniae isolates from six countries, spanning four continents, has shown that K64 mostly found in Vietnam (n = 3) and Singapore (n = 1), was among the important capsule types associated with community acquired pneumonia.3 In addition to cases and outbreaks reported on severe K. pneumoniae infections by K64 with the convergence of carbapenem-resistant phenotypes,4 in one case report, K64-ST1764 K. pneumoniae was found to be a cause of pyogenic liver abscess and endogenous endophthalmitis. K. pneumoniae can asymptomatically colonize the gastrointestinal (proportion between 40% to 66%)5 and upper respiratory tract of healthy humans (14.1%)6 but K64 capsular have rarely been described in healthy carriers. Here, we found K64-K. pneumoniae to be more common among invasive isolates as compared to commensal isolates isolated from Vietnamese individuals.\n\n\nMethods\n\n302 K. pneumoniae were isolated from patients hospitalized at the National Hospital of Tropical Diseases from 2007 to 2011. Ninety-three were isolated from otherwise sterile sites, including blood (n = 70), cerebrospinal fluid (CSF) (n = 7), and pus (n = 16). These were re-cultured and re-confirmed using biochemical test strips (API 20E, Biomérieux, Marcy l’Étoile, France). Antibiotic susceptibility testing (AST) using disk diffusion was done according to Clinical and Laboratory Standards Institute (CLSI) guidelines 2019. To compare invasive with commensal isolates, we used randomization tools (https://www.randomizer.org/) to select 110 of 331 K. pneumoniae isolates from throat swabs of healthy volunteers living in rural (Bavi) and urban (DongDa district), Hanoi in 2012. The epidemiology of these healthy volunteers has been described in our previous study which was designed to investigate K. pneumoniae oropharyngeal carriage and rick factors in Vietnam.6 Commensal isolates were tested and analysed in the same manner as invasive isolates.\n\nInvasive and commensal isolates were tested to identify their capsule types (for capsule types K1, K2, K5, K20, K54, K57, and K64) by polymerase chain reaction (PCR) according to previously described methods.7,8 A specific K64 PCR was developed to detect capsule type K64 that was reported to be common in Southeast Asia3 with the following primers: Forward (5′TTC TTT AAG TCT TCT GGG TAT CA3′) and Reverse (5′AGT CTT TAA TCG CCT TCT3′). The PCR cycling program for K64 consisted of 95°C for 15 min, followed by 30 cycles of 95 °C for 30 sec, 60 °C for 30 sec, 72 °C for 1 min 20 sec and the final elongation step was performed for 7 min at 72 °C. The PCR products were loaded on agarose (1.5%) gel electrophoresis. Samples contained PCR products with size equivalent to 782 bp as K64 positive.\n\nMulti-locus sequence typing (MLST) was performed by sequencing the PCR products of seven house-keeping genes including (gapA, infB, mdh, pgi, phoE, rpoB, tonB). The sequence of these genes was analysed using the BIGSdb-Pasteur website (https://bigsdb.pasteur.fr/) for determining the sequence types. Sequence types (STs) were grouped into clonal complexes (CC) as described previously.9 A clonal complex is defined as a group of STs with at least 6 identical alleles with at least one other member of the group. STs that did not fall within a CC were defined as singletons.\n\nWe used Statistical Package of Social Sciences (SPSS) version 25 (IBM corporation, Armonk (NY), USA) for analysis,10 p values < 0.05 were considered significant (2-sided).\n\nThis study was approved by the Oxford University Tropical Research Ethics Committee (Oxtrec, 49-12) and the National Hospital for Tropical Diseases Institutional Review Board. Before participation, written informed consent from subjects or, in case of minors, their caregivers, was obtained on a standard study consent form.\n\n\nResults\n\nAmong 203 K. pneumoniae isolates, 100 (49.2%) were positive with one of the seven tested capsule (K) types (K1, K2, K5, K20, K54, K57, K64). The most common K types were K1 (n = 39) and K2 (n = 31). Whereas 36/39 (92.3%) K1 isolates belonged to STs that were classified into clonal complex, CC23, K2 isolates were more diverse: the most frequent clonal complex was CC65 (n = 18), followed by CC86 (n = 8) (Table 1). While K2 isolates were more prevalent among invasive than among commensal isolates (22.6% vs 9%, Chi-square, p = 0.01), K1 was relatively equally distributed (14.5% vs 24.7%, p = 0.075), and K57 (n = 18) was detected mostly among commensal isolates (15.4% vs 1%, p < 0.0001). We detected seven isolates with K64, five of which were invasive (p < 0.001). Among five invasive K64 K. pneumoniae, two were isolated from sepsis patients, one from meningitis, one from sepsis-meningitis, and one from the blood of a patient with hospital-acquired pneumonia. Most of these invasive K64 isolates (4/5) were from patients on Intensive Care Units (ICU). Of those patients, two had fatal community acquired pneumonia. The seven K64 isolates (two from commensal, five from invasive isolates) were genotyped by MLST: four belonged to the CC231 (ST231, ST799, ST807) and the other to CC65 (ST692).\n\nOverall, antimicrobial resistant proportions of commensal isolates differed significantly from invasive K. pneumoniae (Table 2). Among K64 isolates, one invasive ST799 isolate from a patient with hospital-acquired pneumonia was multi-drug resistant, with resistance to imipenem, ciprofloxacin, trimethoprim/sulfamethoxazole, piperacillin-tazobactam and gentamicin. Of the remaining K64 isolates, four invasive isolates were non-carbapenem resistant but they either were resistant to trimethoprim/sulfamethoxazole or piperacillin-tazobactam. Whilst, the two commensal isolates with ST1331 and ST1347, were susceptible to all tested antibiotics.11\n\n\nDiscussion and conclusion\n\nIn addition to the emergence of carbapenem-resistant K. pneumoniae worldwide, previous studies have shown that infections caused by hypervirulent carbapenem susceptible K. pneumoniae can also be considered a threat to public health.12 Our study showed that besides capsule type K2, capsule type K64 was overrepresented among invasive strains (5.4% vs 1.8%, Chi-square, p < 0.001), consistent with previous studies.3,13\n\nThe capsular type K64 has been little reported so far, but some reports show simultaneous possession of carbapenem-resistance genes, which poses a treatment challenge.14 ST11-K64 is a common type in China, possibly leading to pyogenic liver abscesses.15 Contrarily, our K64 strains were mainly found in sepsis and meningitis patients with varying STs, including: ST231, ST692, ST799, and ST807. Moreover, it is worth noting that K64 has been common in Klebsiella pneumoniae carbapenemase (KPC) producing ST11 strains in China, and the shift from K47 to K64 has been associated with increased virulence in this strain.16 In our study, the carbapenem-resistant K64-ST799 was isolated from the blood of a hospital-acquired patient in 2011, and was not detected in subsequent years in surveillance efforts.17 Likely, the K64-ST799 strain might have acquired a mobile element carrying a carbapenemase-producing gene.\n\nIn particular, K64 has been recently recognized as a capsular type potentially associated with hypervirulence and invasive disease. Indeed, the presence of K64 with several STs isolated from bacteraemia and meningitis patients in Vietnam and a pyogenic liver abscess patient in China18 provides further evidence that strains with this capsule type are virulent.19\n\nThe present study has several limitations. Because of the retrospective nature of the analyzed data collection, we missed some clinical data (exposures, alcohol history, out come after treatment) of the patients. The results of this study lack evidence to support the hypothesis that the risk factor of infections may be K. pneumoniae colonizers. In addition, we lack the whole genome sequence data of these K64 isolates for further understanding the molecular basis of hypervirulence. However, our results confirm that K64 is associated with severe invasive community acquired K. pneumoniae infections, including sepsis and meningitis. Further studies are needed to unravel the mechanisms of virulence by capsule type K64 in K. pneumoniae.\n\n\nData availability\n\nDryad: Klebsiella pneumoniae with capsule type K64 is overrepresented among invasive disease in Vietnam. https://doi.org/10.5061/dryad.h44j0zpjv11\n\n• Table 1 (Kp_All_AST) provides the detailed information of 203 Klebsiella pneumoniae isolates including source of isolates, date of collection, antibiotic susceptibility profiles, K-serotypes and MLST profiles.\n\n• Serotype_Clinical isolates.rar and Serotype_Community isolates.rar: These folders contain the photographs of the PCR products of agarose gel electrophoresis. Maps of samples on agarose plates are described in two Excel files (Electrophoresis_map.xlsx and Isolate ID on Electrophoresis.gel.xlsx for Clinical isolates and Commensal isolates, respectively).\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nConsent\n\nBefore participation, written informed consent from subjects or, in case of minors, their caregivers, was obtained on a standard study consent form.", "appendix": "References\n\nPeto L, Nadjm B, Horby P, et al.: The bacterial aetiology of adult community-acquired pneumonia in Asia: a systematic review. Trans R Soc Trop Med Hyg. 2014 Jun; 108(6): 326–37. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCillóniz C, Dominedò C, Torres A: Multidrug Resistant Gram-Negative Bacteria in Community-Acquired Pneumonia. Critical Care. 2019 2019/03/09; 23(1): 79. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHolt KE, Wertheim H, Zadoks RN, et al.: Genomic analysis of diversity, population structure, virulence, and antimicrobial resistance in Klebsiella pneumoniae, an urgent threat to public health. Proc Natl Acad Sci U S A. 2015; 112(27): E3574–E81. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nZhang X, Ouyang J, He W, et al.: Co-occurrence of Rapid Gene Gain and Loss in an Interhospital Outbreak of Carbapenem-Resistant Hypervirulent ST11-K64 Klebsiella pneumoniae. Front Microbiol. 2020; 11: 579618. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHuynh BT, Passet V, Rakotondrasoa A, et al.: Klebsiella pneumoniae carriage in low-income countries: antimicrobial resistance, genomic diversity and risk factors.2020 Sep 2; 11(5): 1287–99. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nDao TT, Liebenthal D, Tran TK, et al.: Klebsiella pneumoniae Oropharyngeal Carriage in Rural and Urban Vietnam and the Effect of Alcohol Consumption. PloS one. 2014; 9(3): e91999. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nYeh KM, Lin JC, Yin FY, et al.: Revisiting the importance of virulence determinant magA and its surrounding genes in Klebsiella pneumoniae causing pyogenic liver abscesses: exact role in serotype K1 capsule formation. J Infect Dis. 2010 Apr 15; 201(8): 1259–67. PubMed Abstract \| Publisher Full Text\n\nPan Y-J, Lin T-L, Chen Y-H, et al.: Capsular Types of Klebsiella pneumoniae Revisited by wzc Sequencing. PloS one. 2013; 8(12): e80670. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nDiancourt L, Passet V, Verhoef J, et al.: Multilocus Sequence Typing of Klebsiella pneumoniae Nosocomial Isolates. J Clin Microbiol. 2005; 43(8): 4178–82. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nIBM SPSS Statistics for Windows: Version 25.0. ed.Armonk, NY: IBM Corp; 2017.\n\nBich VTN: Supplementary of: “Klebsiella pneumoniae with capsule type K64 is overrepresented among invasive disease in Vietnam.” DRYAD Dataset. 2021. Publisher Full Text\n\nChoby JE, Howard-Anderson J, Weiss DS: Hypervirulent Klebsiella pneumoniae - clinical and molecular perspectives.2020 Mar; 287(3): 283–300. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nYeh K-M, Kurup A, Siu LK, et al.: Capsular serotype K1 or K2, rather than magA and rmpA, is a major virulence determinant for Klebsiella pneumoniae liver abscess in Singapore and Taiwan. J Clin Microbiol. 2007 2007/02//; 45(2): 466–71. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nYang Q, Jia X, Zhou M, et al.: Emergence of ST11-K47 and ST11-K64 hypervirulent carbapenem-resistant Klebsiella pneumoniae in bacterial liver abscesses from China: a molecular, biological, and epidemiological study. Emerg Microbes Infect. 2020; 9(1): 320–31. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nZhang Y, Jin L, Ouyang P, et al.: Evolution of hypervirulence in carbapenem-resistant Klebsiella pneumoniae in China: a multicentre, molecular epidemiological analysis. J Antimicrob Chemother. 2020 Feb 1; 75(2): 327–36. PubMed Abstract \| Publisher Full Text\n\nZhou K, Xiao T, David S, et al.: Novel Subclone of Carbapenem-Resistant Klebsiella pneumoniae Sequence Type 11 with Enhanced Virulence and Transmissibility, China. Emerg Infect Dis. 2020 Feb; 26(2): 289–97. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWyres KL, Nguyen TNT, Lam MMC, et al.: Genomic surveillance for hypervirulence and multi-drug resistance in invasive Klebsiella pneumoniae from South and Southeast Asia. Genome Med. 2020 2020/01/16; 12(1): 11. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nZhao B, Hu R, Gong L, et al.: Pyogenic Liver Abscess and Endogenous Endophthalmitis Due to K64-ST1764 Hypervirulent Klebsiella pneumoniae: A Case Report. Infect Drug Resist. 2021; 14: 71–7. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMarr CM, Russo TA: Hypervirulent Klebsiella pneumoniae: a new public health threat. Expert Rev Anti Infect Ther. 2019 Feb; 17(2): 71–3. PubMed Abstract \| Publisher Full Text \| Free Full Text" }	[ { "id": "93803", "date": "12 Oct 2021", "name": "John L. Kiley", "expertise": [ "Reviewer Expertise Multi drug resistant Gram-negative infections" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper describes the epidemiology of K64 Klebsiella pneumoniae isolates with a particular focus on K64 from a hospital in Vietnam.\nIntroduction\n\"...but K64 capsular have rarely been described in healthy carriers.\" in the introductory paragraph reads a bit unclearly.\n\nAdding a bit more about the importance of K64 and the differences between classic and hypervirulent types of Klebsiella spp. (as well as how capsules might play a role in this) would better situate the authors' opening argument as to why they are performing this current study.\n\nMethods\n\"302 K. pneumoniae were isolated...\" are these all isolates from the hospital during this time period?\nResults\nI note that ESBL production was determined in Table 2 - please clarify how you determined this in the methods.\nDiscussion and conclusion\nI think some discussion about the small numbers of K64 isolates would also be helpful in the limitations of the paper. The second paragraph starts off by suggesting K64 has \"been little reported so far,\" but I think the data from China would argue against this.\n\nZhang et al., 2020 reported Chinese epidemiological data on K641.\n\nWalker et al., 2020 for general discussion of hypervirulence and association with capsular type2.\n\nCatalán-Nájera et al., 2017 for hypermucoviscious, hypervirulent differences/discussion3.\n\nGreat paper overall!\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Yes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13076", "date": "17 Jan 2025", "name": "Bich Vu Thi Ngoc", "role": "Author Response", "response": "We would like to thank reviewer for your valuable comments. We have addressed all the reviewers’ comments in the revised manuscript, including with additional information, and responded in the point-to-point rebuttal below. We hope our revisions are adequate and make our manuscript clear and publishable. Reviewer 1 This paper describes the epidemiology of K64 Klebsiella pneumoniae isolates with a particular focus on K64 from a hospital in Vietnam. Comment 1: Introduction \"...but K64 capsular have rarely been described in healthy carriers.\" in the introductory paragraph reads a bit unclearly. Response: Thank you very much for your comment. We have now revised the sentence in the updated version as below: “…but carriage of K64 K. pneumoniae in healthy persons has rarely been described.” Comment 2: Adding a bit more about the importance of K64 and the differences between classic and hypervirulent types of Klebsiella spp. (as well as how capsules might play a role in this) would better situate the authors' opening argument as to why they are performing this current study. Response: Thank you very much for your recommendation. We have now included the following sentences in the introduction of the manuscript: K pneumoniae is classified across two main virulence phenotypes, classical (cKp) and hypervirulent (hvKp). Most K. pneumoniae are associated with uncomplicated community acquired infections and nocosomial infections. However, hvKp results in more severe community – acquired infections with manifestations such as pyogenic liver abscess, meningitis, endophthalmitis, and necrotizing fasciitis. The polysaccharide capsule is perhaps the most well-known virulence factor of K. pneumoniae, including for the hvKp phenotype. The capsule surrounding K. pneumoniae cells can be divided into at least 79 capsular types (K1 to K79), among which K1, K2, and K64 are common serotypes of the MDR-hvKp group, which is commonly found in Asia. Comment 3: Methods \"302 K. pneumoniae were isolated...\" are these all isolates from the hospital during this time period? Response: Thank you very much for your question. The total number of isolates from the hospital during this time was 589 isolates; however, because this was a retrospective study, we performed re-culture, and 332/589 isolates were recovered. Of those, 30 isolates had no associated clinical metadata, and were excluded from the study. We now have clarified this in the manuscript as below: “From a total of 589 K. pneumoniae that were isolated from patients hospitalized at the National Hospital of Tropical Diseases between 2007 and 2011, 332 isolates were recovered after re-cultivation. Of those, 30 isolates with lacking clinical metadata were excluded, leaving the remaining 302 isolates for downstream analysis.” Comment 4: Results I note that ESBL production was determined in Table 2 - please clarify how you determined this in the methods. Response: Thank you very much for your comment. We have added the information into the updated version as below: “A phenotypic confirmatory double-disk test was performed for confirmation of ESBL production using CTX (30 mg) and CAZ (30 mg) disks alone and in combination with CA (10 mg) (Mast Diagnostic a GmbH, Reinfeld, Germany).” Comment 5: Discussion and conclusion I think some discussion about the small numbers of K64 isolates would also be helpful in the limitations of the paper. The second paragraph starts off by suggesting K64 has \"been little reported so far,\" but I think the data from China would argue against this. Response: Thank you for your recommendation. We agree that data from China would argue against our statement in the second paragraph starts off by suggesting K64 has \"been little reported so far,\". We now have revised the sentence as below: “The capsular type K64 has been reported worldwide, especially from clinical settings in Asia, Europe, and North America and is one of the K types associated with hypervirulent strains, that have shown simultaneous expression of virulence and carbapenem-resistance genes, posing a treatment challenge.” Regarding the small numbers of K64 isolates in our study, we have added into the limitation: “In this study, the relatively small number of K64 isolates provided only limited data about the serotype's convergent virulence and carbapenem resistance. Also, we lack the whole genome sequence data of these K64 isolates for further understanding of the molecular basis of hypervirulence and the phylogenetic positioning of this rare ST within the genomic taxonomy of K. pneumoniae. However, our results led support to the hypothesis that K64 is associated with severe invasive community acquired K. pneumoniae infections, including sepsis and meningitis. In addition, here, only seven capsule types were selected to investigate the diversity of K. pneumoniae isolates. We recognize that this is one of the limitations of our study. Further studies are needed to unravel the mechanisms of virulence of capsule type K64 in K. pneumoniae.”" } ] }, { "id": "287539", "date": "28 Jun 2024", "name": "Frank R. DeLeo", "expertise": [ "Reviewer Expertise Bacterial pathogenesis and host defense. Primary focus on Staphylococcus aureus", "Klebsiella pneumoniae", "and human neutrophil biology." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nNgoc et al. report capsule type and multilocus sequence type of Klebsiella pneumoniae clinical isolates from patients hospitalized at National Hospital for Tropical Diseases in Hanoi from 2007 to 2011. The authors compared these isolates to commensal isolates obtained by throat swab from healthy volunteers in 2012. The study is interesting and adds to our understanding of the distribution of the K. pneumoniae capsule types associated with human infections. I have a few comments for the authors to consider.\nPlease verify numbers of isolates in Table 1 compared with what is stated in the text. By my count, there are 110 commensal isolates (correct in the text) and 94 (stated as 93 in the text) invasive isolates. These numbers are concordant with the sum of the numbers in the Overall column, which total 204 isolates (the text indicates 203). Please verify for accuracy. It would be optimal to provide text in the Table 1 legend that states what the p-value refers to from a comparison standpoint, and indicate the test used here as well. I recommend providing the rationale for selecting the seven capsule types used to screen isolates in this study. Why were these seven capsule types chosen among others? A conclusion of the study is that “capsule type K64 is overrepresented among invasive strains”. In reality there are only seven K64 isolates out of 204 total isolates and only five of these were from invasive disease. This is 5.4% of the total number of invasive isolates and much less than either K1 or K2. In addition, the Conclusion text on the title page states that K64 K. pneumoniae is associated with community-acquired invasive infections in Vietnam.” Please provide the criteria in the Methods section that were used to determine whether an infection is a bona fide community-acquired infection. It would be fair to state that K64 contributes to invasive disease and is among the top three capsule types tested that are associated with invasive infections. However, the term “overrepresented among invasive strains” might best be restated as “there were significantly more capsule type K64 isolates recovered from patients with invasive infections compared to healthy individuals with commensal isolates” or something along those lines.\nMinor points.\n\nIntroduction: “A genomic analysis of diversity and population structure of 288 human and animal K. pneumoniae isolates from six countries, spanning four continents, has shown that K64 mostly found in Vietnam (n = 3) and Singapore (n = 1), was among the important capsule types associated with community acquired pneumonia.” is not easy to read.\nConsider revising to: “A genomic analysis of diversity and population structure of 288 human and animal K. pneumoniae isolates from six countries, spanning four continents, has shown that K64 was among the important capsule types associated with community acquired pneumonia in Vietnam (n = 3) and Singapore (n = 1).”\nIntroduction, penultimate sentence: change K64 capsular to K64 capsule types\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [] } ]	1	https://f1000research.com/articles/10-454
https://f1000research.com/articles/13-1270/v1	24 Oct 24	{ "type": "Clinical Practice Article", "title": "Autoimmune liver disease revealed by Tuberculosis treatment: report of two cases and literature review", "authors": [ "Ramzi Tababi", "Hela Kchir", "Habiba Debbabi", "Ahmed Nefzi", "Haythem Yacoub", "Dhouha Cherif", "Hajer Hassine", "Khadija Bellil", "Slim Haouet", "Nadia Maamouri", "Hela Kchir", "Habiba Debbabi", "Ahmed Nefzi", "Haythem Yacoub", "Dhouha Cherif", "Hajer Hassine", "Khadija Bellil", "Slim Haouet", "Nadia Maamouri" ], "abstract": "Abstract This article presents two patients who were diagnosed with autoimmune liver disease (autoimmune hepatitis and primary biliary cholangitis overlap syndrome) during anti-tuberculosis therapy, which is a rarely reported occurrence. It highlights the challenges in distinguishing drug-induced liver injury from authentic autoimmune liver disease. It also points out the importance of considering autoimmune liver disease as a potential diagnosis revealed by the setting of drug-induced liver injury.", "keywords": [ "Tuberculosis", "Drug-induced Liver Injury", "Autoimmune Hepatitis", "Primary Biliary Cholangitis", "Overlap Syndrome" ], "content": "Introduction\n\nTuberculosis (TB) remains a significant public health challenge in numerous countries worldwide, raising concerns about the potential risks associated with anti-TB drugs. Specifically, these drugs have been implicated in drug-induced liver injury (DILI) with a reported incidence ranging from 2% to 28%.1 DILI can manifest as mild liver enzyme elevation to life-threatening liver failure, commonly resulting from an idiosyncratic reaction involving either metabolic or immune-mediated mechanisms.2\n\nMoreover, DILI with autoimmune features often presents diagnostic complexities, particularly when distinguishing it from autoimmune liver diseases (ALD) such as autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). In this article, we present two compelling instances of ALD, specifically the AIH-PBC overlap syndrome, which were unveiled during TB therapy. In addition, we conducted a review of the literature, seeking insights into the intricate relationship between TB treatment and ALD.\n\n\nCase 1\n\nA 49-year-old Caucasian woman, with atopic background, was diagnosed with abdominal lymph node and peritoneal tuberculosis (TB). She was started on first-line anti-TB therapy with Isoniazid (INH), Rifampicin (RIF), Pyrazinamide (PZA) and Ethambutol (EMB) following normal pre-treatment liver function tests (LFTs).\n\nA month after starting the treatment, the patient presented with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome attributed to EMB. DRESS syndrome was diagnosed based on a pruritic macular-papular skin rash, fever, eosinophilia (3100/mm3), immunoallergic leukocytoclastic skin vasculitis, and significantly elevated liver enzymes including Aspartate Aminotransferase (AST) at 7 to 9 times the upper limit of normal (ULN), Alanine Aminotransferase (ALT) at 3 to 4 xULN, Alkaline Phosphatase (ALP) at 2.6 xULN, and Gamma Glutamyl Transferase (GGT) at 7 xULN, with normal bilirubin levels (BIL). Anti-TB drugs were suspended, and DRESS syndrome resolved within a month, allowing for the restart of a modified treatment regimen, replacing EMB with a fluoroquinolone: Levofloxacin (LFX) with INH-RIF-PZA during 2 months followed by 6 months of INH-RIF.\n\nHowever, by the 8th month of anti-TB treatment (INH-RIF), the patient exhibited clinical signs of acute hepatocellular injury, presenting with jaundice and significantly elevated levels of AST (18xULN), ALT (10xULN), ALP (1.3xULN), GGT (3xULN), and BIL (12 mg/dl) predominantly conjugated bilirubin (CBIL: 9 mg/dl), with normal factor V levels (84%). There were no clinical or biological signs of hypersensitivity, and abdominal ultrasound (US) showed no abnormalities.\n\nAetiological investigation for liver injury ruled out a viral hepatitis A, B and C, as well as HIV infection (negative anti-HAV IgM, negative HBsAg, positive anti-HBc, negative DNA-HBV, negative anti-HVC and negative HIV serology). Meanwhile, immunological assessment revealed positivity for anti-nuclear antibody (ANA) with a titre of 1/400, anti-Smooth Muscle Antibody (ASMA), anti-Mitochondrial M2 antibody (AMA-M2) and anti-gp210 antibody. The rest of the Liverdot was negative (anti-sp100, anti-LKM1, anti-LC1, anti-SLA/LP). Additionally, the patient had mild hypergammaglobulinaemia (1750 mg/dl) with normal levels of IgA, IgM, and IgG.\n\nBased on these findings and the pharmacovigilance survey, the diagnosis of drug-induced liver injury (DILI) with auto-immune features was considered, leading to the indefinite discontinuation of anti-TB drugs, especially considering that TB was declared cured.\n\nAt follow-up, LFTs returned to normal levels within 2 months. However, the patient complained of persistent right upper quadrant abdominal discomfort without pruritus or fatigue. Immunological assessment at 3 months showed the same previous findings with an increased ANA titre of 1/800. Abdominal ultrasound at 6 months revealed a dysmorphic liver with surface irregularity, right lobe hypotrophy, and left lobe hypertrophy, but no signs of portal hypertension or impaired liver function. Transient elastography using Fibroscan® revealed a median liver elasticity of 12.2 kPa. Subsequently, a liver biopsy was performed for diagnostic and prognostic purposes, which demonstrated septal fibrosis, interface hepatitis (Figure 1), hepatic rosette formation, and non-suppurative destructive lymphocytic cholangitis (florid duct lesions).\n\nHematoxylin and eosin staining showing in (A), on x100 magnification, a portal tract enlarged with fibrosis along with fibrous bands separating clusters of hepatocytes with an annular tendency. This fibrosis contains lymphoplasmacytic and polymorphic inflammatory infiltrate disrupting the limiting plate and extending to periportal hepatocytes, resulting in interface hepatitis (arrows). Ballooned hepatocytes are also visible (*). Lobular inflammatory infiltrate with necrosis (#) is also noted in (B) and in x200 magnification (C).\n\nThese histological features aligned with an overlap syndrome involving AIH and PBC. Accordingly, the patient was started on ursodeoxycholic acid (UDCA) 15 mg/kg/day and azathioprine 1.2 mg/kg/day with good treatment adherence and tolerability. Given that LFTs were normal, no corticosteroids were prescribed, and LFTs remained normal during a 7-month follow-up period.\n\n\nCase 2\n\nA 64-year-old Caucasian man with no prior medical history was diagnosed with pulmonary TB following a positive sputum polymerase chain reaction result. Pre-treatment LFTs showed AST levels at 1.5 xULN with normal levels of ALT, ALP, GGT, and BIL. He received initial anti-TB therapy (INH, RIF, PZA, and EMB) for two months. At the end of this period, the patient developed jaundice due to acute hepatitis, with levels of AST at 15 xULN, ALT at 4 xULN, ALP at 1.6 xULN, GGT at 5 xULN, BIL at 2 mg/dl, and prothrombin time (PT) at 51%. The treatment was consequently discontinued. However, an acute liver injury (ALI) was settled, as indicated by the decline in PT to 46% alongside hypertransaminasemia worsening (AST at 22 xULN, ALT at 8 xULN) and a rise in BIL levels to 3 mg/dl.\n\nAn aetiological investigation revealed active hepatitis B (positive AgHBs, negative AgHBe, and a viral load of 8,000,000 IU/ml). Alcohol intake and other viral hepatitis were excluded (negative IgM HAV, negative IgM HEV, negative anti-HCV, negative HIV serology, and previous immunity to EBV, CMV, and HSV 1 and 2). The patient was started on entecavir 0.5 mg/d. Disease assessment showed a dysmorphic liver on ultrasound with irregular contours and the presence of oesophageal varices on endoscopy.\n\nWithin one week of initiating entecavir, LFTs continued to worsen, with AST reaching 26 xULN, ALT reaching 9 xULN, BIL increasing to 3.5 mg/dl, and PT dropping to 30%. Further immunological assays showed positive ANA at 1/100 and ASMA at 1/100. Other liver-related autoantibodies were negative. The diagnosis of drug-induced autoimmune liver disease was suspected, and the patient was started on oral corticosteroids (prednisolone 30 mg/d) following negative sputum bacilloscopy tests and an expert opinion.\n\nIn 3 weeks, LFTs significantly improved (AST at 5 xULN, ALT at 2 xULN, BIL at 2 mg/dl, and PT at 48%), with persistent cholestasis (ALP at 1.6 xULN, GGT at 5 xULN). A liver biopsy revealed portal and periportal extensive fibrosis with regenerative nodules, lymphoplasmocytic infiltrate in the portal tract extending into the lobule with hepatic rosette formation, and a marked interface hepatitis. Florid bile duct lesions with evident ductopenia were also observed. Several ground glass hepatocytes and central ballooning degeneration were found, attesting to active hepatitis B infection.\n\nIn summary, coupled with other findings, pathology results provided evidence of chronic liver disease at cirrhosis stage with severe activity (A3-F4 according to Metavir score) due to an AIH-PBC overlap syndrome, along with viral hepatitis B. Accordingly, the patient was kept on entecavir and corticosteroids, and UDCA was started at a 15 mg/kg/d.\n\nLFTs continuously improved within two months. Nevertheless, expert opinion recommended no anti-TB restart until the total normalisation of liver enzymes, given that TB symptoms and radiographic lesions had considerably recovered. Immunosuppressive therapy was allowed at that point.\n\nTherefore, the patient was started on azathioprine (50 mg/d, then 100 mg/d) alongside tapering corticosteroids (5 mg/3 weeks), with good compliance and tolerability to the treatment. After six months, biological findings showed complete normalisation of LFTs, and the viral load of HBV was 40 IU/ml.\n\n\nDiscussion\n\nThough the manifestation of AIH-PBC overlap syndrome during anti-TB treatment is uncommon, drug-induced autoimmune liver disease (DIALD), which encompasses various combinations of AIH and DILI, has been increasingly studied. DIALD can be classified into three main types3 (Table 1). First, AIH with DILI includes patients already diagnosed with AIH, who reactivate their quiescent disease upon the introduction of a new drug, often with advanced fibrosis. Second, drug-induced AIH (DI-AIH) involves patients with undiagnosed low-grade disease or genetically predisposed to develop AIH, where the drug generates an immune reaction sustaining AIH, leading to chronic inflammation and requiring continuous immunosuppressive therapy. DI-AIH patients usually carry typical HLA-DR haplotypes associated with AIH. The third type is immune-mediated DILI (IM-DILI), where the drug triggers an adverse immune reaction with hypersensitivity. The liver injury in IM-DILI can be acute or chronic, and it may resolve or remain quiescent after drug cessation. IM-DILI is the most common DIALD type and is also referred to as drug-induced AIH-like injury. It often resembles idiopathic AIH, showing a complete response to corticosteroid treatment, yet with no relapse.4–6\n\nThe immunopathogenesis of DILI with autoimmune features is not fully understood. It has been hypothesised that these idiosyncratic adverse events involve reactive drug metabolites, primarily produced by CYP450, which bind covalently to this enzyme, forming neoantigens that activate humoral and cellular immune reactions, leading to liver injury.2,4\n\nDistinguishing classical AIH from DIALD is challenging as no specific feature is exclusive to either entity. Certain characteristics favour drug-induced AIH-like liver injury, including the presence of hypersensitivity features (in up to 30% of cases), absence of advanced fibrosis or cirrhosis at presentation, and no relapse after steroids discontinuation.4–6\n\nAs both conditions can share similar clinical, biochemical, and serological patterns, histological findings may not always be helpful in distinguishing between the two diagnoses. Nevertheless, Suzuki et al.7 found that certain features such as portal and intra-acinar plasma cells, rosette formation, and emperipolesis, along with more severe histological inflammation scores (Ishak score), supported the diagnosis of AIH. On the other hand, portal neutrophils and intracellular cholestasis were more prevalent in DILI. However, interface hepatitis, emperipolesis, and rosette formation were also present in 89%, 34%, and 40% of DILI cases, respectively.\n\nRecently, Lammert et al.8 suggested that autoantibody profiling could be a promising and useful tool to distinguish idiopathic AIH and DILI with AIH-like phenotype. Among 65 patients with autoimmune phenotype DILI and 17 patients with de novo AIH, they found that the former group had elevated IgM (55%) but not IgG autoantibodies, whereas the latter group had elevated IgG (46%) and IgM (70%) autoantibodies, theorising the unique IgG autoantibodies signature in authentic AIH. Based on this, they developed a model incorporating IgG autoantibodies directed against centromere protein B, myosin, mitochondrial antigen, and nucleosome antigen, which accurately predicted de novo AIH, distinguishing it from autoimmune DILI, with an area under the receiver operating characteristic (ROC) curve of 0.88.\n\nA study by Björnsson et al.9 included 216 patients with AIH, of which 9.2% were drug-induced, and both groups showed similar clinical and histological characteristics. Notably, overlap syndromes with PBC were excluded from this study. They found that nitrofurantoin and minocycline accounted for more than 90% of the drug-induced AIH cases.\n\nAnti-TB drugs are the leading cause of DILI in India and China, given the prevalence of TB in these countries.10,11 The reported incidence of DILI due to anti-TB drugs varies between 2% and 28%.1 Isoniazid, pyrazinamide, and rifampicin are recognised as potentially hepatotoxic drugs. Isoniazid, in particular, is notorious for causing hepatocellular injury and has been incriminated in some cases of idiosyncratic DILI. It ranks second among antimicrobials responsible for DILI (11.7%) in the United States DILI Network registry12 and is considered to have a probable association with liver injuries resembling AIH.5 Previous literature has reported cases of DILI with autoimmune features due to anti-TB treatment.13,14\n\nCertain risk factors have been suggested to predict DILI, including age, female gender, malnutrition, alcohol intake, and pre-existing liver disease.12 Slow acetylator status and specific genetic polymorphisms have also been associated with DILI occurrence due to isoniazid.2,15,16 Additionally, polymorphisms of drug-metabolising enzymes, mainly CYP, and major histocompatibility complex (MHC) are plausible genetic factors for autoimmune DILI susceptibility.2,4\n\nAn interesting study conducted by Lucena et al.17 reported that 9 out of 742 patients experienced a second episode of DILI caused by a different offending agent than the first one. Among these 9 patients, four had a presentation of AIH. The authors concluded that recurrent DILI is likely to be associated with autoimmune features. However, the mystery remains unresolved whether the episode was a DILI unmasking an authentic AIH or an IM-DILI.\n\nImmune-mediated hepatotoxicity can also present with a cholestatic phenotype, characterised by small bile duct injury. This type of DILI is more common in elderly patients and typically exhibits delayed recovery and a tendency to become chronic even after drug withdrawal.4,12,15 In some cases, it may progress to ductopenia, known as vanishing bile duct syndrome (VBDS), and biliary cirrhosis. This DILI phenotype is well established with amoxicillin-clavulanic acid association.4,12,15 Notably, chronic cholestatic hepatitis, or VBDS, has not been linked to anti-TB drugs (INH, RIF, PZA, EMB) according to LiverTox database.\n\nUltimately, both of our patients were diagnosed with overlap syndrome AIH-PBC, based on the Paris criteria, as recommended by guidelines.5,6 An undiagnosed quiescent AIH, unmasked by anti-TB treatment, appeared to be a more plausible explanation than a de novo IM-DILI. The presence of advanced fibrosis, characteristic histology findings, and the association with PBC support this conclusion. Furthermore, PBC is known for its progressive nature and slow onset. Additionally, the positivity of AMA-M2 and anti-gp210, as well as the presence of florid bile duct lesions, strongly suggest PBC and argue against a cholestatic DILI.\n\nIn cases of AIH-like DILI, the backbone of the treatment is cessation of the causative drugs and close monitoring of liver enzymes until recovery, which typically occurs within a month.5 Corticosteroid therapy should be initiated for severe hepatitis or if lab tests do not improve or worsen after drug withdrawal.5,6 Corticosteroids may also be prescribed for severe hypersensitivity reactions, DRESS syndrome, and when autoimmune features are observed on liver biopsy.15 Typically, glucocorticoids lead to a response with no relapse after discontinuation. Unlike authentic AIH, long-term immunosuppression is not required. Therefore, follow-up can help differentiate AIH and DILI.5,6 UDCA might be beneficial in cases of DILI with prolonged cholestasis.4,15\n\nIn the cases of our patients, both of them required immunosuppressive therapy, along with UDCA, given that they were diagnosed with AIH-PBC overlap syndrome. In the first case, discontinuation of anti-TB drugs led to resolution of liver injury without the need for corticosteroids. Instead, the decision to prescribe immunosuppressants was based on histological disease activity and advanced fibrosis. As for the second patient, the withdrawal of anti-TB drugs and the use of entecavir were not sufficient to induce remission of ALI until steroids were introduced. Subsequently, normalisation of cholestasis was slowly achieved with UDCA treatment.\n\nIn conclusion, our article emphasises the significance of monitoring for DILI during TB therapy. It also highlights the importance of considering ALD, despite overlapping features, which can make accurate diagnosis challenging. A comprehensive understanding of these entities, aided by histological findings, is essential for initiating appropriate treatment strategies.\n\n\nEthical approval\n\nEthical approval was not required for this study.\n\n\nConsent\n\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the patients.", "appendix": "Data availability\n\nNo data are associated with this article.\n\nZenodo Repository: CARE checklist for ‘Autoimmune Liver Disease Revealed by Tuberculosis Treatment: Report of Two Cases and Literature Review’. DOI: https://doi.org/10.5281/zenodo.13934956 . 18\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgements\n\nNo acknowledgments to declare.\n\n\nReferences\n\nWang N, Chen X, Hao Z, et al.: Incidence and Temporal Trend of Antituberculosis Drug-Induced Liver Injury: A Systematic Review and Meta-Analysis. J Trop Med. 2022; 2022: 1–10. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSoedarsono S, Riadi ARW: Tuberculosis Drug-Induced Liver Injury. J Respirasi. 2020; 6(2): 49–54. Publisher Full Text\n\nAgustin Castiella EZ, Andrade l J: Drug-induced autoimmune liver disease: A diagnostic dilemma of an increasingly reported disease. World J Hepatol. 2014; 6(4): 160–168. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLiu ZX, Kaplowitz N: Immune-mediated drug-induced liver disease. Clin Liver Dis. 2002; 6(3): 755–774. Publisher Full Text\n\nMack CL, Adams D, Assis DN, et al.: Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology. 2020; 72(2): 671–722. PubMed Abstract \| Publisher Full Text\n\nEASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol. 2015; 63(4): 971–1004. Publisher Full Text\n\nSuzuki A, Brunt EM, Kleiner DE, et al.: The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury. Hepatology. 2011; 54(3): 931–939. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLammert C, Zhu C, Lian Y, et al.: Exploratory Study of Autoantibody Profiling in Drug-Induced Liver Injury with an Autoimmune Phenotype. Hepatol Commun. 2020; 4(11): 1651–1663. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBjörnsson E, Talwalkar J, Treeprasertsuk S, et al.: Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatol Baltim Md. 2010; 51(6): 2040–2048. PubMed Abstract \| Publisher Full Text\n\nDevarbhavi H, Dierkhising R, Kremers WK, et al.: Single-Center Experience With Drug-Induced Liver Injury From India: Causes, Outcome, Prognosis, and Predictors of Mortality. Off J Am Coll Gastroenterol ACG. 2010; 105(11): 2396–2404. Publisher Full Text Reference Source\n\nZhou Y, Yang L, Liao Z, et al.: Epidemiology of drug-induced liver injury in China: a systematic analysis of the Chinese literature including 21 789 patients. Eur J Gastroenterol Hepatol. 2013; 25(7): 825–829. PubMed Abstract \| Publisher Full Text Reference Source\n\nSandhu N, Navarro V: Drug-Induced Liver Injury in GI Practice. Hepatol Commun. 2020; 4(5): 631–645. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMosqueira JR, Anicama S, Ríos JDL: A Severe Autoimmune-like Anti-Tuberculosis Drug-induced Liver Injury: Case Report and Review. J Microbiol Infect Dis. 2018; 08(03): 128–134. Publisher Full Text\n\nRangel MA, Pinto Pais I, Duarte R, et al.: Antituberculosis Drug-Induced Liver Injury with Autoimmune Features: Facing Diagnostic and Treatment Challenges. Case Rep Pediatr. 2017; 2017: 1–4. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nFontana RJ, Liou I, Reuben A, et al.: AASLD practice guidance on drug, herbal, and dietary supplement–induced liver injury. Hepatology. 2022; 77(n/a): 1036–1065. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMushiroda T, Yanai H, Yoshiyama T, et al.: Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients. Hum Genome Var. 2016; 3(1): 16014. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLucena MI, Kaplowitz N, Hallal H, et al.: Recurrent Drug-Induced Liver Injury (DILI) with different drugs in the Spanish Registry: The dilemma of the relationship to autoimmune hepatitis. J Hepatol. 2011; 55(4): 820–827. PubMed Abstract \| Publisher Full Text\n\nTababi R: CARE checklist for “Autoimmune Liver Disease Revealed by Tuberculosis Treatment: Report of Two Cases and Literature Review.” [Dataset]. Published online October 15, 2024. Publisher Full Text" }	[ { "id": "345335", "date": "16 Dec 2024", "name": "Rolf Teschke", "expertise": [], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper requires complete re-writing. Major points:\nIt seems that you are describing Drug induced autoimmune hepatitis (DIAIH), if this is correct, cases need two different diagnostic approaches. One for the DILI part, using the updated RUCAM of 2016, and one for the AIH part using the simplified AIH score of Hennes. Provide scores of both methods in the abstract and the text.\n\nThe focus should be on DIAIH diagnosis. This should be clarified in the title with details in the abstract and under keywords. Authors should discuss the importance of DIAIH and the need to evaluate this disorder characterized by disrupting drugs. Author should include in the discussion DIAIH cases by other drugs and should analyze how these published reports has been assessed for causality.\n\nIs the background of the cases’ history and progression described in sufficient detail? No\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the conclusion balanced and justified on the basis of the findings? Partly", "responses": [ { "c_id": "13069", "date": "17 Jan 2025", "name": "Ramzi Tababi", "role": "Author Response", "response": "Thank you for your valuable feedback. To clarify, the cases presented in our report describe genuine AIH-PBC overlap syndrome, which was only revealed upon the initiation of anti-TB drugs. While drug-induced autoimmune hepatitis (DIAIH) was initially considered as a differential diagnosis, it was ultimately ruled out based on the updated RUCAM scores for both cases, which indicated that DILI was unlikely. The final diagnosis of AIH-PBC overlap syndrome was made according to the \"Paris criteria\", as recommended by international guidelines, which are more appropriate for diagnosing overlap syndrome than the simplified or older AIH criteria. We have revised the manuscript to explicitly clarify these points, including the updated RUCAM scores (as per your recommendation) and the use of the \"Paris criteria\", to prevent any misunderstanding and provide a clearer understanding of our diagnostic approach and conclusions. In the discussion, we have provided a detailed explanation supporting our diagnosis, highlighting the presence of advanced fibrosis, characteristic histological findings, and the association with PBC, all of which reinforce our conclusion of AIH-PBC overlap syndrome, while also addressing the literature on autoimmune-phenotype DILI. To clarify once again, this report is not about drug-induced autoimmune hepatitis; rather, it describes true AIH-PBC overlap syndrome that was unmasked by the initiation of anti-TB drugs. That's why the title was also changed to convey the accurate focus of the manuscript." } ] } ]	1	https://f1000research.com/articles/13-1270
https://f1000research.com/articles/12-73/v1	18 Jan 23	{ "type": "Research Article", "title": "Factors associated with the use of rehabilitation services among people with disabilities in Chile: A population-based study", "authors": [ "Dania Silvia Paredes-Laguna", "William Romeo Calderón-Curiñaupa", "Sandra Liz Soto-Nuñez", "Adriana Berenice Espinoza-Hoempler", "J. Jhonnel Alarco", "Dania Silvia Paredes-Laguna", "William Romeo Calderón-Curiñaupa", "Sandra Liz Soto-Nuñez", "Adriana Berenice Espinoza-Hoempler" ], "abstract": "Background: Rehabilitation services are necessary for people with disabilities to improve their quality of life and be included in society. This study aimed to determine the factors associated with the use of rehabilitation services among people with disabilities in Chile in 2015. Methods: This cross-sectional analysis of secondary data from Chile’s 2015 Second National Disability Study (ENDISC II) included people with disabilities aged ≥18 years. The dependent variable was the use of rehabilitation services in the previous year, and the exposure variables were sociodemographic and confounders. Poisson regression was used to determine associated factors, and prevalence ratios (PR) with their 95% confidence intervals (95% CI) were estimated. All results were weighted according to the ENDISC II complex sampling. Results: A total of 2610 people with disabilities were included, and 19.1% used some rehabilitation services in the previous year. Educational level (PR 0.43; 95% CI 0.25–0.75), having a mental illness (PR 1.77; 95% CI 1.44–2.18), and caregiver assistance (PR 1.57; 95% CI 1.25–1.97) were factors associated with the use of rehabilitation services. Conclusions: In 2015, one-fifth of people with disabilities in Chile used some rehabilitation services in the previous year. People with disabilities with lower educational levels were less likely to access these services. By contrast, people with mental illness and caregiver assistance were more likely to use rehabilitation services.", "keywords": [ "rehabilitation research", "people with disabilities", "demographics", "caregivers", "Chile" ], "content": "Introduction\n\nApproximately 2.41 million people worldwide could benefit from rehabilitation services, which mean that one in three people will need this service at some point in their lives because of an illness or injury.1 Rehabilitation services were estimated to become more necessary as the population ages because of the increase in people with chronic diseases2 and the emergence of increasingly efficient medical treatments.3\n\nThe World Health Organization (WHO) defines rehabilitation as “a set of measures that help people who have or are likely to have a disability to achieve and maintain optimal functioning in interaction with their environment”.4 Recent definitions broaden its application beyond the clinical field, relating it to social, occupational, and educational interventions, independent of its location, i.e., it can be applied in hospitalized or ambulatory patients.5 Furthermore, rehabilitation aims to achieve independence, minimize pain and distress, and improve the ability to adapt and respond to circumstantial changes.6 For a person with disability, access to health services, including rehabilitation services, is essential to improve quality of life.7\n\nThe WHO indicates that approximately 15% of the world’s population has some disabilities, which is more prevalent in women and older people from low-income countries.7 A descriptive study based on an analysis of disability surveys in Latin America conducted between 2001 and 2009, which used the methodology of the International Classification of Functioning, Disability, and Health (ICF), estimated a higher prevalence of disability in Brazil with 14.5%, followed by Chile with 12.9%.8\n\nAccess to rehabilitation services for people with disabilities depends on various factors, such as personal and environmental factors.7 Likewise, disability is associated with several inequity factors that push the person to a situation of social, individual, and family exclusion.9 To reduce these inequities, the WHO created a strategy called “community-based rehabilitation” (CBR), which provides rehabilitation services in the community with equal opportunities and social inclusion and training to people with disabilities, their families, and community members. CBR aims to ensure the maximum social inclusion for these people and the whole exercise of their rights. This strategy has five components, namely, health, education, labor, and social and community strengthening. In Chile, it was implemented between 2004 and 2015, with the objective that 10% of the people served in community rehabilitation centers achieve social inclusion. However, a study using data from all community rehabilitation centers up to December 2016 indicated that the strategy had not been appropriately adopted. This study found that although all centers had physical and occupational therapists, less than half had professionals from other rehabilitation areas such as speech therapists, nurses, psychologists, or nursing technicians, which impedes the correct implementation of CBR due to a lack of trained human resources.9 Likewise, the study found that the implementation of CBR focused on the “health” component, neglecting the other four; the study recommended adequate implementation of the five components so that the target population is duly benefited.8\n\nThus, it is necessary to understand the situation in Chile, where the prevalence of people with disabilities is the second highest in Latin America.9 Although the CBR was maintained for 11 years, the objective was not achieved, and inequality in access to rehabilitation services was not reduced.10 The present study aimed to determine the factors associated with the use of rehabilitation services by persons with disabilities in Chile in 2015. In addition, few studies in Latin America have evaluated the determinants that could influence access to rehabilitation services. Thus, this would be one of the first studies whose results would have national representativeness. For this reason, this study will contribute to reducing the gaps in access to rehabilitation for people with disabilities in Chile.\n\n\nMethods\n\nThis analytical cross-sectional study analyzed secondary data from Chile’s 2015 Second National Disability Study (ENDISC II).10 The study population consisted of residents of urban and rural areas of the 135 communes of the 15 regions of Chile. ENDISC II was conducted between June 30 and September 5, 2015.11\n\nENDISC II is a population-based survey that aims to “determine the prevalence and characterize disability at the national level, identifying the main gaps in access to persons with disabilities”.10 It was conducted jointly by the Ministry of Social Development (MDS) and the National Statistics Institute (INE) and supervised by the National Disability Service (SENADIS) of Chile.11\n\nENDISC II used a probabilistic sampling in two phases. The first phase used a list of households from a previous survey (Case 2013), and the second phase systematically selected households within the strata (communes and rural–urban areas). The final selection unit was the dwelling. ENDISC II’s design allows its results to be nationally and regionally representative because it covers 80% of the total number of households in Chile. Data collection was conducted through personal interviews with paper questionnaires. The surveys were applied to 12,015 dwellings, which included 12,265 people aged ≥18 years. Details of the sample design can be reviewed in their methodology book.10\n\nFor this study, we included persons with disabilities aged >18 years of both sexes and excluded records with missing or inconsistent data on the variables of interest.\n\nTo measure the prevalence of disability, ENDISC II applied a methodology based on the Model Disability Survey (MDS) used by the WHO in the II World Report on Disability, which measures three aspects, namely, functioning, health status, and environmental factors.10 The MDS was developed after the review of 179 health and disability surveys from around the world, following the implementation of the ICF in 2001.12 The application of this methodology in the Americas is novel because it is different from surveys that use few questions to identify persons with disabilities, such as those of the Washington group.13 This methodology is based on the item response theory and uses a metric scale that places different questions associated with greater or lesser disability. Thus, it is possible to identify the degrees of difficulty and adequately estimate the total prevalence of disability.13\n\nThe outcome variable was rehabilitation services in the previous year for persons with disabilities. This variable is of a nominal qualitative type and was measured with the question, “In the last 12 months, did you receive any rehabilitation services?” The response categories were yes and no.\n\nThe exposure variables were sex (male and female), age group (18–29, 30–44, 55–59, and 60+), educational level (no education, elementary, middle, and high school), marital status (married/cohabiting, widowed/separated/divorced, and single), origin (urban and rural), indigenous identification (no and yes), current job (no and yes), health insurance system (FONASA, FFAA, and Order, ISAPRE, none or private, and other/does not know), chronic diseases (which included diabetes, hypertension, arthritis/arthrosis, heart diseases, respiratory diseases, migraine, and AIDS/HIV diagnosed by a doctor; “Has a doctor ever told you that you have [name of disease/health condition]?” no and yes; mental illness (which included persons with physician-diagnosed anxiety and depression; “Have you ever been told by a doctor that you have [name of disease/health condition]?” no and yes), recreational activities (“During the past 6 months, did you engage in or attend the following activities or places?” no and yes), physical activity (“In the past month, did you play sports or engage in physical activity outside of your work schedule, for 30 min or more?” no and yes), caregiver assistance (“Because of your health, do you have someone to help you at home or outside your home, including family and friends, to perform the following activities?” no and yes), and perceived discrimination “In the past 12 months, have you felt discriminated against (i.e., been prevented from doing something, bothered, or made to feel inferior?” no and yes).\n\nSelf-reporting bias may increase the prevalence of disability.14 However, surveys and population censuses have widely used self-reported questions to measure this condition. For example, the Washington Group questions measure disability quickly, effectively, and economically and have been used in more than 69 national censuses worldwide.15 ENDISC II also uses self-report questions through an interview conducted by trained enumerators and has already been applied in 10 countries, Chile being the first in Latin America.12\n\nThe data were downloaded from the SENADIS web page and analyzed with STATA version 16 (Stata Corporation, College Station, TX, USA). To select the subgroup of people with disabilities aged >18 years, the variable disc_adult was used through the sub pop command. Frequency distribution tables and weighted percentages with their 95% confidence intervals (95% CI) were prepared. In the bivariate analysis, to evaluate differences in the characteristics of people with disabilities who use or do not use rehabilitation services, the chi-square test was corrected with the F statistic for survey design. In the multivariate analysis, Poisson regression was used to estimate prevalence ratios (PR) with their 95% CI. A crude model was developed, and variables having a p-value <0.25 were included in the adjusted model. All results were weighted according to the complex sample design of the ENDISC II. A p-value of p <0.05 was assumed to be statistically significant. The possible multicollinearity among the variables of the adjusted model was also checked through the manual calculation of the variance inflation factor (VIF).16 A VIF ≥10 was an indication of collinearity. We did not perform any stratification according to sex, as previous studies have not shown that this variable is associated with the use of rehabilitation services in people with disabilities.17\n\nThe ENDISC II database is publicly accessible and available on the SENADIS website. Data are coded and do not allow the identification of participants. The Human Medicine career approved the present secondary analysis of the Universidad Científica del Sur. It was exempted from review by the institutional ethics committee according to resolution N° 407-DACMH-DAFCS-U. CIENTIFICA-2022, issued on August 1, 2022.\n\n\nResults\n\nThe database had information on 2,618 persons with disabilities. We excluded eight due to a lack of data on the variables of interest (2 in educational level, 2 in indigenous identification, and 4 in the health insurance system). Finally, we included 2610 persons with disabilities, of whom 64.3% were women, and 47.3% were 60 or older. A total of 39.3% had elementary education, and 54% reported being married or cohabiting. Most were from urban areas and did not identify with indigenous populations (86.5% and 92.6%, respectively). Most of the participants (66.6%) did not have a job at the time of the survey, and 84 (8%) had the National Health Fund (NASA) as their healthcare provider. Likewise, 74.2% and 68.2% reported having a chronic illness and mental illness, respectively. In addition, 75% were engaged in recreational activities, and 17% were physically active. Moreover, 41.2% had a caregiver, and 23.7% had perceived discrimination. Finally, 19.1% admitted that they had used some rehabilitation service in the last 12 months (Table 1).\n\na Percentage weighted according to ENDISC II complex sampling.\n\nb Included diabetes, hypertension, arthritis/arthrosis, heart diseases, respiratory diseases, migraine, and AIDS/HIV diagnosed by a doctor.\n\nc Included anxiety and depression diagnosed by a doctor.\n\nIn the bivariate analysis, a higher prevalence of the use of rehabilitation services was found in persons with disabilities who had a provisional health system, mainly in those who received care in Social Security Health Institutions (ISAPRE), with 28.9% (p < 0.028). Similarly, in persons with disabilities and mental illness, the prevalence of rehabilitation services was 27.6% compared with persons with disabilities who did not have a mental illness, with 15.1% (p < 0.001). A higher prevalence of the use of rehabilitation services was also found in persons with disabilities who had a caregiver (23.3%) compared with those without a caregiver (16.2%) (p = 0.001) (Table 2).\n\na Chi-square test.\n\nb Included diabetes, hypertension, arthritis/arthrosis, heart diseases, respiratory diseases, migraine, and AIDS/HIV diagnosed by a doctor.\n\nc Included anxiety and depression diagnosed by a doctor.\n\nIn the crude model, the variables that were significantly associated with the use of rehabilitation services were primary education (PR 0.72; 95% CI 0.53–0.99, p < 0.043), no education (PR 0.5; 95% CI 0.32–0.80, p < 0.004), marital status (PR 1.24; 95% CI 0.97–1.58, p = 0.078), indigenous identification (PR 0.71; 95% CI 0.47–1.08, p = 0.109), health insurance system in the ISAPRE category (PR 1.56, 95% CI 1.10–2.23, p = 0.015), mental illness (PR 1.83; 95% CI 1.48–2.25, p < 0.001), caregiver assistance (PR 1.44; 95% CI 1.16–1.79, p = 0.001), and perception of discrimination (PR 1.22; 95% CI 0.96–1.55, p = 0.104). Other variables such as sex, age groups, origin, current job, chronic disease, recreational activities, and physical activity were not significantly associated with rehabilitation services (Table 3).\n\na Included diabetes, hypertension, arthritis/arthrosis, heart diseases, respiratory diseases, migraine, and AIDS/HIV diagnosed by a doctor.\n\nb Included anxiety and depression diagnosed by a doctor.\n\nThe adjusted model’s associated variables were educational level, mental illness, and caregiver assistance. Persons with disability without education were 57% less likely to use rehabilitation services (PR 0.43; 95% CI 0.25–0.75, p = 0.003) than persons with disability with higher education. Likewise, persons with disability who had a mental illness were 77% more likely to use rehabilitation services than persons with disability who did not have a mental illness (PR 1.77; 95% CI 1.44–2.18, p < 0.001). Persons with disabilities who had caregiver assistance were 57% more likely to use rehabilitation services than persons with disabilities who have no caregiver assistance (PR 1.57; 95% CI 1.25–1.97, p < 0.001), all adjusted for educational level, marital status, ethnic identification, health insurance system, mental illness, assistance of a caregiver, and perception of discrimination (Table 3).\n\nIn the adjusted model, no evidence of multicollinearity was found among the variables (VIF < 10).\n\n\nDiscussion\n\nThe results of this study show that in 2015, one-fifth of the people with disabilities in Chile used some rehabilitation services in the previous year. In addition, low educational level, mental illness, and caregiver assistance were significantly associated with the use of rehabilitation services.\n\nApproximately 19.1% of people with disabilities in Chile used some rehabilitation services in the previous year. A systematic review that included 77 studies, of which 28 measured access to rehabilitation services in persons with disabilities, found low coverage of rehabilitation in India (5%), Turkey (5%), and Bangladesh (7%) and high coverage in Brazil (80%), Malaysia (76%), Philippines (70%), and South Africa (71%).18 The present study described similar results. A population-based analysis of 13,659 individuals with disabilities in southern Brazil found that only 9.2% of people used rehabilitation services.19 A study in a Ugandan community of 318 randomly selected persons with physical disabilities reported a prevalence of 26.4% of rehabilitation service utilization.17 Another study in Uganda of 284 persons with physical disabilities receiving CBR services found a prevalence of access to rehabilitation services of 41.1%, although only 6.8% had access to physical therapy.20\n\nThis variability in the prevalence of rehabilitation services could be explained by the diversity of methodological designs, different instruments used to measure disability, or differences in access to rehabilitation services. As long as methodologies for measuring disability are not standardized, these differences will remain unexplained. Thus, caution should be exercised when comparing similar studies.\n\nPeople with disabilities with lower educational levels were less likely to use rehabilitation services than those with higher education levels. These results are consistent with studies conducted in Uganda,17 Brazil,21–23 Poland,24 and Peru,25 which indicates that low educational level decreases the use of rehabilitation services. A study in Brazil also found that older adults with low educational level were more likely to have a functional disability.22 In this regard, several population-based studies have shown that educational disparities are associated with a higher incidence of disability26,27; this would be explained by the physical and intellectual demand that is necessary to achieve a higher level of education, and because of their condition, people with disabilities would not reach this level. Moreover, limited economic resources would increase these inequalities.28 The more significant disability in people with lower educational levels would explain our study’s greater need for rehabilitation services.\n\nPeople with disabilities and mental illnesses such as depression or anxiety were more likely to use rehabilitation services. Depression and disability have a reciprocal association. Several factors, such as social stereotyping, abuse, poverty, environmental barriers, or lack of access to health services, predispose people with disabilities to suffer up to depressive symptoms three times more than their non-disabled peers; moreover, depression can lead to disability.29 This association is clearly described in several studies.30,31 However, there is limited information on depression and its association with the use of rehabilitation services in people with disabilities. Some studies have shown results similar to ours. In 3,568 adults with disabilities in Korea, those who received rehabilitation services had a higher risk of depressive symptoms than those who did not (OR 1.23; 95% CI 1.01–1.50).32 A population-based study of 195,033 Americans found a higher prevalence of depressive symptoms in adults with disabilities who used assistive technologies (30.4%) than those who did not (7.4%).33 Another study in Germany involving 4,020 patients with cancer reported a higher prevalence of depression in those patients coming from cancer rehabilitation centers (28%) compared with inpatients (24%) or outpatients (21%), increasing this probability up to six times.34\n\nAccording to our findings and the evidence reviewed, there is an increase in depressive symptoms in people who used rehabilitation services. This may be due to situations inherent to the rehabilitation process, such as pain, embarrassment, or frustrations experienced by patients when their rehabilitation takes longer than expected or when the disability is permanent. Information on this topic is limited, but some studies have described this explanation.32\n\nFinally, people with disabilities who have caregiver assistance were more likely to use rehabilitation services. One of the consequences of disability is dependence on performing basic activities, which leads to the need for a caregiver.35 A population-based study in Peru found that 40.5% of people with disabilities were dependent on a caregiver; this function was mainly assumed by female family members.25 The role of the caregiver mainly falls on a family member, either the children or the partner.36 A study in China conducted on informal caregivers of people with intellectual disabilities found that 85% of the caregivers were the parents of the patients.37 Therefore, family members would have an essential role in the decision to access rehabilitation services, especially in those with severe limitations and almost absolute dependence on the caregiver. This explanation has been postulated by Medeiros et al. to justify the high prevalence of rehabilitation services in minors with disabilities.19 The role of the caregiver in the success of rehabilitation is fundamental because the caregiver often becomes the channel of communication between the physician and the patient. In addition, health professionals rely on caregivers to extend the rehabilitation process at home.38\n\nThis study has some limitations. First, social desirability and recall biases could alter the prevalence of rehabilitation services in persons with disabilities. Second, certain variables related to the use of rehabilitation services, such as transportation, architectural barriers, or quality of medical care, were not available in the ENDISC II. Third, stratification according to age groups was not performed; in older adults, the associated factors may vary concerning other age groups. Fourth, the use of rehabilitation services only included the last 12 months. Their use before that time is unknown, especially in patients with chronic disabilities. Fifth, some categories of the exposure variables may not have an adequate sample size to show an association with the use of rehabilitation services. Sixth, causality between the main variables cannot be affirmed because of the study’s cross-sectional design. As a strength, ENDISC II is a population-based survey; thus, the results of this study would be representative of people with disabilities in Chile.\n\n\nConclusions\n\nIn Chile, in 2015, one-fifth of people with disabilities used some rehabilitation service in the previous year. People with lower educational levels were less likely to access this service. Having a mental illness, such as depression, and receiving caregiver assistance significantly increased the likelihood of accessing rehabilitation services. These results should guide rehabilitation professionals in identifying depressive or anxious conditions that may impair compliance and correct performance of therapies. Likewise, it is necessary to encourage the caregiver to participate in the rehabilitation therapies of a person with disability. Finally, future studies should include a more significant number of possible factors that may explain the use of rehabilitation services in persons with disabilities.", "appendix": "Data availability\n\nENDISC II data is available on the website of the National Disability Service (SENADIS) of Chile: https://www.senadis.gob.cl/pag/356/1625/base_de_datos .\n\nThe data is available in SPSS or Stata form and a codebook is available (Spanish).\n\nfigshare: [Extended data] Factors associated with the use of rehabilitation services among people with disabilities in Chile: A population-based study. https://doi.org/10.6084/m9.figshare.21749291. 39\n\nThis project contains the following extended data:\n\n• Supplementary material (Table of operationalization of variables – this provides English translations of the relevant column labels/questions in the data file, as well as a data key)\n\n• Stata do-file (Contains the commands used for data analysis)\n\n• The ENDISC II questionnaire (Spanish)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nCieza A, Causey K, Kamenov K, et al.: Global estimates of the need for rehabilitation based on the Global Burden of Disease study 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2021 Dec 19; 396(10267): 2006–2017. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWorld Health Organization: Rehabilitation2030. [cited 2022 Aug 12].Reference Source\n\nLi Z, Zhang Z, Ren Y, et al.: Aging and age-related diseases: from mechanisms to therapeutic strategies. Biogerontology. 2021 Apr; 22(2): 165–187. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBethge M, von Groote P , Giustini A, et al.: The World Report on Disability: a challenge for rehabilitation medicine. Am. J. Phys. Med. Rehabil. 2014 Jan; 93(1 Suppl 1): S4–S11. Publisher Full Text\n\nMeyer T, Kiekens C, Selb M, et al.: Toward a new definition of rehabilitation for research purposes: a comparative analysis of current definitions. Eur. J. Phys. Rehabil. Med. 2020 Oct; 56(5): 672–681. PubMed Abstract \| Publisher Full Text\n\nWade DT: What is rehabilitation? An empirical investigation leading to an evidence-based description. Clin. Rehabil. 2020 May; 34(5): 571–583. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMlenzana NB, Frantz JM, Rhoda AJ, et al.: Barriers to and facilitators of rehabilitation services for people with physical disabilities: A systematic review. Afr. J. Disabil. 2013 Sep 19; 2(1): 22. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nNeves-Silva P, Álvarez-Martín E: Estudio descriptivo de las características sociodemográficas de la discapacidad en América Latina. Ciênc Saúde Coletiva. 2014 Dec [cited 2022 Mar 4]; 19(12): 4889–4898. PubMed Abstract \| Publisher Full Text Reference Source\n\nBesoain-Saldaña Á, Sanhueza JR, Hizaut MM, et al.: Community-Based Rehabilitation (CBR) in primary care centers in Chile. Rev. Saude Publica. 2020 Apr 6; 54: 38. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nServicio Nacional de la Discapacidad: Libro de resultados II Estudio Nacional de la Discapacidad. SENADIS;2015.Reference Source\n\nServicio Nacional de la Discapacidad: Metodología de diseño muestral de la encuesta del Segundo Estudio Nacional de la Discapacidad, 2015. Santiago:SENADIS;2016.Reference Source\n\nSabariego C, Fellinghauer C, Lee L, et al.: Generating comprehensive functioning and disability data worldwide: development process, data analyses strategy and reliability of the WHO and World Bank Model Disability Survey. Arch. Public Health. 2022 Jan 4; 80(1): 6. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nThe Washington Group on Disability Statistics: The Washington Group on Disability Statistics.[cited 2022 Sep 9].Reference Source\n\nAlthubaiti A: Information bias in health research: definition, pitfalls, and adjustment methods. J. Multidiscip. Healthc. 2016 May 4; 9: 211–217. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nGroce NE, Mont D: Counting disability: emerging consensus on the Washington Group questionnaire. Lancet Glob. Health. 2017 Jul; 5(7): e649–e650. PubMed Abstract \| Publisher Full Text\n\nHow can I check for collinearity in survey regression?:[cited 2022 Oct 28].Reference Source\n\nZziwa S, Babikako H, Kwesiga D, et al.: Prevalence and factors associated with utilization of rehabilitation services among people with physical disabilities in Kampala, Uganda. A descriptive cross sectional study. BMC Public Health. 2019 Dec 27; 19(1): 1742. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBright T, Wallace S, Kuper H: A Systematic Review of Access to Rehabilitation for People with Disabilities in Low- and Middle-Income Countries. Int. J. Environ. Res. Public Health. 2018; 15(10): 2165. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMedeiros A d A, Galvão MHR, Barbosa IR, et al.: Use of rehabilitation services by persons with disabilities in Brazil: A multivariate analysis from Andersen’s behavioral model. PLoS One. 2021 Apr 29; 16(4): e0250615. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHamid LN, Kobusingye O, Baine SO, et al.: Disability Characteristics of Community-Based Rehabilitation Participants in Kayunga District, Uganda. Ann. Glob. Health. 2017 May; 83(3–4): 478–488. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMoretto LC, Longo GZ, Boing AF, Arruda MP. Prevalência da utilização de serviços de fisioterapia entre a população adulta urbana de Lages, Santa Catarina. Braz. J. Phys. Ther. 2009 Apr [cited 2022 Aug 12]; 13(2): 130–5. 10Publisher Full Text\n\nPereira GN, Bastos GAN, Del Duca GF, et al.: Indicadores demográficos e socioeconômicos associados à incapacidade funcional em idosos. Cad Saúde Pública. 2012 Nov [cited 2022 Aug 12]; 28(11): 2035–2042. PubMed Abstract \| Publisher Full Text\n\nAmaral FLJ d S, Motta MHA, da Silva LPG , et al.: Fatores associados com a dificuldade no acesso de idosos com deficiência aos serviços de saúde. Ciênc Saúde Coletiva. 2012 Nov [cited 2022 Aug 12]; 17(11): 2991–3001. PubMed Abstract \| Publisher Full Text\n\nSzybalska A, Broczek K, Slusarczyk P, et al.: Utilization of medical rehabilitation services among older Poles: results of the PolSenior study. Eur. Geriatr. Med. 2018 Jun 20; 9(5): 669–677. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBernabe-Ortiz A, Diez-Canseco F, Vásquez A, et al.: Disability, caregiver’s dependency and patterns of access to rehabilitation care: results from a national representative study in Peru. Disabil. Rehabil. 2016; 38: 582–588. PubMed Abstract \| Publisher Full Text\n\nHuisman M, Kunst A, Deeg D, et al.: Educational inequalities in the prevalence and incidence of disability in Italy and the Netherlands were observed. J. Clin. Epidemiol. 2005 Oct; 58(10): 1058.e1–1058.e10. PubMed Abstract \| Publisher Full Text\n\nMontez JK, Zajacova A, Hayward MD: Disparities in Disability by Educational Attainment Across US States. Am. J. Public Health. 2017 Jul; 107(7): 1101–1108. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKlijs B, Nusselder WJ, Looman CW, et al.: Educational disparities in the burden of disability: contributions of disease prevalence and disabling impact. Am. J. Public Health. 2014 Aug; 104(8): e141–e148. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nNoh JW, Kwon YD, Park J, et al.: Relationship between Physical Disability and Depression by Gender: A Panel Regression Model. PLoS One. 2016 Nov 30; 11(11): e0166238. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMcDermott S, Moran R, Platt T, et al.: Depression in adults with disabilities, in primary care. Disabil. Rehabil. 2005 Feb 4; 27(3): 117–123. Publisher Full Text\n\nShen SC, Huang KH, Kung PT, et al.: Incidence, risk, and associated factors of depression in adults with physical and sensory disabilities: A nationwide population-based study. PLoS One. 2017 Mar 31; 12(3): e0175141. Publisher Full Text\n\nLee Y, Hong I, Lee MJ, et al.: Identifying Risk of Depressive Symptoms in Adults With Physical Disabilities Receiving Rehabilitation Services: Propensity Score Approaches. Ann. Rehabil. Med. 2019 Jun; 43(3): 250–261. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nOkoro CA, Strine TW, Balluz LS, et al.: Prevalence and correlates of depressive symptoms among United States adults with disabilities using assistive technology. Prev. Med. 2010 Apr; 50(4): 204–209. PubMed Abstract \| Publisher Full Text\n\nHartung TJ, Brähler E, Faller H, et al.: The risk of being depressed is significantly higher in cancer patients than in the general population: Prevalence and severity of depressive symptoms across major cancer types. Eur. J. Cancer. 2017 Feb; 72: 46–53. PubMed Abstract \| Publisher Full Text\n\nBoerner K, Schulz R: Caregiving, bereavement and complicated grief. Bereave. Care. 2009 Dec 1; 28(3): 10–13. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBlomgren J, Breeze E, Koskinen S, et al.: Help from spouse and from children among older people with functional limitations: comparison of England and Finland. Ageing Soc. 2012 Aug [cited 2022 Oct 27]; 32(6): 905–933. Publisher Full Text\n\nSit HF, Huang L, Chang K, et al.: Caregiving burden among informal caregivers of people with disability. Br. J. Health Psychol. 2020 Sep; 25(3): 790–813. Publisher Full Text\n\nMlenzana NB, Eide AH, Frantz JM: Perceptions and satisfaction of caregivers regarding rehabilitation services from selected rehabilitation centres in the Western Cape. Afr. J. Disabil. 2018 Oct 25; 7: 415. Publisher Full Text\n\nParedes-Laguna DS, Calderón-Curiñaupa WR, Soto-Nuñez SL, et al.:Factors associated with the use of rehabilitation services among people with disabilities in Chile: A population-based study. [Dataset]. figshare. 2022. Publisher Full Text" }	[ { "id": "164255", "date": "27 Feb 2023", "name": "Kaloyan Kamenov", "expertise": [ "Reviewer Expertise Disability", "rehabilitation" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for submitting this interesting and important article. I think that the paper has its merits but will benefit from some changes and improvements, especially in the concept of rehabilitation. Here are my suggestions:\nOne overall comment - I understand that the study focuses on persons with disabilities. I don't know if this is because the authors think that rehabilitation is only for persons with disabilities, or simply because you are interested in this population. If it is the first one, I would suggest you expand your scope and look at the whole population that did the survey, because rehabilitation is a service for everyone, not just persons with disabilities. You can still maybe explore whether having a disability is a factor for the use of rehabilitation, and see whether persons with disabilities experience more barriers to access. If it is the second one, the it is ok and you can leave it as it is, but you have to make sure you explain that rehabilitation is not a service exclusively for persons with disabilities.\nAbstract\nIn the following sentence \"Rehabilitation services are necessary for people with disabilities to improve their quality of life and be included in society\", please indicate that rehabilitation is necessary for many persons with disabilities, and not for all. Not every person with a disability would need rehabilitation. Also, rehabilitation primarily improves the functioning of a person rather than quality of life, so I would either replace quality of life with functioning, or use both.\nIntroduction\nThe definition of rehabilitation provided is not correct. WHO has moved from this definition for years. Please, use the new definition, provided here: https://www.who.int/news-room/fact-sheets/detail/rehabilitation\n\nIt is important to make the distinction between rehabilitation and disability - rehabilitation is a service for anyone - with or without a disability, and the other way around - many people with disabilities will require rehabilitation, but not all, and certainly they are not the only ones.\n\nIn general, most of the references in the introduction are old. I would suggest to include more recent ones. There are a lot of systematic reviews published in the past 5 years.\n\nWHO's new estimate of prevalence of disability is 16%, according to the Global report on health equity for persons with disabilities published in 2022.\n\nWhile it is true that WHO introduced the CBR approach, since 2017 WHO has been promoting the Rehabilitation 2030 initiative, which focuses on the overall importance of strengthening health systems to provide rehabilitation across all levels of care, including, but not only rehabilitation provided in the communities. I understand that you are providing examples before 2015 when your data is from, but I would certainly talk about Rehabilitation 2030, and simply give the CBR example of what was done in Chile, without emphasizing the whole CBR strategy as the only thing that WHO promotes, because it is not true. In addition, do you have any other evidence of what was done in Chile after 2015? Any new initiatives, is rehabilitation part of universal health coverage?\n\nMethods\nIn measurement of disability you say that the methodology is based on the MDS used by WHO in the II World Report on Disability, which is not true. It is based on the MDS and this is sufficient, because firstly, there is no II World Report on Disability, there is only one World Report on Disability, and second - MDS was created after the world report was published in 2011, so it cannot be included there. In addition, the MDS explores functioning, capacity (not health status), and environmental factors.\nResults\nI would also do an ad hoc or sensitivity analysis with the sample without disability and see whether there are any differences in the factors, compared to those with disabilities\nDiscussion\nIn the section \"Prevalence of the use of rehabilitation services in people with disabilities\" you are comparing your results with a systematic review on unmet needs for rehabilitation, which is not correct. Your analysis does not show gaps in the use of rehab services, because your questions does not ask that. Your question which you use as a dependent variable asks whether people with disabilities have used services, which indicates service utilization, not met or unmet needs. You don't know whether every person with a disability needs rehabilitation services? It may be that everyone who needed rehabilitation received it. The systematic review that you cite is based on questions like \"did you receive rehabilitation when you needed it?\" or something in this line. I would suggest you delete this section.\n\n\"this would be explained by the physical and intellectual demand that is necessary to achieve a higher level of education, and because of their condition, people with disabilities would not reach this level.\" - this is absolutely not true. There is no study that can show that having a disability makes it too effortful for someone to study. However, there are many studies showing that environmental barriers stop people with disabilities to study - lack of accessible educational materials, infrastructure in schools, negative attitudes by teachers, etc. Please, change this statement.\n\n\"The more significant disability in people with lower educational levels would explain our study’s greater need for rehabilitation services.\" - or maybe people with lower education don't have access to information and don't know that there are rehab services available. I am sure that if you run the same analysis with the sample of people without disability, you will find the same result.\n\n\"According to our findings and the evidence reviewed, there is an increase in depressive symptoms in people who used rehabilitation services.\" - you used data from a cross-sectional study. How do you know that there is an increase in depressive symptoms due to the rehabilitation? You can't know that. You simply know that those who had rehabilitation also had depressive symptoms, but they may have had these symptoms already before, and maybe they don't have anything to do with the rehab process.\n\n\"One of the consequences of disability is dependence on performing basic activities, which leads to the need for a caregiver\" - this is not a consequence of a disability. It is simply that some people with disability, who have an underlying condition that require assistance may need a caregiver.\n\nIn the paragraph on caregivers, it sounds like the persons with a disability does not have any opinion or decision, and everything depends on the caregiver, which is not true. I would soften the language and reflect the importance of persons with disabilities taking their own decisions, which, in some cases, can be taken by the caregivers in reality.\n\n\"First, social desirability and recall biases could alter the prevalence of rehabilitation services in persons with disabilities.\" - please, explain what you mean.\n\nplease, change \"chronic disabilities\" with chronic health conditions.\n\nThe discussion has not even one sentence on the implications of this study. What do these results mean? How can these results be used to address any gaps as you mention in the abstract? How are your findings important for research and clinical practice? Please, include some thoughts on that.\n\nConclusions\n\"These results should guide rehabilitation professionals in identifying depressive or anxious conditions that may impair compliance and correct performance of therapies.\" - this doesn't make any sense. It is important, of course, that a rehab professional knows if a person has anxiety or depression, but I am not sure how will this change their intervention if someone has a physical disability? I would imagine that the person will also be treated for their depression or anxiety, but will this be done by the rehab professional? I think that more explanation is needed here.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "13050", "date": "17 Jan 2025", "name": "Jhonnel Alarco", "role": "Author Response", "response": "Reviewer: Thank you for submitting this interesting and important article. I think that the paper has its merits but will benefit from some changes and improvements, especially in the concept of rehabilitation. Here are my suggestions: One overall comment - I understand that the study focuses on persons with disabilities. I don't know if this is because the authors think that rehabilitation is only for persons with disabilities, or simply because you are interested in this population. If it is the first one, I would suggest you expand your scope and look at the whole population that did the survey, because rehabilitation is a service for everyone, not just persons with disabilities. You can still maybe explore whether having a disability is a factor for the use of rehabilitation, and see whether persons with disabilities experience more barriers to access. If it is the second one, the it is ok and you can leave it as it is, but you have to make sure you explain that rehabilitation is not a service exclusively for persons with disabilities. Response. Thank you very much for your comment. Indeed, this study focuses exclusively on individuals with disabilities. However, we find the suggestion to evaluate whether having a disability serves as a predictor for the use of rehabilitation services to be highly insightful. In future studies where disability is analyzed as an outcome, we will consider incorporating this variable. Additionally, we have clarified that rehabilitation services are not exclusively intended for individuals with disabilities. Reviewer: Abstract In the following sentence \"Rehabilitation services are necessary for people with disabilities to improve their quality of life and be included in society\", please indicate that rehabilitation is necessary for many persons with disabilities, and not for all. Not every person with a disability would need rehabilitation. Also, rehabilitation primarily improves the functioning of a person rather than quality of life, so I would either replace quality of life with functioning, or use both. Response. Thank you very much for your comment; we completely agree. The sentence has been revised to state: \"Rehabilitation services are necessary for many people with disabilities to improve their functioning and be included in society\". Reviewer: Introduction The definition of rehabilitation provided is not correct. WHO has moved from this definition for years. Please, use the new definition, provided here: https://www.who.int/news-room/fact-sheets/detail/rehabilitation Response. Thank you very much for your comment. The new WHO definition of rehabilitation “a set of interventions designed to optimize functioning and reduce disability in individuals with health conditions in interaction with their environment” has been added and the bibliographic reference has been updated. Reviewer: It is important to make the distinction between rehabilitation and disability - rehabilitation is a service for anyone - with or without a disability, and the other way around - many people with disabilities will require rehabilitation, but not all, and certainly they are not the only ones. Response. Thank you very much for your comment. A distinction has been made between rehabilitation and disability, emphasizing that not all individuals with disabilities require rehabilitation. Reviewer: In general, most of the references in the introduction are old. I would suggest to include more recent ones. There are a lot of systematic reviews published in the past 5 years. Response. Thank you very much for your comment. A new bibliographic search has been conducted, and the references have been updated accordingly. The majority of the cited articles are now less than five years old. Reviewer: WHO's new estimate of prevalence of disability is 16%, according to the Global report on health equity for persons with disabilities published in 2022. Response. Thank you very much for your comment; we agree. The global prevalence of disability has been updated to 16%, as reported in the 2022 Global Report on Health Equity for Persons with Disabilities. Reviewer: While it is true that WHO introduced the CBR approach, since 2017 WHO has been promoting the Rehabilitation 2030 initiative, which focuses on the overall importance of strengthening health systems to provide rehabilitation across all levels of care, including, but not only rehabilitation provided in the communities. I understand that you are providing examples before 2015 when your data is from, but I would certainly talk about Rehabilitation 2030, and simply give the CBR example of what was done in Chile, without emphasizing the whole CBR strategy as the only thing that WHO promotes, because it is not true. In addition, do you have any other evidence of what was done in Chile after 2015? Any new initiatives, is rehabilitation part of universal health coverage? Response. Thank you very much for your comment. We have revised the section discussing Community-Based Rehabilitation (CBR), placing greater emphasis on the Rehabilitation 2030 initiative and including examples of actions implemented in Chile after 2015. Reviewer: Methods In measurement of disability you say that the methodology is based on the MDS used by WHO in the II World Report on Disability, which is not true. It is based on the MDS and this is sufficient, because firstly, there is no II World Report on Disability, there is only one World Report on Disability, and second - MDS was created after the world report was published in 2011, so it cannot be included there. In addition, the MDS explores functioning, capacity (not health status), and environmental factors. Response. Thank you very much for your comment; we agree and regret the error. The information regarding the MDS has been corrected to indicate that it examines functioning, capacity, and environmental factors. Reviewer: Results I would also do an ad hoc or sensitivity analysis with the sample without disability and see whether there are any differences in the factors, compared to those with disabilities Response. Thank you very much for your comment; however, we respectfully disagree. This analysis focuses exclusively on the population with disabilities. Comparing the associated factors between individuals with and without disabilities falls outside the scope of the study's objectives. Reviewer: Discussion In the section \"Prevalence of the use of rehabilitation services in people with disabilities\" you are comparing your results with a systematic review on unmet needs for rehabilitation, which is not correct. Your analysis does not show gaps in the use of rehab services, because your questions does not ask that. Your question which you use as a dependent variable asks whether people with disabilities have used services, which indicates service utilization, not met or unmet needs. You don't know whether every person with a disability needs rehabilitation services? It may be that everyone who needed rehabilitation received it. The systematic review that you cite is based on questions like \"did you receive rehabilitation when you needed it?\" or something in this line. I would suggest you delete this section. Response. Thank you very much for your comment; we agree. We have decided to exclude this systematic review from the discussion. Reviewer: \"this would be explained by the physical and intellectual demand that is necessary to achieve a higher level of education, and because of their condition, people with disabilities would not reach this level.\" - this is absolutely not true. There is no study that can show that having a disability makes it too effortful for someone to study. However, there are many studies showing that environmental barriers stop people with disabilities to study - lack of accessible educational materials, infrastructure in schools, negative attitudes by teachers, etc. Please, change this statement. Response. Thank you very much for your comment; we agree. This statement has been revised to emphasize environmental barriers as a primary factor contributing to the lack of access to education for individuals with disabilities. Reviewer: \"The more significant disability in people with lower educational levels would explain our study’s greater need for rehabilitation services.\" - or maybe people with lower education don't have access to information and don't know that there are rehab services available. I am sure that if you run the same analysis with the sample of people without disability, you will find the same result. Response. Thank you very much for your comment. Both explanations have been included. Unfortunately, we do not have data on the use of rehabilitation services among individuals without disabilities. Therefore, we cannot conclude that lower educational attainment increases the use of rehabilitation services in this group. Reviewer: \"According to our findings and the evidence reviewed, there is an increase in depressive symptoms in people who used rehabilitation services.\" - you used data from a cross-sectional study. How do you know that there is an increase in depressive symptoms due to the rehabilitation? You can't know that. You simply know that those who had rehabilitation also had depressive symptoms, but they may have had these symptoms already before, and maybe they don't have anything to do with the rehab process. Response. Thank you very much for your comment; we agree. The wording has been revised accordingly. Reviewer: \"One of the consequences of disability is dependence on performing basic activities, which leads to the need for a caregiver\" - this is not a consequence of a disability. It is simply that some people with disability, who have an underlying condition that require assistance may need a caregiver. Response. Thank you very much for your comment; we agree. The wording has been revised accordingly. Reviewer: In the paragraph on caregivers, it sounds like the persons with a disability does not have any opinion or decision, and everything depends on the caregiver, which is not true. I would soften the language and reflect the importance of persons with disabilities taking their own decisions, which, in some cases, can be taken by the caregivers in reality. Response. Thank you very much for your comment; we agree. We have ensured that the wording appropriately emphasizes the importance of individuals with disabilities making their own decisions. Reviewer: \"First, social desirability and recall biases could alter the prevalence of rehabilitation services in persons with disabilities.\" - please, explain what you mean. Response. Thank you very much for your comment. The wording has been revised, and the explanation of social desirability and recall biases has been clarified and improved. Reviewer: please, change \"chronic disabilities\" with chronic health conditions. Response. Thank you very much for your comment. The term has been corrected. The discussion has not even one sentence on the implications of this study. What do these results mean? How can these results be used to address any gaps as you mention in the abstract? How are your findings important for research and clinical practice? Please, include some thoughts on that. Response. Thank you very much for your comment. A section is added to discuss the implications of the findings for public health in Chile. Reviewer: Conclusions \"These results should guide rehabilitation professionals in identifying depressive or anxious conditions that may impair compliance and correct performance of therapies.\" - this doesn't make any sense. It is important, of course, that a rehab professional knows if a person has anxiety or depression, but I am not sure how will this change their intervention if someone has a physical disability? I would imagine that the person will also be treated for their depression or anxiety, but will this be done by the rehab professional? I think that more explanation is needed here. Response. Thank you very much for your comment. The conclusions have been revised to specify that health professionals, not exclusively rehabilitation professionals, should identify depressive or anxious conditions." } ] }, { "id": "177959", "date": "07 Jul 2023", "name": "Dorcas Gandhi", "expertise": [ "Reviewer Expertise Stroke rehab", "low cost stroke rehab models", "technology in stroke rehab", "clinical practice guidelines and protocols", "tele-rehabilitation", "capacity building models" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for this much needed study. And congratulations on the well described manuscript.\nIntroduction, kindly use the updated definition of rehabilitation provided by WHO\n\nResults: Most were urban areas and did not identify with indigenous population: Would this affect the interpretation of results in anyway? Please comment.\n\nPerceived discrimination with respect to? Please provide details if available.\n\nPlease comment on the type of disability and correlate with rehab service use wherever possible. This would add value to the study.\n\nIs here information of the type of caregiving that influence rehab service seeking behaviour? Informal or formal caregiving?\n\nIn intro and discussion, most references are old, kindly update with recent evidence\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "13051", "date": "17 Jan 2025", "name": "Jhonnel Alarco", "role": "Author Response", "response": "Thank you for this much needed study. And congratulations on the well described manuscript. Introduction, kindly use the updated definition of rehabilitation provided by WHO Response. Thank you very much for your comment. The current WHO definition of rehabilitation—\"a set of interventions designed to optimize functioning and reduce disability in individuals with health conditions in interaction with their environment\"—has been included, and the bibliographic reference has been updated accordingly. Results: Most were urban areas and did not identify with indigenous population: Would this affect the interpretation of results in anyway? Please comment. Response. Thank you very much for your comment. The results are not affected. ENDISC II is a specialized, nationally representative survey, ensuring that the findings for urbanity and the non-indigenous population are consistent with those of the general population in Chile. http://www.censo2017.cl/descargas/home/sintesis-de-resultados-censo2017.pdf Perceived discrimination with respect to? Please provide details if available. Response. Thank you very much for your comment. Unfortunately, the question regarding perceived discrimination does not specify the reason for the discrimination. It is a general question that asks: “In the past 12 months, have you felt discriminated against (i.e., been prevented from doing something, bothered, or made to feel inferior)?” Please comment on the type of disability and correlate with rehab service use wherever possible. This would add value to the study. Response. Thank you very much for your comment. Unfortunately, the ENDISC II defines types of disability as permanent or long-term conditions, which are not necessarily present in all individuals with disabilities. For this reason, we are unable to include it as a variable associated with the use of rehabilitation services. Is here information of the type of caregiving that influence rehab service seeking behaviour? Informal or formal caregiving? Response. Thank you very much for your comment. Unfortunately, the ENDISC II does not provide information on the type of care received by individuals with disabilities. This limitation is acknowledged in the study. In intro and discussion, most references are old, kindly update with recent evidence Response. Thank you very much for your comment. A new bibliographic search has been conducted, and the references have been updated accordingly. The majority of the cited articles are now less than five years old." } ] } ]	1	https://f1000research.com/articles/12-73
https://f1000research.com/articles/14-105/v1	17 Jan 25	{ "type": "Research Article", "title": "Diversity, Distribution, and Phenotypic Characterization of Cultivable Wild Yeasts Isolated from Natural Forest", "authors": [ "Teshome Tadesse", "Degife Dese", "Anbessa Dabassa", "Ketema Bacha", "Degife Dese", "Anbessa Dabassa", "Ketema Bacha" ], "abstract": "Background Yeasts are unicellular fungi that inhabit a variety of environments including plant surfaces, water, soil, and animal hosts. However, limited research has been conducted on soil and plant associated yeasts in Africa, with most studies originating from developed regions.\n\nMethods This study explored the diversity, distribution, and phenotypic characterization of cultivable wild yeast in samples from rhizosphere soil, leaves, litter, and tree bark collected from South West Ethiopia. Yeast isolates were characterized using morphological, physiological and biochemical methods, Stress-tolerant yeast species were identified using Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF).\n\nResults Based on morphological, physiological, and biochemical analyses, a total of 15 yeast genera were identified from 23 plant species. Predominant yeast species included Candida spp., Saccharomyces spp., Meyerozyma spp., Pichia spp., Geotrichum spp., and Hanseniaspora spp. Plant species with the highest yeast diversity were Ficus vasta, Ficus exasperata, Ficus sycomorus, Cordia africana, and Ritchiea albersii. Bark samples yielded more yeast isolates than rhizosphere soil, litter, and leaves. Stress-tolerant species such as Saccharomyces cerevisiae, Candida pelliculosa, Meyerozyma guilliermondii, Pichia kluyveri, and Trichosporon asahii were identified using MALDI-TOF. Correlation analysis revealed no significant relationship between yeast populations in bark and leaf samples or between rhizosphere soil and leaves, though a weak positive correlation was found between rhizosphere soil and bark or litter. Seasonal analysis showed a strong positive correlation between yeast abundance in spring and summer, but no association between autumn and spring.\n\nConclusion Ethiopian forests are home for various yeast species including the stress-tolerant wild yeasts. This study highlights the significant yeast diversity in Ethiopian forests, with potential applications in improving industrial fermentation processes that operate under stressful conditions.", "keywords": [ "Distribution", "Ethiopia", "Forest", "Stress Tolerant Yeast", "Wild Yeast" ], "content": "1. Introduction\n\nYeasts are a diverse group of microorganisms that occupy a vast array of ecological niches. These include plant substrates such as bark, leaves, flowers, and fruits, as well as non-plant environments like soil, air, water, and the surfaces of animals.1 While significant numbers of research have focused on interactions between bacteria and plants, the study of yeast-plant relationships has received much less attention. Forest ecosystems, particularly, are rich in yeast diversity due to the presence of varied substrates like plant litters and forest soil.1,2 Wild yeasts inhabiting natural forest ecosystems display remarkable diversity in terms of morphology, color, and ecological roles.3–5 However, despite the invaluable importance of yeasts in ecological functions and biotechnology, understanding their distribution patterns and the factors governing their abundance remains incomplete, especially in complex ecosystems like forests.\n\nThe geographic locations and environmental conditions in different regions of the globe significantly influence the composition and structure of yeast communities. Forest ecosystems often host higher densities and numbers of yeast species compared to other habitats due to their diversity in plant and soil substrates. However, many factors such as climate, geography, biota, and natural disturbances affect their distribution and abundance.1 Studies conducted in Jimma and Iluabaor zones of southwest Ethiopia suggest that the diversity of yeast communities is influenced by substrates such as soil, plant parts, and litter. Similarly, climate is a key global determinant of yeast abundance, with tree species, soil texture, and vegetation cover playing important roles.5 Despite these insights, gaps persist in our understanding of yeast dynamics in forest ecosystems, particularly in natural forests of southwestern Ethiopia.\n\nYeasts are not only ecologically significant but are also important in industrial biotechnology. Wild yeasts have been used for millennia in food and beverage fermentation and are now essential in processes such as ethanol production, microbial oil synthesis, and single-cell protein production.6–9 Their roles as decomposers and research models further underscore their importance in both natural ecosystems and biotechnological applications.2 However, characterizing wild yeasts for use in industrial fermentation remains challenging. The phenotypic characterization of yeasts involves testing their ability to metabolize diverse carbon sources, their tolerance to alcohol, and their survival under extreme environmental conditions like high or low pH and temperature.10–12 Previous studies, including our own preliminary findings, have demonstrated the potential application of wild yeasts of forest origin in ethanol production.13\n\nOverall, despite the ecological and biotechnological significance of wild yeasts, there is a notable lack of scientific reports on the distribution and physiological diversity of wild yeasts associated with different substrates in the natural forests of southwestern Ethiopia. This gap in knowledge hampers efforts to conserve yeast diversity and predict future changes in yeast populations within forest ecosystems. Addressing this knowledge gap is crucial for the scientific community, notably the mycologists, and industries relying on novel microbes isolated from natural resources. Therefore, the present study aims to assess the diversity, distribution, and phenotypic characterization of wild yeasts isolated from selected forests in southwest Ethiopia.\n\n\n2. Methods\n\nA total of 200 samples of bark (n = 66), leaves (n = 38), rhizosphere soil (n = 54), and leaf litter (n = 42) were collected from natural stands of trees from three separate regions of Jimma (Belete-Gera and Boter Bacho) and the Iluabaor (Yayo Biosphere Reserve) zones. Briefly, bark and leaf samples were collected from surfaces of different plant species of the forest using sterile polythene bags. Bark samples of old logs of trees were collected from 0 to 3 m height of the logs at different gradients of the stem base, whereas the rhizosphere soils were collected at a depth of 0–10 cm from underneath the selected old logs after the collection of leaf litter samples. The study was conducted from September 2021 to June 2022.\n\nThe three regions (Belete-Gera , Yayo Biosphere Reserve, and Boter Bacho) of Afromontane moist forests under study shared the following 23 different populations of tree species ( Table 1): Albizia grandibracteata, Syzygium guineense, Ficus exasperata Vah, Milletia ferruginea, Croton macrostachyus, Sapium ellipticum, Schefflera abyssinica, Ritchiea albersii, Albizia gummifera, Ficus sycomorus, Ekebergia capensis, Acacia abyssinica, Diospyros abyssinica, Trichilia dregeana, Albizia malacophylla, Pinus Patula, Polyscios fulva, Acokanthera shimperi, Olinea rochetiniana, Ficus vasta, Catharanthus roseus, and Cordia africana. The randomly chosen old trees in the plots were used to gather rhizosphere soil and plant substrates, such as bark, green leaves, and litter.\n\nThe methods used in this study for yeast isolation and identification were adapted from our previously established protocols.14 Briefly, four grams of the solid samples (leaf, bark, and litters) were cut into smaller pieces before being added to the enrichment medium containing 1% yeast extract (Oxoid), 2% peptone (Oxoid), and 2% D-glucose (Fisher Chemical), along with 1 M HCl from 37% HCl (Fisher Chemical) in a 45 mL capacity flask. Each sample was cultured for 7 to 14 days at 30°C until signs of the beginning of fermentation were noticed. This step facilitated the growth and enrichment of indigenous yeast populations present in the samples. All the chemicals and media used in this study are products of Sigma-Aldrich (Oxoid Limited, USA) and HiMedia, India, unless specified otherwise.\n\n(a). Isolation of yeasts\n\nAfter the enrichment phase, actively fermenting cultures were diluted and plated onto yeast extract peptone dextrose (YPD) agar, supplemented with 0.2 g/L chloramphenicol (HiMedia, India) to inhibit bacterial growth. Approximately 100 μL of each diluted culture was spread on the surface of YPD agar plates. The plates were incubated at 30°C for 2 to 3 days, allowing yeast colonies to develop. Colonies exhibiting yeast-like morphology were selected for further analysis. A total of 406 wild yeast isolates were obtained from 200 environmental samples, including tree bark (163 isolates), rhizosphere soil (120 isolates), leaf litter (64 isolates), and leaves (59 isolates) collected from three distinct forest regions: Belete-Gera forest (54 isolates), Yayo Biosphere Reserve (80 isolates), and Boter-Bacho forest (66 isolates) ( Tables 1 and 2). The steps detailed below were followed rigorously to ensure optimal recovery and identification of yeast strains.\n\n(b). Colony purification and microscopic examination\n\nIsolated colonies were inoculated into 10 mL of sterile YPD broth for subsequent purification. After an additional growth phase, the cultures were streaked onto fresh YPD agar plates for purification. Morphology was observed after incubation, and colony purity was confirmed using phase-contrast microscopy at 100x magnification. Cultures showing characteristic yeast cell morphology (unicellular, budding cells) were deemed pure.\n\n(c). Preservation of yeast isolates\n\nFor long-term storage, saturated cultures of pure yeast isolates were mixed with sterile 50% glycerol (Sigma Aldrich) and stored at -70°C for future analysis and characterization.\n\n(d). Genus-level identification\n\nTo classify the yeast isolates to the genus level, a combination of biochemical, morphological, and physiological assays was employed. The Wikerham medium, which contained peptone (10 g/L), yeast extract (5 g/L), phenol red (HIMEDIA) (24 mg), and distilled water (1 L), was used to assess the yeast isolates’ capacity to ferment sugars (Fisher Chemical), such as glucose, galactose, fructose, maltose, lactose, xylose, and sucrose, using the standard procedure recommended by Zaid et al.15 At a concentration of 2% (w/v), the sugars were dissolved. Each isolate’s active yeast cells (about 0.1 mL) were injected separately into test media that had been produced in Durham tubes. The test media was then incubated for three days at 30°C without any agitation.14\n\nFollowing procedures described in Tadesse et al.14 research, the yeast isolates were spread out separately on YPD agar and incubated at 37, 40, 42, 44, and 45°C for 72 hours in order to assess the temperature tolerance of ethanol-tolerant yeasts. It was confirmed whether the yeast isolates were growing by looking directly at the colonies that formed on YPD agar plates. Parts of actively developing yeast cultures (1x107 cells/ml) were transferred into YPD broth that had been adjusted to different glucose concentrations (i.e., 40, 50, and 60%) in order to measure the osmotolerance of the yeast isolates. The growth was then assessed using optical density measurements taken at 600 nm using a UV-Vis spectrophotometer (Analytik Jena, Germany) after they had been cultured for 72 hours at 30 °C and 150 rpm.\n\n(e). Species-level identification by MALDI-TOF MS\n\nMatrix-Assisted Laser Desorption Ionization-Time-of-Flight Mass Spectrometry (MALDI-TOF MS), Zybio EXS3000 (Zybio Inc., China), was used to further identify a subset of yeast isolates that exhibited prominent physiological or phenotypic characteristics down to the species level. As mentioned in brief in our earlier study,14 one colony was pipetted off the plate into a 1.5 ml tube (Eppendorf, Germany) and well mixed with 300 ml of water. Following a 2-minute centrifugation at 15,500 g with the addition of 900 ml of 100% ethanol, the mixture was discarded along with the supernatant. The pellet was left at room temperature to air dry for an hour. After that, the pellet was thoroughly combined with 50 milliliters of 70% v/v formic acid and then added to 50 milliliters of acetonitrile. For two minutes, the mixture was centrifuged again at 15,500 g. After applying one microliter of the supernatant to a section of the steel target, it was allowed to air dry at room temperature. As stated by Xiong et al.,15 one microliter of the matrix solution (cyano-4-hydroxycinnamic acid) was applied to each sample, and it was then left to air dry. A mass spectrometer, the EXS300 MALDI/TOF, was then used to make the measurements. The following categories were applied to the identifications using the manufacturer’s proposed modified score values: A score of 1.7 meant no identification, a score of >2 meant species identification, and a score of 1.7 to 1.9 meant genus identification.\n\nD-glucose (Fisher-Chemical, India), sodium chloride (NaCl) (NICE CHEMICALS LTD, India), and laboratory-grade 100% ethanol (SLC CHEMICALS DELHI, India) were used to choose the testing conditions. Using glucose concentrations ranging from 50 to 60% w/v, we assessed osmotolerance. Increasing concentrations of the stress factors were used to evaluate halotolerance (NaCl at 8, 10, and 12%) and ethanol tolerance (ethanol at 8, 10, 12, 14, and 16% v/v). Yeast Extract Peptone Dextrose (YPD) agar plates were utilized for the growth experiments. For the investigation of thermotolerance, isolates were grown on regular YPD agar without any test substance and then incubated at 37, 40, 42, and 45°C.\n\nGraphPad Prism version 9.4.0 for Windows, developed by GraphPad Software, San Diego, California, USA (www.graphpad.com), was used to create the heatmap plot and other graphs. Data were also analyzed using a repeated measures one-way ANOVA with a Geisser-Greenhouse’s epsilon correction to show a significant difference. Pearson’s correlation was used to evaluate correlations between sample substrates and seasons. The means were calculated, and significant differences between the means (p < 0.05) were evaluated using analysis of variance (ANOVA). A Venn diagram (https://bioinfogp.cnb.csic.es/tools/venny/) was used to indicate the distribution of stress-tolerant yeast species in sample sources.\n\n\n3. Results and Discussion\n\nAmong the habitats explored for diversity and distribution of yeasts, plant surfaces, especially epiphytic yeasts on leaves and bark, showed the highest diversity. These findings are consistent with prior research, which reported the prevalence of yeasts in soil, marine environments, wildflowers, and even honey bee colonies.16–19 Among the collected samples, the highest yeast abundance was observed in bark samples (163 isolates), followed by soil (120 isolates) ( Table 2). This supports the assumption that yeasts colonize plant surfaces more prolifically than other habitats, possibly due to the diverse and dynamic microhabitats available in the phyllosphere. Bark, in particular, provides favorable niches for yeast proliferation, mainly due to its moisture retention and shelter from extreme environmental factors.20\n\nGeographical location might also play a significant role in shaping the yeast community structure. The Yayo Biosphere Reserve in the Iluabaor Zone yielded the most diverse range of wild yeast genera, followed by the Boter-Bacho Forest in Jimma Zone ( Table 2). This geographic variation in yeast isolation rates highlights the influence of local environmental conditions, such as temperature, humidity, and substrate composition, on yeast biodiversity.1\n\nOur results show that different substrates, including soil and phyllo-plane, harbor distinct yeast communities, suggesting substrate specificity in yeast colonization. This is in line with findings from previous studies, which reported that substrate type significantly influences yeast distribution patterns.16–19 For example, the yeast genera associated with soil were more diverse than those on the phyllo-plane, possibly due to the soil’s richness in organic matter and its ability to serve as a reservoir for microbial life. By examining the relationships between yeast genera and their respective habitats, we provide new insights into the ecological roles and dispersal strategies of these microorganisms.\n\nYeast colonies grown on YPD medium were classified into distinct phenotypes based on observable morphological traits. Predominant macroscopic characteristics included smooth (62%) or rough (14%) colony textures, circular (92.4%) or wrinkled (4.7%) shapes, smooth (75.9%) or filiform (17.5%) margins, and coloration ranging from white (46%) to cream (5.6%) or white-cream (35.7%) (Figure 1).\n\nMicroscopic examination revealed diversity in cell shape and size, with apiculate (17.2%), round (28.1%), and oval (20.3%) shaped cells being most common. Cell sizes varied between small (17%), medium (57.6%), and large (25.1%), and the majority of cells reproduced by budding (82.7%), while the remaining cells (17.2%) did not exhibit budding (Figure 2). Further analysis of wild yeast isolates from diverse sources displayed some characteristics, including creamy white pigmentation, smooth or rough colony texture, opacity, convex elevation, and entire or undulating margins. Other cells exhibited ellipsoidal, ogival, spherical, or oval morphologies, results consistent with findings from prior studies.21\n\nPhysiological and biochemical profiling, including sugar fermentation, tolerance to ethanol salt, and growth temperature, was conducted on 406 yeast isolates, classified based on their morphological characteristics. Substrate fermentation was assessed over 72 hours, with measurements taken at 12-hour intervals. Among tested carbon sources, D-glucose supported the most rapid yeast growth and fermentation, with about 50% of the isolates fermenting D-glucose, a crucial trait in biotechnological applications. Hexose transporters (Hxt) and high-affinity glucose transporters (Hgt), with up to 20 distinct transporters contributing to rapid glucose metabolism in yeast cells, might facilitate glucose uptake.22 Isolates screened from bark samples displayed the highest fermentation rates, followed by those from rhizosphere soil, while tree leaf isolates showed relatively slower growth and fermentation (Figure 3a). Notably, 18% of the isolates initiated glucose fermentation within 12 hours. Additionally, 27% and 34% of the isolates were capable of fermenting galactose and sucrose, respectively (Figure 3b and c), indicating possession of the gene responsible for the transport of sugars. GAL2 genes are known to play a critical role in galactose transport.23 After 72 hours, 52% of the isolates fermented fructose, surpassing sucrose fermentation at 44%, which is consistent with previous findings by Camargo et al. and other researchers.22–24 About 23% of the isolates could ferment sucrose, aided by the enzyme invertase.\n\na. Evaluation of gas-producing wild yeasts and the duration of fermentation in glucose cultures derived from soil, litter, and bark. b. Percentage of gas producing yeasts at different fermentation times from glucose, fructose, and sucrose. c. percentage of sugar fermenter wild yeast isolates cultured on different substrates after 72 h of incubation.\n\nApproximately 20% of wild yeasts were able to ferment maltose, suggesting their potential applications in brewing and baking industries. Maltose25 metabolism requires a proton gradient and expression of maltose permease for efficient carbohydrate utilization.25 Additionally, 65% of the isolates fermented both glucose and fructose separately, while only a smaller proportion fermented lactose (10%) and xylose (9%) (Figure 3c). The ability to ferment xylose, a crucial substrate for biofuel production, highlights the industrial relevance of these yeasts. These results significantly surpass previous findings by Camargo et al.24 and other researchers26 demonstrating broader metabolic versatility among wild yeast isolates, particularly in lactose, xylose, and maltose fermentation. Wild yeast strains that can ferment xylose are becoming increasingly crucial as lignocellulosic substrates are used to produce ecological fuels.27,28\n\nIn this study, a total of 406 yeast isolates were screened from various plant surfaces and rhizosphere soils and identified using morphological, physiological, and biochemical characteristics following the standard procedure suggested by Yarrow,29 before categorizing them into 15 genera. Among these genera, four were basidiomycetes (Cryptococcus spp., Rhodotorula spp., Sporidiobolus spp., and Trichosporon spp.), while 11 were ascomycetes (Candida spp., Kodamaea spp., Meyerozyma spp., Pichia spp., Saccharomyces spp., Geotrichum spp., Kloeckera spp., Rhodotorula spp., and Hanseniaspora spp.). Our research contradicted the conventional wisdom that ascomycetous yeasts were more common and abundant in agricultural soils, orchards, and grasslands.30 Although ascomycota were the more diverse genera, their abundance was significantly higher than that of basidiomycetes ( Table 3 and Figure 4).\n\nRegarding the frequency of identification of yeast genera, the highest numbers were derived from the plants Ficus vasta (52 isolates), Cordia africana (41), Ritchiea albersii (35), Ficus exasperata Vah (32), and Ficus sycomorus (28) (Figure 4). In contrast, the lowest genera of yeast were counted from Ekebergia capensis and Acokanthera shimperi. Among the dominant genera associated with the above plants was Candida spp. On the other hand, ascomycetes were the most abundant yeasts in Ficus exasperata Vah, while Saccharomyces spp. and Meyerozyma spp. were prevalent inFicus sycomorus and Albizia grandibracteata, respectively.1,31,32 The least common genera across all plant samples were Kloeckera spp. and Rhodotorula spp. (basidiomycetes), each representing only 0.5% of the total isolates ( Table 3, Figure 4) in agreement with previous reports.20,33 Yeast diversity also varied by source, with rhizosphere soil, bark, leaf, and litter samples showing different compositions. Across all sampling sources, the most frequently isolated genera were Candida spp. (24%), Saccharomyces spp. (12.3%), Meyerozyma spp. (10.8%), Pichia spp. (10%), Geotrichum spp. (9.9%), and Hanseniaspora spp. (9.4%) ( Table 3). These genera were isolated from almost all plant samples, though their relative abundances varied. The dominance of Candida spp. (98 isolates, 24%) in all plant sources except for litter highlights its widespread occurrence. Previous studies, such as Rao et al.34 and Koricha et al.,14 have similarly isolated yeast taxa, including Pichia, Candida, and Rhodotorula, from fruits and tree barks.\n\nSaccharomyces spp. were predominantly isolated from the bark samples of Ficus sycomorus (Harbuu), Syzygium guineense (Baddeessa), Ficus vasta (Qilxuu), and Cordia Africana (Wadeessa), with the highest numbers from Botor-Becho sites (13 isolates) and Yayo Biosphere Reserve (12 isolates) ( Table 3). Saccharomyces spp. were absent from the leaf samples of Belete-Gera and the rhizosphere soil of Botor-Becho. This genus, commonly associated with locally fermented foods and beverages as practiced by humans,35 is often found on oak trees, damaged fruits, and tree bark36 and plays a key role in industrial applications such as ethanol production, enzyme synthesis, and feed fermentation.37\n\nMeyerozyma spp., notably Meyerozyma guilliermondii, were prevalent in the bark samples from Botor-Becho (13 isolates) but absent from the leaves and litter of Belete-Gera and Botor-Becho ( Table 3). Meyerozyma spp. is known for their efficiency in xylose fermentation, with a conversion rate of 85%, making them valuable for xylitol production from lignocellulosic materials. This yeast has been isolated from various environments such as tree bark, decaying wood, and soil.\n\nPichia spp. were identified across all sample sources except for bark and rhizosphere soil from Belete-Gera. It was more prevalent in the rhizosphere soil of Yayo Biosphere Reserve (11 isolates) and the bark of Botor-Becho (9 isolates) than in other sample sources. Pichia spp., particularly Pichia kudriavzevii, are notable for their potential in microbial oil production, single-cell proteins, ethanol production, and phytase activity.8,38,39 Isolates, such as P. kudriavzevii KVMP10, are recognized for their thermotolerance, showing promise for their application in high-temperature fermentation processes. A number of thermotolerant yeast species, including Pichia kudriavzevii KVMP1040 and P. kudriavzevii KKU–TH33 and KKU–TH43,41 were isolated from natural habitats and have been identified.\n\nGeotrichum spp. and Candida spp. were the dominant genera isolated from Belete-Gera , while Meyerozyma and Pichia spp. were most prevalent in Botor-Becho ( Table 3). At Yayo Biosphere Reserve, Candida spp., Hanseniaspora spp., and Saccharomyces spp. were the most dominant isolated genera, with frequencies of 27.7%, 14.9%, and 12.82%, respectively. Geotrichum spp., commonly found on fruits and leaves, are linked to soil and can be spread by insects and other environmental factors. Among the commonly identified yeast species, Candida species, such as C. shehatae, are used in xylose fermentation.42–44\n\nAmong the 60 stress-tolerant species identified using MALDI-TOF MS technology, the dominant ones are Meyerozyma guilliermondii (10 isolates), Candida pelliculosa (7), Trichosporon asahii (8), Pichia kudriavzevii (7), and Saccharomyces cerevisiae (6) (Figure 5). These species were widely distributed across various sample types. As reported earlier, the non-conventional yeasts, known for their stress tolerance, were represented by Saccharomyces, Schizosaccharomyces, Dekkera, Pichia, Pachysolen, Kluyveromyces, Candida, and Meyerozyma.21,45 The bark of Sysygium guineense (Baddeessa), Ficus vasta (Qilxuu), Ficus sycomorus (Harbuu), and Cordia Africana (Wadeessa) were key sources of S. cerevisiae.\n\nYeast species distribution varied across substrates. For instance, 25% of the species were exclusively associated with bark, and 6.3% each with rhizosphere soil and leaves. Species commonly found across all substrates except leaves were S. cerevisiae, M. guilliermondii, Pichia norvegensis, T. asahii, and C. pelliculosa. Notably, Pichia kluyveri and C. krusei. Kodamaea ohmeri was specific to leaves and leaf litter, while bark, leaf, and litter shared P. norvegensis and C. valida (Figure 6).\n\nThe distribution of yeast isolates varied significantly across seasons, with the highest number of isolates recorded during the summer. Specifically during the summer season, 29 yeast isolates were obtained from Ficus sycomorus, 25 from Ficus exasperata Vah, and Ritchiea albersii. Additionally, 19 isolates were recorded from Cordia africana in autumn and 23 from Ficus vasta in the spring. Accordingly, summer yielded the most common yeast species, namely Candida spp. (41 isolates), followed by Hanseniaspora spp. (24) and Saccharomyces spp. (21). In autumn, Candida spp. (39) and Geotrichum spp. (27) dominated the isolated yeast population, while in spring, Meyerozyma and Pichia spp. were the most frequently encountered yeast species (Figure 7).\n\nSeasonal variations in yeast abundance were also significant. While no correlation was observed between autumn and spring, a strong correlation was found between autumn and summer (r = 0.79, P = 0.009). Spring and summer also showed a favorable correlation (r = 0.53, P = 0.043), indicating seasonal fluctuations in yeast distribution. Seasonal variations, plant species, soil type and depth, and site characteristics were identified as key factors influencing yeast diversity and abundance.44 Deciduous and evergreen leaves, along with their respective environments, greatly impact seasonal shifts in the composition of leaf-associated yeast communities.33 Some of these leaf yeasts enter the soil community as leaves decompose, although their numbers decrease significantly. Seasonal variations in yeast populations, such as a rise from 105 to 107 per gram of pasture grass leaves, have been observed, with the highest numbers occurring in summer and the lowest in winter, as noted by Robinson et al.46 Temporal shifts in yeast communities on tree bark have been documented in temperate forests, though it remains unclear whether these patterns are seasonal or random.3,47\n\nThis study explores the impact of various factors, including seasons, sample type, sample location, and host plant quality, on the abundance and diversity of wild yeast isolates. Tree bark was found to harbor the highest mean abundance of yeasts (10.7), while a weak positive correlation between yeast abundance in soil and bark (r = 0.326, P < 0.040) was observed. No correlation was found between yeast presence in bark and leaves (r = 0.064, P < 0.697), but significant differences between bark and leaf samples (t39 = 5.19, P < 0.00) were identified. The study also showed a significant positive correlation between yeast abundance in the rhizosphere soil and litter (r = 0.370, P = 0.019), confirming the interaction between soil and litter. The data indicated that rhizosphere soil and leaves differed significantly in yeast abundance (t39 = 3.293, P = 0.002), while no correlation was detected between bark and litter or leaves and litter (Figure 8).\n\nThe Yayo Biosphere Reserve yielded the highest mean number of yeast genera (13), demonstrating a significant difference in yeast populations between study sites. Across the study locations, the mean abundance of yeast genera was significant (Figure 8a). There was a noticeable difference in the mean yeast genus abundance between the bark and leaf and between the rhizosphere soil and litter. But there was no significant variation between the rhizosphere soil and the bark (Figure 8b). The structure of yeast communities in litter was found to be strongly influenced by the predominant tree type, with the litter contributing secondary metabolites that act as nutritional sources for specific yeast species. These metabolites were proposed to be the primary factor influencing yeast composition, rather than the nutrient content.48\n\nThe study also highlights that microbial communities vary between litters with identical nutritional content but differing origins, with soils beneath litter supporting a more diverse yeast community compared to those under logs. Tree bark in natural forests was identified as a rich habitat for stress-tolerant Ascomycetes species, resistant to adverse laboratory conditions, which may play a role in nitrogen cycling and community resilience in variable moisture conditions.\n\nTable 4 displays the wild yeasts’ tolerance profile to various factors. Eighteen isolates from Boter-Becho sites in the spring and eleven from Yayo Biosphere Reserve sites in the summer were the highest isolates of wild yeast that could tolerate 42 °C from tree bark. Eight isolates of wild yeast from summertime litter at Yayo Biosphere Reserve locations had the highest tolerance rate, able to withstand 16% of ethanol. Fifty-one wild yeast isolates from tree bark collected in the spring at Boter-Becho sites had the maximum ability to tolerate glucose, at 60%. In spring, 11 isolates from Boter-Becho sites’ tree bark and leaf and 14 isolates from Yayo Biosphere Reserve sites’ tree bark throughout summer were the greatest number of wild yeast that could tolerate 12% salt concentration.\n\n3.8.1 Ethanol tolerance of wild yeasts\n\nComparatively speaking, Candida spp. (n = 10) and Meyerozyma spp. (n = 3) exhibited greater resistance to high ethanol concentrations (16%) than other yeast genera. While the isolates from other genera only showed some inhibition at 12% ethanol, the majority of the latter genus isolates were severely inhibited at 14% and 16% ethanol. Particularly, the genera of Candida spp, Meyerozyma spp, Saccharomyces spp, and Hanseniaspora spp proved to be more resistant to this stress (Figure 9a). Litter strains outperformed isolates from other origins in terms of average ethanol tolerance levels, whereas leaf strains showed significantly lower tolerance to all tested ethanol concentrations. The majority of ethanol-tolerant wild isolates at 16% ethanol concentration were found in litter, although isolates from rhizosphere soil and bark did not differ significantly in their ethanol tolerance of 8–12% of the ethanol concentration (Figure 9b).\n\nAccording to reports, several species in this genus have a high tolerance to ethanol and can even dominate industrial bioethanol fermentations and wine as contaminants.49 This implies that achieving a greater ethanol titer through very-high-gravity fermentation could be an effective way to prevent these industrial contaminants. In yeast, ethanol decreases the growth, viability, and rate of fermentation of cells. A useful method for characterizing yeast species and strains that are being examined for use in alcoholic fermentations is to expose the yeast culture to ethanol at several concentrations until cellular growth inhibition occurs. This process allows one to determine the yeast’s tolerance to ethanol. Similar to other wild yeast isolates reported by,50 we found that the growth of the isolates reduced with increasing ethanol concentration in the medium.\n\nThere were fewer tolerant genera of yeast in samples that were incubated at 30 °C when the ethanol concentration was raised from 8 to 16%. Figure 9a shows the results of a repeated measures one-way ANOVA with a Geisser-Greenhouse’s epsilon correction, which showed a significant change (P = 0.0260) of the number of tolerant yeasts to ethanol concentrations between genera of yeasts (columns) and a highly significant difference (P < 0.0001) between ethanol concentrations (rows). Additionally, the analysis revealed a significant difference (P = 0.0007) in the number of tolerant yeasts to ethanol concentrations between sample sources (columns) but no significant change (P = 0.0786) across rows, as illustrated in Figure 9b.\n\nRemarkably, 50% w/v glucose was tolerated by at least some isolates of the majority of the assessed yeast genera. This is rather unexpected because many of those genera’ tested strains were isolated from environments without high sugar concentrations, which would seem to make them less likely to have developed tolerance mechanisms specific to osmotic stress. Consequently, these genera’s high general stress tolerance may be the cause of their tolerance to high sugar. It is commonly recognized that in many yeast species, the capacity to effectively transport glycerol into the cells is a crucial defense against osmotic stress.20,51–54 It is therefore probable that the majority of these yeast taxa possess a strong route for both the manufacture and absorption of glycerol. However, because of the high osmotic pressure brought on by high glucose concentrations, a reduced rate of yeast cell multiplication was noted as the glucose rose.55\n\nFigure 9a shows the outcomes of a repeated measures one-way ANOVA with a Geisser-Greenhouse’s epsilon correction. The findings showed that there was no significant variation (P = 0.1233) in the number of yeasts that were tolerant to osmotic pressure across genera of wild yeasts (columns), but there was a significant difference (P = 0.0017) between rows (glucose concentration). Additionally, as Figure 7b illustrates, the study revealed no significant variation (P = 0.0959) in the number of tolerant yeasts to osmotic pressure between columns, but a significant change (P = 0.0149) across rows (Figure 9b).\n\n3.8.2 Temperature tolerance of wild yeasts\n\nAt 37, 40, 42, and 45 °C respectively, about 57, 24, 20, and 2.46 % of the isolates showed marked resistance to the assessed temperature. We have found several yeast genera that grow at 42 °C in this investigation. Specifically, when exposed to a high temperature, the majority of isolates of Candida (23), Meyerozyma (13), Saccharomyces (8), and Pichia (10) showed tolerance to the highest temperature tested (42 °C) (Figure 9a). Based on sample sources, bark collected from natural forests was the source of isolation for the majority of the thermotolerant wild isolates (Figure 9b). Interestingly, resistant isolates of Saccharomyces (1), Meyerozyma (1), Pichia (4), and Candida (4) were found to be tolerant at the maximum temperature (45 °C) that was tested. As shown in Figure 9b, out of all the 45 °C tolerant isolates mentioned above, five were isolated from tree leaves. The sudden changes in relative humidity and temperature that leaves experience could have an effect on the yeast population. One of the most prominent features of the leaf surface environment is that microorganisms have probably had to adapt to high fluxes of UV radiation.56,57 Because thermo-tolerant can reduce cooling costs, avoid bacterial contamination, and shorten the optimal temperature difference between enzymatic hydrolysis (45–50 °C) and fermentation (30–37 °C), a yeast that can ferment above 40 °C is chosen for usage in manufacturing environments.49 Based on sample sources, bark collected from natural forests was the source of isolation for the majority of the thermotolerant wild isolates (Figure 9b).\n\nThe results of a repeated measures one-way ANOVA with a Geisser-Greenhouse’s epsilon correction. The data indicated a highly significant difference (P<0.0001) between rows and no significant change (P = 0.0894) in the number of tolerant yeasts to temperature stress between genera of wild yeasts (across columns). Furthermore, as shown in Figure 7b, the analysis indicated a significant change (P = 0.0017) across rows but no significant variation (P = 0.1109) in the number of tolerant yeasts to temperature stress between sample sources (columns).\n\n3.8.3 Halotolerance (NaCl) of wild yeasts\n\nFigure 9a provides an overview of the salt tolerance for each yeast genus. About 94.5, 61, 29, and 24% of the isolates showed significant resistance at 4, 8, 10, and 12% of NaCl, respectively. To be more specific, most isolates of Candida (22), Meyerozyma (15), Saccharomyces (12), Pichia (12), and Hanseniaspora spp. (6) exhibited resistance when exposed to a high concentration of NaCl (12%) (Figure 9a). For instance, strains of Zygosaccharomyces and Schizosaccharomyces, which were previously thought to be osmotolerant, were discovered to be susceptible to salt stress. This might point to a specific osmotolerance mechanism of these genera that fails to protect against ion toxicity brought on by salt stress at high sugar concentrations. It is vital to investigate how well yeasts tolerate high concentrations of salt (ionic stress) in commercial fermentations, as salt can promote yeast growth, improve ethanol production, and lower the danger of contamination by low-halotolerance microorganisms.50 According to Mukherjee et al.,58 stress brought on by high concentrations of sodium chloride (NaCl) has been demonstrated to be more harmful from high intracellular cation concentrations than from hyperosmotic stress. Our findings supported previous observations54 that yeast cell development is enhanced by a combination of mild temperature and salt stressors. On average, isolates with varying sample sources showed differing levels of tolerance towards NaCl. Accordingly, the majority of halotolerant wild isolates were found in rhizosphere soil and bark from natural forests; yeast genera from these sources had a higher tolerance to NaCl than litter and leaves.\n\nThe data indicated a highly significant difference (P < 0.0001) between rows and no significant change (P = 0.0894) in the number of tolerant yeasts to salt stress between yeast genera across columns (Figure 9a). Additionally, Figure 9b displayed the distribution of NaCl stress-tolerant yeasts from various sources. The result revealed that while there was no significant variation (P = 0.0626) in the number of tolerant yeasts to NaCl stress between sample sources, there was a highly significant shift (P < 0.0001) across salt concentrations.\n\n\nConclusions\n\nThis study provides a comprehensive analysis of the diversity, distribution and phenotypic characterization of yeast species in the rhizosphere soil and plant surfaces within a natural forest in southwestern Ethiopia. The findings revealed the presence of diverse yeast genera, including Candida, Saccharomyces, Meyerozyma, Pichia, Geotrichum, and Hanseniaspora, with the highest yeast isolation rates occurring from the bark of tree species such as Qilxuu, Waddeessa, Deqoo, Baalantaa’ii, and Harbuu. The prevalence of yeast isolates in tree bark suggests that it serves as a primary substrate for yeast colonization, while some genera were found to inhabit multiple plant hosts, indicating non-host-specific behavior.\n\nThe weak positive correlations between yeast abundance in rhizosphere soil and both bark and litter suggest some interaction between these substrates. However, there was no significant correlation between yeast counts in leaves and either bark or rhizosphere soil, highlighting the distinct microbial communities associated with different plant parts. Additionally, seasonal variations were observed, with spring and summer showing a strong positive correlation in yeast abundance, whereas autumn displayed no significant associations with other seasons.\n\nThe study identified several stress-tolerant yeast species, such as Meyerozyma guilliermondii, Trichosporon asahii, Candida pelliculosa, Pichia kluyveri, and Saccharomyces cerevisiae, which were capable of surviving under extreme conditions, including ethanol, heat, osmotic stress, and saline environments. These species were found across a variety of substrates, demonstrating their adaptability to different ecological niches.\n\nIn general, substrate type and geographic location significantly influence the distribution of yeast species in natural ecosystems. The identification of stress-tolerant yeasts with biotechnological potential further highlights the importance of natural forests as reservoirs for microbial diversity. These findings not only contribute to the understanding of yeast ecology but also offer a foundation for future bioprospecting efforts and ecological monitoring in similar environments.\n\n\nCredit authorship contribution statement\n\nKB: Conceptualization, Formal analysis, Supervision, Manuscript review; TT: Conceptualization, Investigation, Formal analysis, Writing - original draft, Visualization; AD: Formal analysis, oversight, conceptualization, original draft review, visualization, and funding acquisition; DD: Research, Formal examination and composing a first draft.", "appendix": "Data availability\n\nFigshare: Diversity, Diversity and Tolerance profile of Wild Yeasts from Natural Forests, https://doi.org/10.6084/m9.figshare.28078370.59\n\nThe underlying data for this project includes the following:\n\n• Distribution and abundance of wild yeasts in the examined substrates collected from the study areas and plant species.\n\n• Distribution of wild yeast isolates at different seasons.\n\n• Tolerance profile of wild yeast genera to particular stress conditions.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgement\n\nThe authors wish to express their sincere gratitude to Jimma University’s College of Natural Sciences for providing financial assistance.\n\n\nReferences\n\nYurkov J, Inácio IY, Chernov Á: Fonseca, Yeast Biogeography and the Effects of Species Recognition Approaches: The Case Study of Widespread Basidiomycetous Species from Birch Forests in Russia. 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Publisher Full Text" }	[ { "id": "360818", "date": "31 Jan 2025", "name": "Pablo Villarreal", "expertise": [ "Reviewer Expertise Microbial ecology" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript by Tadesse et al., Diversity, Distribution, and Phenotypic Characterization of Cultivable Wild Yeasts Isolated from Natural Forest, presents an interesting and relevant study on the diversity and distribution of cultivable yeasts in rhizosphere samples and other plant-associated habitats from natural forests in Africa.\nThis study could significantly contribute to the understanding of yeast ecology in a geographically underexplored region, highlighting the importance of these microorganisms in natural ecosystems. The data obtained through morphological, physiological, and biochemical analyses, combined with MALDI-TOF identification, are valuable and can be a reference for future studies. However, the manuscript has some limitations and areas that should be improved before indexing.\nOne of the major concerns is the methodology used for yeast isolation, which introduces a significant bias throughout the study. Using an enrichment medium (pre-culturing the samples in YPD) selectively favors certain yeast species, which may skew the results and lead to overgeneralized ecological conclusions. For example, observing that more yeasts were isolated from bark than from soil could be a direct consequence of the isolation technique rather than an actual ecological pattern. Without a more unbiased approach, the findings should be interpreted with caution.\nAdditionally, MALDI-TOF is not an entirely reliable method for species-level identification and should ideally be complemented with molecular marker sequencing, such as ITS or D1/D2, to confirm species assignments. The manuscript does not clearly explain the rationale behind sample selection and does not justify why more samples were collected from specific locations than others.\nThis inconsistency extends to seasonal comparisons, where varying samples across different seasons could introduce biases. If higher yeast abundance is observed in a specific location or season, it may result from sampling inconsistencies rather than a proper ecological pattern.\nFurthermore, there is a lack of methodological details on how yeast growth was measured. It is unclear how growth curves were performed, what specific parameters were measured, and which kinetic factors were compared. These details are crucial for ensuring reproducibility and validating the conclusions drawn from the data. The figures presented in the manuscript also do not support the conclusions. A comparison of ODmax between isolates or growth rates could provide more robust evidence regarding stress tolerance among the yeast strains.\nIn summary, while the manuscript presents valuable findings, it lacks methodological rigor in several key aspects. A major revision is necessary to clarify the methodology, improve data interpretation, and ensure the results fully support the conclusions. Addressing these issues will significantly enhance the manuscript’s impact and reliability.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [] } ]	1	https://f1000research.com/articles/14-105
https://f1000research.com/articles/14-102/v1	17 Jan 25	{ "type": "Research Article", "title": "“Analyzing the determinants of rural household welfare in Ethiopia: Does agricultural technology adoption matters”: Using seemingly unrelated multi-variate probit model”", "authors": [ "Tadesse Wudu Abate", "Henok Ezezew Sheferaw", "Kalid Wendimnew Sitotaw", "Sisay Genanu Mulaw", "Henok Ezezew Sheferaw", "Kalid Wendimnew Sitotaw", "Sisay Genanu Mulaw" ], "abstract": "Background This study analyzed the nexus between rural household welfare and agricultural technology adoption in Ethiopia using secondary data from the Ethiopian Socioeconomic Survey (ESS). The agricultural sector plays a pivotal role in Ethiopia’s economy, contributing significantly to income, consumption, and employment. This research aims to analyze how adopting agricultural technologies such as improved seeds, fertilizers, and irrigation affects poverty and food insecurity among rural households. The research examined poverty and food insecurity levels in Ethiopia and investigates the impact of adopting agricultural technologies on rural household welfare.\n\nMethods We used both Descriptive and econometric methods, in which descriptive analysis has been used to assess poverty and food insecurity levels, and a seemingly unrelated bivariate and multivariate probit model applied to analyze the effect of agricultural technology adoption.\n\nResult From descriptive summary, it is noted that out of a total sample of the study, 47.61% (2322 out of 4877) are adopting agricultural technologies in many forms more than 70% of female-headed households are food secured and non-poor and 68% of male-headed households are food secured and nun poor. The findings from regression model indicate that access to irrigation, improved seeds, and fertilizers significantly reduces the likelihood of poverty and food insecurity among rural households.\n\nConclusion Based on these results, policy recommendations include promoting agricultural technologies, enhancing access to credit, investing in agricultural extension services, diversifying livelihoods, improving education, and implementing targeted poverty alleviation programs. Further research is encouraged to explore the reasons behind insignificant variables and to identify additional factors affecting rural household welfare in Ethiopia.", "keywords": [ "Agricultural technology adoption", "Gender Inequality", "Household welfare", "Multi-variate probit model", "seemingly unrelated regression" ], "content": "1. Introduction\n\nAgricultural sector had a paramount contribution and dominant role to the growth and development of many countries in the world (Nonvide, 2024) since it constitutes the highest share of income, consumption and employment generation (Pan et al., 2020). More specifically, in agricultural sector-dominated economies of least developed countries like those in sub Saharan Africa, their success and failure in bringing economic development are highly determined by their performance in agricultural sector (Adams & Jumpah, 2021). This is because of their high dependence on this sector, with more than 80% of their GDP share and employment creation coming form the agricultural sector (Wordofa & Sassi, 2020; Gelata, Han, & Limo, 2024; Habtewold, 2021; Shikur, 2023).\n\nIntroducing improved innovations and technology in agriculture is an important way to increase the productivity of Africa’s smallholder farmers, promoting economic growth and the well-being of millions of poor households (Adams & Jumpah, 2021). Unlike in many other parts of the world, many governments in Africa do not collect, research, and report critical data in the appropriate format and within the required time frames (Ali, Menza, Hagos, & Haileslassie, 2023). Without basic, descriptive information about who adopts improved agricultural technologies and who does not, it is difficult to develop effective policies to improve agricultural productivity (Asrat, Anteneh, Adem, & Berhanie, 2022).\n\nAdopting modern agricultural technology has a significant impact on improving the welfare of a given society by supporting the fundamental need for food and feeding an ever-growing population (Korir et al., 2023). Agricultural productivity can be improved when agricultural technologies are adopted by farmers, thereby reducing the poverty status of household farmers by increasing their income and consumption (Mutungi et al., 2023). Using this idea as starting point, many researchers have investigated the impact of agricultural technology adoption on the welfare of societies in different countries, including Ethiopia (Tesfay, 2023; Gelata et al., 2024). They have conducted research to assess the nexus between household welfare and agricultural technology adoption and noted that rural household’s welfare in terms of access to food, income, and expenditure is significantly increased with adopting modern agricultural technologies (Zegeye, Fikire, & Assefa, 2022).\n\nEthiopia, as a key constituent of the burgeoning economies within Sub-Saharan Africa, exhibits a profound economic reliance on agriculture, with over 70% of its export revenues, 80% of its GDP, and 60% of employment originating from this sector (Legesse, Srivastava, Kuhn, & Gaiser, 2019). A substantial portion of the population is still tethered to crop cultivation and pastoral activities, despite the pervasive use of antiquated production methods (Wassihun, Nega, Kebede, Fenta, & Ayalew, 2022). To elevate the living standards and welfare of Ethiopian citizens, it is crucial to supplant these obsolete agricultural practices with state-of-the-art technological innovations, such as enhanced seed varieties, fertilizers, modern irrigation systems, and agrochemicals to (Gebre, Amekawa, & Rahut, 2023). According to Abate (2024a), the alleviation of poverty and the achievement of sustained economic progress are contingent upon the transformation of the agricultural sector through the embracement of modern agricultural technologies. This sector’s pivotal role in rural livelihoods, in a nation where poverty is endemic, positions it at the epicenter of development strategies and policy interventions (Biru, Zeller, & Loos, 2020).\n\nIn this vein, various investigations have probed the effects of rural technology adoption on food insecurity, agricultural efficiency, and poverty reduction in Ethiopia. For instance (Ayenew, Lakew, & Kristos, 2020), applied propensity score matching (PSM) techniques to assess the impact of agricultural technology adoption on household welfare in the Amhara region. Their analysis revealed that the adoption of agricultural technologies substantially augmented household consumption, thereby enhancing welfare by mitigating poverty. In a similar vein (Bekana & Takele, 2020), employed PSM methods to examine the repercussions of adopting agricultural technologies on income inequality, finding that while innovations such as chemical fertilizers and improved seed varieties bolstered household income, they simultaneously exacerbated disparities in income distribution. Belay and Mengiste (2023) explored the effect of adopting a combination of complementary technologies on smallholder consumption, poverty, and vulnerability, determining that technology adoption markedly amplified consumption expenditure, with the most pronounced benefits occurring when multiple complementary technologies were integrated.\n\nAtinafu, Lejebo, and Alemu (2022) investigated the influence of introducing improved wheat varieties on the welfare of 4,444 households in Ethiopia. Their study found that factors such as credit availability, agricultural extension services, soil fertility, land size, off-farm employment, household head age, proximity to input markets, and farming experience were pivotal in shaping adoption decisions and intensity. Furthermore, BELETE (2023) reported that food insecurity in Sub-Saharan Africa and Eastern Africa stood at 26% and 28%, respectively, based on 2016 data. The trajectory toward achieving the 2030 goal of eradicating hunger is beset by numerous challenges. In alignment with (Gebre et al., 2023), Ethiopia is ranked among the African nations—such as South Sudan, Nigeria, Somalia, and the Central African Republic—experiencing the most acute levels of hunger in the reporting period.\n\nAs elucidated in numerous scholarly investigations, Ethiopian citizens continue to endure diminished welfare, as evidenced by indicators such as livelihood conditions, food security, and poverty levels (Sebsibie, Asmare, & Endalkachew, 2014). A prime example of this is the elevated incidence of poverty and household food insecurity in rural Ethiopia, which constitutes a formidable obstacle in the pursuit of sustained economic growth and development (Zegeye et al., 2022). The interim report further underscores that rural poverty remains disproportionately higher than its urban counterpart across all temporal intervals (Abate, 2024a). Notably, the nation-wide reduction in poverty is predominantly attributed to the alleviation of urban poverty, although both rural and urban areas have witnessed a general decline in poverty (measured in both incidence and depth). Nevertheless, the income distribution among the rural poor has shown negligible improvement (Ayenew et al., 2020).\n\nIn contrast, the prevailing drivers of hunger and impoverished living conditions in Ethiopia are widely considered to be a confluence of factors, including the widespread devastation wrought by the COVID-19 pandemic, civil unrest, internal strife, and constrained agricultural productivity. These elements are encompassed within the scope of this study (Bekana & Takele, 2020). To ameliorate the prevailing low welfare and living standards, it is imperative to analyze both the extent and the determinants of welfare, alongside its intricate relationship with the adoption of agricultural technology. Thus, the overarching aim of the present study is to explore the nexus between rural household welfare and the uptake of agricultural technology within the Ethiopian context. Specifically, the study seeks to probe the interdependencies between various welfare metrics and examine the influence of agricultural technology adoption on rural household welfare.\n\nThis research contributes to the extant body of literature in three distinct ways. First, it utilizes the seemingly unrelated multivariate probit model to investigate the impact of agricultural technology adoption on household welfare (Atinafu et al., 2022). This methodological innovation provides new insights by simultaneously considering three welfare dimensions uni-dimensional poverty, multidimensional poverty, and food insecurity rather than relying on a singular measure, as is commonly the case in much of the existing research (Mulugeta Habtewold & Heshmati, 2023).\n\nSecondly, this study considers the effect of recurrent internal conflicts and wars on the welfare of households, which was not previously considered. Thirdly, this study analyzes the interdependence of rural household welfare measurements instead of using only one proxy variable to indicate the welfare of a society. This means this study is the first to check whether households facing multidimensional poverty are also facing food insecurity.\n\nThe rest of the paper follows this structure, and the next section presents a concise review of the theoretical literature on the factors that affect rural household welfare, with special emphasis on agricultural technology adoption. It also includes empirical literature on the determinants of households’ welfare, both in Ethiopia and globally. Section III outlines the methodology, followed by a discussion of the estimation results in Section IV. The final section provides conclusions and recommendations.\n\n\n2. Literature review\n\nTheoretically, the adoption of agricultural technology is expected to enhance household welfare by boosting agricultural productivity and reducing poverty (Hawas & Degaga, 2023). However, the actual impact of adopting new technology largely depends on whether farmers decide to embrace it and, if they do, how quickly they adopt it. The rate of adoption is typically measured by how long it takes for a certain proportion of the population to incorporate the innovation. Additionally, innovations that are perceived as having a substantial relative advantage, high compatibility, low complexity, ease of repair, and clear visibility tend to experience faster adoption (Korir et al., 2023; Legesse et al., 2019).\n\nAdoption decisions are often framed as the result of an optimization process, where individuals seek to maximize expected returns (Massresha, Lema, Neway, & Degu, 2021). These returns are influenced by factors such as land allocation, the productivity of the technology, input costs, and output prices (Merga, Sileshi, & Zeleke, 2023). The positive effects of agricultural technology on economic growth, in terms of increased productivity and poverty reduction, will only be fully realized if the technology is widely adopted and consistently used (Mekonnen, 2017; Merga et al., 2023).\n\nThe diffusion of innovation transpires through a succession of individual determinations concerning the utilization of novel technologies (Mogess & Ayen, 2023). These choices are frequently made by juxtaposing the ambiguous advantages of a new invention against the uncertain costs of its deployment (Mujeyi, Mudhara, & Mutenje, 2021). When farmers contemplate the adoption of a specific technology, they are compelled to assess its potential ramifications against its economic, social, and technical viability (Mulugeta Habtewold & Heshmati, 2023).\n\nAlthough numerous studies have established that access to credit exerts a positive influence on household well-being (Mutungi et al., 2023), certain research contends that credit may have an adverse effect on household happiness (Nonvide, 2024). Conversely, research by Nsabimana and Adom (2024) and Ogundari and Bolarinwa (2019) has revealed that loans tend to diminish household consumption. Notably, Pan et al. (2020) found a 15 percent reduction in both permanent and non-permanent household consumption within the treatment group in comparison to the control group. Furthermore, Shikur (2020, 2023) explored the impact of informal credit on poverty and inequality, concluding that credit fosters poverty alleviation.\n\nThe extant literature substantiates the assertion that technology adoption engenders significant enhancements in productivity, poverty reduction, and overall living standards globally (Shita, Kumar, & Singh, 2023). Similarly, empirical studies within Ethiopia have demonstrated that the adoption of advanced agricultural technologies enhances productivity and societal welfare (Shokati Amghani, Mojtahedi, & Savari, 2023), while simultaneously bolstering food security for smallholder farmers (Sinha & Nag, 2023).\n\nAccording to Tefera, Haji, and Ketema (2023), the exclusive utilization of enhanced seed varieties and synthetic fertilizers has the potential to augment crop productivity in Ethiopia by 7.38% and 6.32% annually, respectively. Notwithstanding the escalating adoption rates and their salutary effects on agricultural output and productivity, a significant proportion of rural households in Ethiopia continue to subsist under precarious living conditions. Presently, wheat cultivation occupies roughly 16% of the nation’s total arable grain production area, with approximately 36% of grain-producing households being directly dependent on wheat farming. Despite these figures, the national average wheat yield remains suboptimal at 1.83 tons per hectare (Tesfay, 2023), a marginal increase from 2.7 tons per hectare in 2018. Moreover, wheat productivity is projected to rise to 2.77 tons per hectare during the 2019/2020 harvest season, expanding the total cultivated area to 1.66 million hectares. However, Ethiopia remains incapable of fulfilling its domestic wheat requirements, with annual production estimated at approximately 4.6 million tons, while consumption substantially exceeds this output, reaching approximately 6.3 million tons per annum (Tesfaye & Tirivayi, 2018; Tilahun, Bantider, & Yayeh, 2023). In addition to the persistently low yield levels, the demand for wheat continues to escalate in both rural and urban sectors of Ethiopia’s economy (Tilaye, Delele, & Ogeto, 2023), intensifying the disparity between supply and demand, thereby exacerbating the prevailing poverty endemic to the nation.\n\nAccording to Tolola (2023), many countries have contact builders such as Model Builders in Ethiopia and Master or Progressive Builders (Verkaart, Munyua, Mausch, & Michler, 2017) in Malawi to assist government advisors in technology transfer and information provision. There is a long tradition of doing so (Wordofa et al., 2021).\n\nAccording to Wordofa and Sassi (2020) and Wossen et al. (2017), model farmers represent a distinct cohort characterized by relatively superior resource endowment, a proclivity for early adoption of agricultural innovations, and the capacity to implement a substantial portion typically at least 70% of the technology packages promoted by agricultural extension systems. These farmers are operationalized as those who not only incorporate advanced farming systems but also meet specific definitional thresholds. Their influence within the agricultural milieu is acknowledged by development practitioners and grassroots workers, who regard them as key drivers of agricultural modernization. The discourse surrounding the impact of credit on household welfare is multifaceted. While savings are conceptualized as a mechanism for ensuring future economic stability, credit is positioned as an instrument of financial liberation, providing a conduit for households to transcend immediate fiscal constraints and, thereby, preserve or augment their current well-being (Ali et al., 2023).\n\nCreditworthiness is contingent upon mutual trust from both the creditor and debtor’s vantage points (Bekana & Takele, 2020). The creditor’s utility is influenced by the propensity to defer current consumption in favor of future savings, while the debtor’s welfare is shaped by the trade-off between immediate financial relief and the eventual burden of future obligations, including interest payments. Should the arrangement falter, the debtor bears the onus of repayment. Although a plethora of studies assert that credit exerts a salutary effect on household well-being, there exists a corpus of literature that posits a deleterious impact of credit on household felicity.\n\nOn the negative side, research by Atinafu et al. (2022) identified a deleterious effect of loans on household consumption. Specifically, it revealed a 15% reduction in the consumption of both durable and non-durable goods among 4,444 households in the treatment group relative to the control cohort. Similarly, Atumo and Samago (2023) and Ayenew et al. (2020) explored the ramifications of informal credit on poverty alleviation and inequality, concluding that credit exerts a favorable influence on poverty reduction. Their findings showed that 4,444 impoverished regions predominantly accessed loans from informal rather than formal institutions, with a marked decline in borrower poverty rates by 8 percentage points. BELETE (2023) emphasized the intrinsic link between poverty, consumption, and wealth, suggesting that poverty reduction is inextricably tied to heightened consumption levels and overall welfare enhancement. Additionally, the analysis by Bruno, Florencia, Esther, and William on micro-credit’s effect on household consumption expenditures found a marginally negative influence of credit on consumption patterns (Belay & Mengiste, 2023).\n\nThe use of aggregate consumption as a household-level welfare indicator to measure poverty has often been criticized (Gebre et al., 2023). This is because people think they don’t really show what folks actually use. This article looks at when and how we can tweak spending data from household surveys to get a clearer picture of what essential services people actually use. Habtewold (2021) asserts that markets impacted by subsidy structures, allocation rationing, and elevated cross-border tariffs are analyzed, with incremental recalibrations suggested to mitigate these economic distortions. The study by Feyisa (2020) conducted a study using the Tobit model to explore the drivers behind the implementation and usage intensity of barley malting technology in the Limna Bilbiro, Shashemene, and Kofere districts within the Oromia National Regional State (Gelata et al., 2024; Assaye, Habte, & Sakurai, 2023).\n\nAnother study was conducted by Kebede (2022) focuses on investigation that delves into the elements swaying the uptake and level of commitment to the barley malting tech package in Marga Woreda, by leveraging the Tobit model. The findings reveal that key aspects influencing the inclination to adopt and used include schooling, family headcount, plot size, loan access, co-op membership, access to hands-on learning, and exposure to demos (Gebre, Isoda, Amekawa, & Nomura, 2019). Moreover, the total number of critters and how far they are from the nearest marketplace play a meaningful role in shaping farmers’ decisions to hop on board and how fully they commit to adopting (Zegeye et al., 2022).\n\nAfter considering the previously conducted studies indicated above, the contextual frame work of the study is developed as follows. In the diagram below ( Figure 1), the nexus between rural household’s welfare and agricultural technology adoption is briefly analyzed. How the agricultural technology adoptions in the form of improved seeds, fertilizers and irrigation can affect farmer’s welfare as measured by food insecurity, unidimensional poverty, and multi-dimensional poverty. In addition to those agricultural technology adoptions, the effect of socio-economic and contextual factors such as education level, household age and dependency ratio on welfare is analyzed.\n\n\n\n\n\n\n\n3. Method\n\nThe data used in this study is secondary data obtained from ESS (Ethiopian Socio-economic survey). The Ethiopian Socioeconomic Survey (ESS) data was collected by the Central Statistical Agency (CSA) of Ethiopia in collaboration with the Living Standards Measurement Study Integrated Surveys on Agriculture (LSMS-ISA) of the World Bank. The data collection process included the following steps. The ESS sample was designed to be representative of Ethiopia’s small towns and rural areas. The sampling frame included households from the Amhara, Oromia, Southern Nations, Nationalities, and Peoples’ Region (SNNP), Tigray, Afar, Benshangul Gumuz, Gambella, Harari, and Somali Regional States, as well as the city government of Dire Dawa. The survey involved a two-stage stratified sampling technique. In the first stage, enumeration areas (EAs) were selected from each region based on probability proportional to size. In the second stage, households within these EAs were randomly selected. A total of 4,870 households were included in the sample for the study. This sample size was determined to ensure that the survey results would be statistically significant and representative of the broader population. Data was collected through household interviews using structured questionnaires. The survey covered various socio-economic indicators, including household demographics, education, health, employment, agriculture, and income. To ensure the quality and accuracy of the data, field supervisors conducted regular checks and validation of the collected data. The data collection process also involved training enumerators and supervisors on the survey instruments and data collection procedures.\n\nBoth qualitative and quantitative methods of analysis with descriptive and econometric applications are used. Descriptive analysis is used to investigate the extents of poverty and food insecurity in the study area while econometric analysis is applied to identify the determinants of rural household’s welfare by considering agricultural technology adoption as the major factor to affect welfare of the society. Uni-dimensional Poverty (Wossen, Alene, Abdoulaye, Feleke, & Manyong, 2019) can be measured using per adult consumption expenditure per households and individual household is uni-dimensional poor if they are living under the absolute poverty line of the area. Household with per adult consumption expenditure represented by “Y” and poverty line by “Z”, and then poverty is defined by Y∗=Z−Y , hence household is poor if Y∗ > 0.\n\nMultidimensional poverty measure non income poverty by considering deprivations of households for basic needs. In this study, the UNDP Multidimensional poverty index is developed using ten indicators categorized under three dimensions namely health (nutrition and child mortality), education (school enrollment, years of schooling and living standard with indicators of access to water, electricity, sanitation, cooking fuel, floor and, assets (Kovacevic & Calderon, 2014).\n\nPrincipal component analysis (PCA) was used to estimate the household food security index. Similarly, PCA was employed in empirical research to create indices of household food security (Hawas & Degaga, 2023). Researchers created a food security index for this analysis using food consumption score, dietary diversity, consumption expenditure, calorie intake, and hunger months. The PCA linearly divides the indicator variables into smaller components while retaining most information from the original indicators (Massresha et al., 2021). Stated mathematically, from an initial set of correlated indicator food security variables (X1, X2, X3…, X n), PCA creates uncorrelated indices or components whereby each component is a linear weighted combination of the initial variables as follows:\n\nwhere FSI. j the food security index follows a normal distribution with a mean of 0 and a standard deviation of 1. F i is the weight for the ith variable in the PCA model, X ji is the jth ’ ‘household’s value for the ith variable, and X i and S i are the mean and standard deviations for all households.\n\nSeemingly unrelated multivariate probit model is applied for this research. The seemingly unrelated regression model is preferable (Baltagi, 2012) and (Pan et al., 2020) when there are more than one regression models and the dependent variables are affected by similar co-variate or interdependent variables (Kim & Cho, 2019). Rural household’s welfare for this study is measured using two dummy variables of multi-dimensional poverty and food insecurity status when those variables are determined by similar co-variate. The regression model is developed as follows:\n\nYi = Rural household welfare and has a multiple category of 1 for unidirectional poverty, 2 for Multidimensional poverty and 3 for Food insecurity\n\nWhere y1 = 1 for uni-dimensional poor, y2 = 1 for multidimensional poor and y3 = 1 for food in-secured and the variance of the co-variate error is given by\n\nMy merging uni-dimensional and multi-dimensional poverty in to one variable (to be poverty) from the above multi-variate probit model, the bi-variate probit regression model is also specified as follows;\n\nYi = Rural household welfare and has two categories of 1 for Multidimensional poverty and 2 for Food insecurity (1 is assigned for poor and food in secured)\n\nWhere y1 = 1 for poor and y2 = 1 for food in-secured and the variance of the co-variate error is given by\n\nWelfare as measured by three proxy variables of uni-dimensional poverty, multi-dimensional poverty and food insecurity is expected to have specified relationship with explanatory variables as presented in the following Table 1.\n\n\n4. Result and Discussion\n\nUnder this descriptive analysis part, the issue of gender is addressed and what proportion of female headed farmers are food-insecure and poor is analyzed. For this sake, the bar graph presented below shows the proportion of females from the total sample and how many of those households are living under low welfare as measured by poverty and food insecurity.\n\nOut of a total sample of the study, 47.61% (2322 out of 4877) are adopting agricultural technologies in many forms. The remaining 52.39% are not using modern agricultural inputs and irrigation to increase the productivity of their agricultural outputs. Among those their welfare status is analysed based on their gender as presented below ( Figure 2).\n\nOut of a total sample of 4887 rural household farmers in Ethiopia, more than 3787 farmers are male headed and the remaining 1090 households are female headed ( Figure 1). Out of male headed households, about 68% are food secured and the remaining 32% are food insecure households. When we see their female headed counter parts, out of a total of 1090 female headed rural households, about 70% are food secured and the remaining 30% are food insecure This shows us there is no significant difference of food security status based on their gender.\n\nThe below Figure 2 presents the male female composition of the sample and the numbers households living under multi-dimensional poverty. About 67% of male headed households are facing multi-dimensional poverty and about 71% of female headed households are multi-dimensional poor. From this result we can observe that majority of the population is facing multi-dimensional poverty either they are male headed or female headed regardless of their gender differences.\n\nMoreover, the provision of credit across the male and female-headed households are analyzed here below using pie chart ( Figure 3). Majority of female-headed households accessed credit provision when compared with their male-headed counter parts.\n\nAs seen from the above pie chart, 36% of female-headed households accessed credit even though female-headed household’s accounts for about 40%of the total sample and the remaining 4% are not accessing credit. From those no credit accessed categories, 96.32% are male-headed households and hence we can say that more priority is given for females in the area of credit provision from governmental and non-governmental donors ( Figure 4).\n\nAfter analyzing the data obtained from the focused group discussion, the following findings had been drawn relating to the impact of internal conflict on rural household’s agricultural activities and their welfare. Internal conflicts and wars have profound and far-reaching impacts on rural household welfare, particularly in agricultural contexts such as Ethiopia. These impacts can be broadly categorized into several areas:\n\nDisplacement and migration: Conflicts often lead to the displacement of populations, forcing rural households to abandon their homes and farmland. This displacement disrupts agricultural activities, leading to loss of crops, livestock, and income sources. Migration also increases competition for resources in safer areas, exacerbating food insecurity and poverty.\n\nDestruction of infrastructure: Wars and conflicts typically result in the destruction of critical infrastructure such as roads, irrigation systems, storage facilities, and markets. The damage to infrastructure hampers the ability of farmers to access markets, sell their produce, and obtain necessary agricultural inputs like seeds and fertilizers.\n\nLoss of agricultural productivity: The direct impacts of conflict, such as destruction of crops and livestock, combined with the disruption of farming activities, result in significant losses in agricultural productivity. Farmers may miss planting and harvesting seasons, leading to reduced yields and food shortages.\n\nEconomic instability: Conflicts lead to economic instability, characterized by inflation, loss of income, and decreased investment in the agricultural sector. The uncertainty and risk associated with conflict discourage both local and foreign investment, reducing the financial resources available for agricultural development.\n\nFood insecurity: The combination of displacement, infrastructure destruction, and reduced agricultural productivity culminates in heightened food insecurity. Rural households struggle to produce and purchase sufficient food, leading to malnutrition and increased vulnerability to diseases.\n\nSocial disruption: Conflicts erode social cohesion and trust within communities. Traditional support systems, which are crucial for coping with economic and environmental shocks, are weakened. This social fragmentation makes it more difficult for rural households to recover and rebuild their livelihoods post-conflict.\n\nLoss of human capital: Wars and conflicts result in the loss of human capital through death, injury, and the disruption of education. Now currently, internal conflict is experienced in many parts of the study area and it leads to devastating human capital level. The absence of able-bodied family members reduces the household labor force, impacting agricultural productivity. Additionally, children’s education is often interrupted, limiting future opportunities and perpetuating the cycle of poverty.\n\nPsychological impact: The trauma and stress associated with living in conflict zones have long-term psychological impacts on individuals and communities in the study area. Mental health issues can reduce the ability of individuals to engage in productive activities, further diminishing household welfare.\n\nUnder this section, the effect of agricultural technology adoption had been analyzed using econometric results obtained from bi-variate probit regression model. First results obtained from the bi-variate probit (Table 2) is used to analyze the relationship that exists between Welfare and its determinant with special emphasis of the effect of agricultural technology adoption of rural household’s welfare. With this regard, overall significance test of the model is applied using Chi-square test and individual variables statistical significance is tested using simple students t- test with the application of general rule of thumb (the null hypothesis H0: estimated coefficients are zero can be rejected when t-statistics values are greater than two).\n\nThe maximum likelihood estimation result of the bivariate probit model gives us a chi-squared probability value of zero (0.000), indicating the overall significance of the model by rejecting the null hypothesis that states the coefficients of all variables are zero. In addition to the overall significance test, all independent variables are tested to determine if they are significant using Z and probability values. Variables with Z values greater than two or P-values less than 0.05 (Baltagi 2012) are statistically significant in affecting the level of rural welfare as measured by poverty and food insecurity.\n\nNegative coefficients for poverty and food insecurity suggest that adopting the specified agricultural technologies is associated with a lower likelihood of being in each respective state of poverty or food insecurity. It’s important to consider the statistical significance of these coefficients (t-values) and their practical significance in the context of the study.\n\nAs seen from Table 2, all independent variables included in the model, except for access to credit, education, and access to pesticides, are statistically significant in affecting both poverty and food insecurity. Accordingly, among indicators of agricultural technology adoption, access to irrigation (Tilahun, Bantider et al. 2023), access to improved seeds (Mutungi, Manda et al. 2023), and use of fertilizers (Ayenew, Lakew et al. 2020) significantly and positively affect the status of being non-poor and food-secure households (Biru, Zeller et al. 2020). More specifically, the results of the bivariate probit model state that having access to irrigation and improved seeds is associated with respective probabilities of 0.014 and 0.049 of being under the non-poor and food-secured category when compared with households without access to irrigation and improved seeds. Adopting improved seeds is associated with a statistically significant reduction in the likelihood of poverty. The negative coefficient indicates that, holding other variables constant, adopting improved seeds is linked to a decrease in the probability of being poor. Adopting irrigation has a strong and statistically significant negative association with poverty. Farmers using irrigation are much less likely to be poor compared to those who do not adopt irrigation. This result is supported by many research findings such as (Legesse, Srivastava et al. 2019; Belay and Mengiste 2023; Atinafu, Lejebo et al. 2022; Korir, Manning et al. 2023). Existing research often supports the idea that adopting agricultural technologies like improved seeds leads to increased crop yields and, subsequently, improved welfare of farmers. This is consistent with findings from (Biru, Zeller et al. 2020; Asrat, Anteneh et al. 2022; Habtewold 2018) that state improved seeds are associated with a lower likelihood of poverty and food insecurity. This result contradicts the findings of (Wossen, Alene et al. 2019; Wordofa and Sassi 2020; Tilaye, Delele et al. 2023) who state that their results deviate from the theory due to the target population and method of sampling used in the study.\n\nAdditionally, using one kilogram of fertilizer is associated with increasing the probability of being non-poor by 0.007. Adopting fertilizers is associated with a statistically significant decrease in the likelihood of poverty, as stated by Mulugeta Habtewold and Heshmati (2023), Mogess and Ayen (2023), Legesse, Srivastava et al. (2019) Gebre, Amekawa et al. (2023), though the effect is not as strong as with improved seeds. The negative coefficient suggests a reduction in the probability of poverty when farmers adopt fertilizers.\n\nIn this study, the age of households and dependency ratio are associated with a high probability of being poor and food-insecure households. When the age of the household head increases by one year, the probability of being poor and food insecure increases by 0.013 and 0.067, respectively. The remaining variable affecting poverty and food insecurity status is the number of livestock owned by households (Mekonnen 2017; Korir, Manning et al. 2023). One-unit increase in livestock is associated with increasing the probability of being non-poor and food-secure by 0.137. Hence, we can say that the number of livestock is a key determinant of household welfare, and an increased number of livestock has the power to reduce the level of poverty and food insecurity (Shikur 2023). Existing research often supports the idea that adopting improved seeds leads to increased crop yields and, subsequently, improved economic outcomes for farmers. This is consistent with the findings of (Bekana and Takele 2020; Belay and Mengiste 2023; Mogess and Ayen 2023), who also state that the adoption of improved seeds is associated with a lower likelihood of poverty and food insecurity.\n\nVariables such as access to credit, use of pesticides, and education level are statistically insignificant (Gebrehiwot 2015; Habtewold 2018), and access to agricultural extension service is negatively related to rural household welfare as measured by proxy variables of poverty and food security, in contrast to the results of (Nonvide 2024; Kebede 2022; Hawas and Degaga 2023). These results are somewhat unexpected and deviate from theories. Researchers analyzed the reason behind these results as follows:\n\nAccess to credit had an insignificant impact on rural household welfare in the study area because many agricultural credits are provided by credit associations to farmers with high interest rates, creating difficulty in repaying the credit. Instead of improving the welfare of rural households, high-interest payments create tension, and farmers are obliged to sell their assets to repay the credited money with high interest, negatively affecting household welfare. Agricultural extension service support is not improving the welfare of households, and farmers with extension support are relatively under low welfare status, necessitating a re-evaluation of the relevance of agricultural extension. Additionally, the education level is statistically insignificant since almost all farmers in rural Ethiopia are either illiterate or have only completed the first cycle of elementary education, resulting in no significant difference in welfare associated with their levels of education. In addition to the bi-variate model, the seemingly unrelated multi-variate probit model with few selected independent variables of the research are presented in the table below (Table 3) and results are interpreted and analyzed as follows.\n\nThe overall significance of the model, with a p-value less than 5% (Table 3), showed that the model is developed with significant co-variates since the null hypothesis, which states that all variables coefficients are zero, can be rejected. With this in mind, we proceed to the interpretation of statistically significance variables by examining individual hypothesis testing results for all variables.\n\nAccording to the estimation result from the multi-variate probit model ( Table 3), the size of cultivated land owned by household farmers significantly affect their welfare. Land size is positively related with food security but inversely related with uni-variate and multi-variate poverty. This shows, when household’s cultivated land size increased by one hectare, the probability of being food secured increased by 0.047, while increased land size is associated with a decrease in the probability of being multidimensional and multidimensional poor by 0.006 and 0.0055 respectively. This means that a large size of cultivated land may help households to be food secured (Shita et al., 2023), but households with increased land size are living under uni dimensional and multi-dimensional poverty. This result aggres with the findings of Mekonnen (2017) and Habtewold (2021). Additionally, provision of agricultural extension services, numbers livestock are significance variables affecting rural households, welfare as measured by three proxy variables of food insecurity, uni dimensional poverty, and multi dimensional poverty. This result is supported by the bi-variate probit model regression result analyzed previously ( Table 2). This result is also similar to the findings of Gelata et al. (2024), Atinafu et al. (2022) Habtewold (2018), Gebrehiwot (2015) and Wordofa & Sassi (2020). From the probit regression model, we observed the interdependence of three measures of welfare, all of which are significantly affected by similar explanatory variables. This means that individual household farmers which are facing food insecurity are also facing both uni-dimensional and multi-dimensional poverty. Farmers living under uni-dimensional poverty are also facing multidimensional poverty and food insecurity. Finally, multi-dimensional poverty is occurred in line with food insecurity and uni-dimensional poverty. This result is supported by the findings of Merga et al. (2023).\n\n\n5. Conclusion and recommendations\n\nThis study analyzed the determinants of rural household welfare in Ethiopia, with a special emphasis on the effect of agricultural technology adoption on improving the welfare of rural household farmers. The analysis using the bivariate probit regression model revealed several key findings regarding the relationship between agricultural technology adoption and rural household welfare in Ethiopia. From descriptive summary, it is noted that out of a total sample of the study, 47.61% (2322 out of 4877) are adopting agricultural technologies in many forms more than 70% of female headed households are food secured and no poor and 68% of male headed households are food secured and nun poor. The overall significance test of the model indicated its relevance in explaining the determinants of welfare, particularly the impact of agricultural technology adoption. The results showed that variables such as access to irrigation, improved seeds, and fertilizers were statistically significant in reducing the likelihood of poverty and food insecurity. These findings are consistent with previous research, suggesting that adopting these technologies can lead to increased crop yields and improved welfare for farmers. However, variables like access to credit, education, and access to pesticides were found to be statistically insignificant, indicating the need for further investigation into their impact on welfare outcomes.\n\nMoreover, the seemingly unrelated multivariate probit model provided additional insights into the relationship between selected independent variables and welfare indicators. The results highlighted the significance of variables such as cultivated land, agricultural extension services, and livestock ownership in affecting welfare outcomes. Larger cultivated land size was associated with increased food security but decreased uni-dimensional and multidimensional poverty, suggesting a complex relationship between land size and welfare. Additionally, the provision of agricultural extension services and livestock ownership were found to have a positive impact on welfare, consistent with the findings from the bivariate probit model.\n\nBased on the analysis of the relationship between agricultural technology adoption and rural household welfare in Ethiopia, the following recommendations can be made to improve welfare outcomes:\n\nPromotion of Agricultural Technologies: Policymakers should prioritize the promotion and adoption of agricultural technologies such as irrigation, improved seeds, and fertilizers. This can be done through targeted extension programs, subsidies, and incentives to encourage farmers to adopt these technologies. Providing access to high-quality and affordable agricultural inputs can significantly improve crop yields and enhance food security.\n\nEnhanced Access to Credit: Although access to credit was found to be statistically insignificant in this study, efforts should be made to improve access to credit for rural farmers. This can be achieved by establishing rural credit institutions, providing credit guarantees, and offering low-interest loans to farmers. Access to credit can help farmers invest in agricultural inputs and technologies, leading to increased productivity and improved welfare.\n\nImprovement of Education: Although the education level was found to be statistically insignificant in this study, improving access to education can have long-term benefits for rural households. Policymakers should focus on improving the quality and accessibility of education in rural areas, including investing in school infrastructure, providing scholarships, and promoting adult education programs. Education can help improve livelihood opportunities and empower rural communities to make informed decisions about their welfare.\n\nTargeted Poverty Alleviation Programs: Based on the findings regarding age and dependency ratio, policymakers should consider implementing targeted poverty alleviation programs for vulnerable groups such as the elderly and households with high dependency ratios. These programs can include social safety nets, cash transfer programs, and food assistance to help improve the welfare of these groups.\n\nFurther Research and Monitoring: Finally, further research is needed to explore the reasons behind the insignificant impact of certain variables and to identify additional factors that may affect rural household welfare. Continuous monitoring and evaluation of welfare programs can help policymakers tailor interventions to address specific challenges and improve overall welfare outcomes in rural areas.\n\nThis study, titled “Analyzing the determinants of rural household welfare in Ethiopia: does agricultural technology adoption matters”: using seemingly unrelated multi-variate probit model” was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. The research received ethical approval from the Research and Community Service Bureau of the College of Business and Economics at Woldia University on December 14, 2023, under approval number RCSTT/184/2023. The following ethical standards were adhered to throughout the research process:\n\n1. Compliance with the Declaration of Helsinki: The study was conducted in line with the principles of the Declaration of Helsinki, which emphasizes the protection of human participants, respect for their rights and dignity, and the promotion of well-being. This research prioritized participants’ health, welfare, and confidentiality.\n\n2. Informed Consent: All participants were fully informed about the objectives, methods, risks, and potential benefits of the study. Participation was voluntary, and verbal informed consent was obtained from each participant prior to their involvement. Participants were also made aware of their right to withdraw from the study at any time without consequences.\n\n3. Confidentiality and Data Protection: Personal data was handled in strict confidence. Participant identities were anonymized, and no personally identifiable information was disclosed in the final analysis or publications. All data were securely stored, and only the research team had access to them. Data protection protocols were followed to prevent unauthorized access.\n\n4. Non-Coercion and Autonomy: No participant was coerced or pressured into participating. Autonomy was respected throughout the study, and participants were encouraged to make informed decisions regarding their participation. The research ensured that vulnerable groups, such as women or economically disadvantaged individuals, were not subjected to any form of exploitation or undue influence.\n\n5. Protection of Vulnerable Populations: The study took particular care to protect vulnerable individuals. No minors were involved in the study. “In this study, participants provided verbal consent after being fully informed about the research’s purpose, procedures, and potential risks. Verbal consent was documented as per ethical guidelines, ensuring participants understood their voluntary involvement and right to withdraw at any time. Institutional approval was obtained to use verbal consent instead on written consent because of the presence of many illiterate farmers who can no read and write.” The research team made every effort to minimize any potential risks or harms, both physical and psychological, to participants. Interview questions were designed to be non-intrusive, and participants were assured that they could skip any questions that made them uncomfortable. Should any participant experience distress, protocols were in place to provide support and discontinue the interview if necessary.\n\n7. Transparency and Feedback: Participants were informed about how the research results would be used and how they could access the findings if desired. The results will be disseminated to local communities, policymakers, and other relevant stakeholders, ensuring that the research findings contribute to improving the livelihood and economic well-being of rural households involved in traditional opal mining", "appendix": "Data availability statement\n\nZenodo: Determinants of Rural Households Welfare In Ethiopia, Doi: https://zenodo.org/records/14282852 (Abate, 2024b).\n\nThis project contains the following underlying data:\n\n• Data ATA.xlsx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nZenodo: Review guidline for determinants of welfare. Doi: https://doi.org/10.5281/zenodo.14560932 (Tadesse Wudu, 2024).\n\nThis project contains the following extended data:\n\n• inretview guide line.xlsx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAbate TW: Analysis of agricultural technology adoption: the use of improved maize seeds and its determinants in Ethiopia, evidence from Eastern Amhara. J. Innov. Entrep. 2024a; 13(1): 1–19. Publisher Full Text\n\nAbate TW: Determinants of Rural Households Welfare In Ethiopia. In determinants of Rural Welfare in Ethiopia. Zenodo. 2024b. Publisher Full Text\n\nAdams A, Jumpah ET: Agricultural technologies adoption and smallholder farmers’ welfare: Evidence from Northern Ghana. Cogent Econ. Financ. 2021; 9(1): 2006905. Publisher Full Text\n\nAli H, Menza M, Hagos F, et al.: Impact of climate smart agriculture on households’ resilience and vulnerability: An example from Central Rift Valley, Ethiopia. Clim. 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Publisher Full Text\n\nTilaye KA, Delele BT, Ogeto MA: Adoption and impact of improved teff varieties adoption on food security: Micro level evidence from North Eastern Amhara Regional state, Ethiopia. PLoS One. 2023; 18(9): e0291434. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nTolola TA: ADOPTION OF IMPROVED ENSET FARMING AND ITS IMPACT ON HOUSEHOLD FOOD SECURITY IN KOFELE WOREDA WEST ARSI ZONE, OROMIA REGIONAL STATE, ETHIOPIA. Haramaya University; 2023.\n\nVerkaart S, Munyua BG, Mausch K, et al.: Welfare impacts of improved chickpea adoption: A pathway for rural development in Ethiopia? Food Policy. 2017; 66: 50–61. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWassihun AN, Nega YM, Kebede WM, et al.: Smallholder households’ willingness to pay for sustainable agricultural water supply in case of North West Ethiopia. Lett. Spat. Resour. Sci. 2022; 15(1): 79–98. Publisher Full Text\n\nWordofa MG, Hassen JY, Endris GS, et al.: Adoption of improved agricultural technology and its impact on household income: a propensity score matching estimation in eastern Ethiopia. Agric. Food Secur. 2021; 10: 1–12. Publisher Full Text\n\nWordofa MG, Sassi M: Impact of agricultural interventions on food and nutrition security in Ethiopia: uncovering pathways linking agriculture to improved nutrition. Cogent Food Agric. 2020; 6(1): 1724386. Publisher Full Text\n\nWossen T, Abdoulaye T, Alene A, et al.: Impacts of extension access and cooperative membership on technology adoption and household welfare. J. Rural. Stud. 2017; 54: 223–233. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWossen T, Alene A, Abdoulaye T, et al.: Agricultural technology adoption and household welfare: Measurement and evidence. Food Policy. 2019; 87: 101742. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nZegeye MB, Fikire AH, Assefa AB: Impact of agricultural technology adoption on food consumption expenditure: evidence from rural Amhara Region, Ethiopia. Cogent Econ. Financ. 2022; 10(1): 2012988. Publisher Full Text" }	[ { "id": "360896", "date": "08 Feb 2025", "name": "Jiqin Han", "expertise": [ "Reviewer Expertise agribusiness", "international agricultural governance" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study analyzed the determinants of rural household welfare in Ethiopia, with a special emphasis on the effect of agricultural technology adoption on improving the welfare of rural household farmers. The agricultural technologies were indicated by improved seeds, fertilizers, and irrigation, while rural household welfare provision of agricultural extension services, numbers livestock are significance variables affecting rural households, welfare as measured by three proxy variables of food insecurity, uni dimensional poverty, and multi dimensional poverty. The major findings indicated that access to irrigation, improved seeds, and fertilizers significantly reduces the likelihood of poverty and food insecurity among rural households. The following areas need to be improved:\n1. Marginal contribution needs to be improved This study has some significance to justify the importance of agricultural inputs such as seeds, fertilizers and irrigation in improving rural households’ food security level. The research findings are the general consensus in academia. For example, a large size of cultivated land may help households to be food secured, the significance of variables such as cultivated land, agricultural extension services, and livestock ownership in affecting welfare outcomes. These findings are not contributing to new knowledge.\n2. The title The authors use the seemingly unrelated multivariate probit model to analyze the determinants of household welfare. While this model is suitable for analyzing multiple binary outcomes that may be correlated, the rationale for choosing this specific model could be expanded. It is not immediately clear how the different binary outcomes (e.g., technology adoption, improved welfare, etc.) are interrelated in this context. The authors should clearly explain the relationships between the outcomes analyzed in the model. For example, are households that adopt one technology more likely to adopt others? Or, is technology adoption correlated with other welfare-enhancing factors, such as access to credit or extension services? Detailing these connections would help justify the use of the multivariate probit model over alternative methods.\n3. Methodology The authors tried to use the multivariate probit model (MVP). The model is typically used to analyze correlated binary outcomes (dependent variables) that may be jointly determined or interdependent. In this study, the three welfare dimensions—unidimensional poverty, multidimensional poverty, and food insecurity—are modeled as interdependent binary outcomes. The MVP model is appropriate if:\nThere is theoretical and empirical justification for interdependence among the dependent variables. The covariance matrix of the error terms captures unobserved correlations between these outcomes.\n4. Limitations （1） The study does not provide sufficient justification for why the MVP model was specifically chosen over other models (e.g., ordered probit or structural equation modeling). Are these welfare dimensions truly interdependent, or could they be analyzed independently? （2） If the welfare dimensions are independent or weakly correlated, using an MVP model may be unnecessary and could lead to inefficient or biased estimates. Methodology Vs Result （1） The coefficients for some variables (e.g., access to credit, education) are insignificant or inconsistent with theoretical expectations. This may indicate issues with model specification, variable selection, or the underlying dataset. （2） The discussion does not adequately connect the results of the MVP model to its theoretical purpose—capturing interdependencies among welfare dimensions. 5. Literature: (1) The reference for more than 2 authors should be used according to the requirements of the Journal. (2) There are mistakes in the way of citing literature, e.g. in alignment with (Gebre et al., 2023) on page 3 6. Language: language editing is needed since there are expression problems in the article.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [] } ]	1	https://f1000research.com/articles/14-102
https://f1000research.com/articles/13-845/v1	30 Jul 24	{ "type": "Case Study", "title": "Flexible modular dwelling for rural environments; specific case: Cebadas – Ecuador", "authors": [ "Karina Elizabeth Cajamarca Dacto", "Jean Carlos Montero Riofrio", "Erick Fabricio Nieto Páez", "Dany Marcelo Tasan Cruz", "Maikol Josueé González Espinosa", "Jean Carlos Montero Riofrio", "Erick Fabricio Nieto Páez", "Dany Marcelo Tasan Cruz", "Maikol Josueé González Espinosa" ], "abstract": "Background Sustainable modular dwelling design for rural areas should focus on creating healthy and economically accessible spaces, sensitive to local needs and integrating environmental, functional, sociological and technological aspects. Flexibility is essential to reduce the initial investment and allow future transformations, optimizing the recovery and reuse of materials. These houses must be adaptable, safe and have basic services, satisfying the needs and stages of families’ development. In Ecuador, poverty and energy inefficiency worsen the quality of life in rural areas. This project in the Cebadas parish proposes modular dwelling that applies bioclimatic and sustainable criteria, using local materials to improve habitability and promote the social and economic development of the community.\n\nMethod The research approach is qualitative-quantitative. Qualitative, since it is necessary to identify the qualities of the sector, bibliographic exploration of guidelines and sustainable strategies. Quantitative, to evaluate the degree of affectation through a diagnosis of the study site and to provide efficient solutions that respond to the context and social reality.\n\nResults The spaces presented in the proposal respond to the spatial need for growth and expansion of the users of the sector, through 6 basic guidelines that this type of dwelling should have: Environment, Visual, Form, Function, Bioclimatic and Materials.\n\nConclusions The flexible modular dwelling project for rural environments addresses complex housing needs, highlighting the flexibility and adaptability of an expandable module. It includes income generation with a duplex apartment, fosters communal and cultural life with public and commercial spaces, promotes tourism and rural development with landscape design and crops. In addition, it ensures sustainability through bioclimatic strategies and responsible use of resources.", "keywords": [ "Housing", "sustainability", "rural", "design", "modular", "flexible", "bioclimatic", "adaptable" ], "content": "1. Introduction\n\nAs part of sustainable design in the creation of healthy spaces, economically viable and sensitive to local needs, Garzón (2010), mentions that “Buildings should be designed and constructed in such a way that their purposes (environmental, functional, sociological and symbolic aspects) are interrelated and achieved through their means (technological and morphological aspects) in order to allow their habitability, operation and maintenance with the efficient use of natural and cultural resources of the area and with low levels of dependence (energy, economic, etc.) to minimize the impacts on their contexts. This is how the term flexibility is born as a viable option for rural housing, since it allows reducing the initial investment and facilitates the dwelling to be transformed, improved and completed over time, according to the needs, possibilities and preferences of the household members in a sustainable way.\n\nSanchez (2011) states that sustainable design refers to buildings that allow managing their end-of-life cycle efficiently. It ensures that the disassembly of the building reduces waste generation and maximizes the recovery of its high-value components, as well as materials for reuse and recycling. This process should encourage builders to design structures that are flexible in order to ensure the efficient operation of the construction, its maintenance, as well as its dismantling; allowing a variety of future scenarios for the building.\n\nThe key to achieve a truly flexible and adaptable dwelling is the ability and ease to recover the components and materials that make it up. Much of the current difficulties with deconstruction are due to the design inflexibility and unsuitability, as well as the demands of new requirements. Therefore, existing buildings at the end of their life cycle should be seen as new sources for new constructions, and for this, it must be understood that spatial systems cannot be treated independently from technical ones, since spatial transformations are directly related to the technical composition of the building. Consequently, spatial flexibility can be defined as: Spatially extensible, Divisible to reconfigure its space, Multifunction within the same space. Also, technical flexibility is related to the ease for: interchangeability, displacement, reuse and recycling of the elements and systems that define the structure such as: accessibility, replacement, reconfiguration and separation.\n\nTherefore, buildings should be able to adapt to new trends, adopting new technological advances and facilitating the updating of its elements and systems, that is to say that they must be designed to adapt and deconstruct; creating sustainable buildings means designing to build demountable structures, maximizing their flexibility both in their spatial configuration and in having a lesser impact on the environment; this will be achieved by taking into account their complete life cycle, which goes from extraction to the end of their use, that is, their manufacture, design, construction, use and renovation. Hence, sustainable design is established as a combination of design strategies that address the same problem at different scales. These approaches are: design to recover, to reuse, to be durable, to use materials efficiently, to reduce waste, to regenerate, to repair, to adapt. In order to formulate an adaptive strategy, it is necessary to define what is sustainable housing, which can be defined as the habitable enclosure containing the minimum components to house a family nucleus. This basic unit, in an adaptive process such as the one we are trying to understand here, is an initial phase understood as a structure that is delivered unfinished, and with time, consolidates into a complete dwelling, this initial phase corresponds to the basic unit with maximum space and minimum cost, to house human activities in an adequate manner. For this, it must comply with some basic characteristics translated both in spaces and services.\n\nHousing must be stable (safe) and have basic household services. In addition, it must differentiate spaces to properly house the different activities that take place within, “the four vital activities: rest, food preparation, sanitary activities, as well as family and cultural development gatherings” (Moncaleano & Morales, 2006). Not only does each family nucleus have different needs, but the stages of a family’s development over time must also be taken into account. The stages of household development must be attended to simultaneously. A consolidated household with children needs a complete dwelling or one in the process of being so; on the other hand, a newly couple may only need a rented space for the first stages of family consolidation; a flexible modular dwelling must consider the evolutionary factor in the organization of the different spaces that make it up.\n\nAddressing the issue of housing requires a more comprehensive approach, focusing on interculturality and social, economic and environmental sustainability, hence it is essential to consider access to housing within the framework of rural development proposals that include support for production, implementation of marketing circuits, inclusion of new productive alternatives such as ecotourism or community tourism, development of energy technologies, strengthening of the social fabric and intercultural coexistence, among others.\n\nThe problem of self-construction and informality in Ecuador are only one aspect of the social problem of housing. Energy inefficiency and the high carbon emissions generated by construction increase the environmental impact of housing, as well as the existing poverty of the sectors, which together cause unsustainability and inefficiency. According to Pinto and Ruiz (2009) one out of every three Ecuadorian families lives in rural areas, where despite the fact that the population growth rate is three times lower than in the urban population, they concentrate the highest poverty rates. As a result, it is estimated that 4 out of every 5 families in rural areas are poor, which is evident in the quality of housing. It is estimated that more than 80% of them do not meet the habitability conditions necessary to ensure the life quality of families, due to lack of services, poor quality construction, overcrowding and insecurity. In the case of housing in Cebadas, one of the poorest parishes in Ecuador, 80.19% of the houses do not have acceptable living conditions, affecting the quality of life and development of the people.\n\nConsequently, this research aims to suggest an architectural proposal for flexible modular dwelling in the Cebadas parish of Guamote canton in the province of Chimborazo, in response to the spatial requirements for growth and expansion presented by the inhabitants of the sector through strategic ideas that address bioclimatic criteria, modular design, using local materials, thus establishing principles of sustainability to be considered in future buildings, so that they are projected as sustainable, flexible housing.\n\n\n2. Methods\n\nThe research is qualitative-quantitative; qualitative, since it is necessary to identify the qualities of the area, bibliographic exploration of guidelines on flexibility, modulation, bioclimatic, sustainability, among others, which will help to generate a solid basis for the sustainable proposal. Quantitative, to evaluate the degree of affectation through a diagnosis of the study site and providing efficient solutions.\n\nThis research aims to raise an architectural proposal of flexible modular dwelling in the Cebadas parish of the Guamote canton in the province of Chimborazo, which responds to the spatial need for growth and expansion presented by the inhabitants of the sector, it will also allow to solve current and future problems of sustainable criteria in buildings. Therefore, the ideal is to use a mixed approach, since it will allow obtaining necessary and essential qualitative data for the analysis of the sector, allowing to generate a broad vision on the critical thinking about architectural design, construction, standard of living, and quality of materials in the sector. Quantitative, for the collection of data, to have explicit values about the spatial needs in housing, as well as their functional and bioclimatic quality; in order to generate a proposal that addresses all these issues to solve them with a sustainable and flexible architectural design.\n\nExploratory and propositional. The exploratory type identifies the problems affecting the area under study, which will provide data and diagnostic results. Propositional is the one that coerces the research previously developed, to provide ideas of an architectural proposal as well as sustainable strategies to solve the problems previously identified.\n\nApplied or Practical, since its intention is to improve the quality of life in the Cebadas parish in the province of Chimborazo and contribute to the construction of new knowledge in the field of rural housing sustainability.\n\nThe research is developed with an inductive and analytical method. Inductive, through observation and analysis of the different conditions of the place, which allows formulating the design premises according to the needs of the site. And analytical, starting from the analysis of the theoretical bases of the research, together with the analysis of the problems encountered and the conditions of the site, are the starting point for the proposing solutions to adapt and solve the needs of the population.\n\nField studies will be applied to diagnose the current state of the area. For data collection, the bibliographic research technique will be used to gather information about the cosmovision, traditions and available materials, as well as the existing problems in the study area by the inhabitants of the place. Once the information is obtained, it will be analyzed to design a plan according to the situation and needs of the sector.\n\nDue to the territorial extension of the Cebadas parish, it has been considered to establish the research in Zone 2, in the parish head of Cebadas. Initially, it is planned to obtain information from the Decentralized Autonomous Government of Pichincha and the Development and Land Use Plan of Cebadas, as well as from the critical observation of the site visit, and then conduct a diagnosis of the place to obtain more accurate data on the needs of the sector.\n\n\n3. Results\n\nFollowing the suggested methodology, the analysis of the houses in the study sector revealed that most of them are in a state of deterioration or in ruins. The evident precariousness of the sector prevents the maintenance or improvement of the houses, generating insecurity because of the deterioration of the structure, leading to disuse and abandonment.\n\nRegarding the function of the houses, it is important to emphasize that they present: spaces whose dimensions do not respond to the needs of their inhabitants, lack of elements of direct connection with the immediate environment; such as large windows or balconies; poorly lit and uninhabitable spaces, lack of consideration in the future projection of housing, as well as lack of adaptability and flexibility of the spaces. All this has caused the abandonment of the houses, absence of spaces for production and breeding, and lack of bioclimatic and sustainability strategies.\n\nIn the formal approach, it should be noted that those dwellings that have undergone changes to adapt to the new conditions of the users have suffered formal affectations. Meanwhile, in the bioclimatic aspect, it is evident that despite the fact that the buildings are constructed with materials of high thermal inertia, the lack of lighting and the use of passive air conditioning systems have caused the internal spaces to be cold and unwelcoming.\n\nTherefore, in the second stage an analysis of the bioclimatic requirements for outdoor and indoor spaces in the study area is carried out, to make informed decisions during the design, in order to optimize both thermal comfort and energy efficiency.\n\nFigure 1 shows the bioclimatic chart of Olgyay (1963), applied to Cebadas. It shows a comfort zone that includes the ideal temperature and humidity values for outdoor environments. The ideal temperature values range between 18 and 24 degrees Celsius, and the relative humidity between 20% and 80%. In the case of Cebadas, most of these points are outside the comfort zone, presenting temperature ranges from 2 to 21 degrees Celsius and relative humidity from 81% to 100%. This indicates that heat is required during all months of the year, highlighting the need to use materials, colors and textures with high thermal inertia to absorb heat and prevent heat loss.\n\nThe psychrometric chart by Givoni (1969), also known as the indoor design chart, establishes ideal temperature values between 18.5 and 23.5 degrees Celsius, and relative humidity between 18% and 80%. In Cebadas, most conditions are outside this comfort zone, with temperatures ranging from 2 to 21 degrees Celsius and relative humidity from 44% to 98%. Therefore, corrective methods are needed to capture heat:\n\n• Conventional heating: For temperatures below 2.5 degrees Celsius, the use of coal, gas or electric power is required.\n\n• Active solar heating: For temperatures between 2.5 and 8.5 degrees Celsius, support systems such as pumps and fans are required.\n\n• Passive solar heating: For temperatures between 8.5 and 15 degrees Celsius, systems that passively capture and distribute solar energy are used.\n\n• Internal gain heating: For temperatures between 15 and 21.5 degrees Celsius, comfort is achieved through heat generated by occupants and electrical equipment.\n\nAbove 18.5 degrees Celsius, solar protection is necessary to avoid the direct incidence of solar radiation, combining it with other strategies to protect the interior of the building. As shown in Figure 2:\n\nAfter these analyses, a flexible modular dwelling proposal is presented for the Cebadas parish of Guamote canton in the province of Chimborazo, in response to the spatial need for growth and expansion presented by the inhabitants of the sector through 6 basic guidelines that this type of housing should have: Environment, Visuals, Form, Function, Bioclimatic and Materials.\n\n3.2.1 Environment\n\nThis indicator shows that the location of the project is an elemental factor in the design proposal. Therefore, it is suggested to generate a layout that takes advantage of the immediate surroundings to generate visuals and points of attraction for users, in addition to proposing collaborative and shared social spaces for a new form of community life, taking advantage of a direct connection with the main access roads and integration with paths that project a route through the design.\n\nFlexible modular dwelling proposal Cebadas – Ecuador: The project, proposed in the rural-urban area of Cebadas center, carefully manages the relationship with the immediate environment, hence it is surrounded by agricultural green areas and other houses in the sector that have been urbanized over time.\n\nThe project is located in isolation, in response to the rural environment in addition to taking advantage of the strategic location of implementation. The house responds to the natural landscape that characterizes the rural area of Cebadas, as a result the project not only seeks to integrate into the environment but also to blend in and mimic the exterior. The spaces are designed in a multifunctional way accompanied by a sensory landscape design with floor layout patterns to connect all the accesses to the rear of the project to revalue urban life with urban gardens for the sustenance of the family members. As shown in Figure 3:\n\n3.2.2 Visuals\n\nIt is suggested to directly connect the surrounding environment with the architectural spaces using large windows that allow framing the visuals to appreciate the vegetation outside or at the same time, generate an interior landscape proposal, thus creating an atmosphere of tranquility for these spaces.\n\nFlexible modular dwelling proposal Cebadas-Ecuador: The project carefully manages the visuals of the project in an introspective way, through landscaped frames oriented to the interior garden, the barbecue area and the orchards. As shown in Figure 4:\n\n3.2.3 Form\n\nThe project should start from a basic concept of modulation that generates new spaces according to the user’s needs. The formal organization of the building responds to several organizing principles with a spatial correlation.\n\nFlexible modular dwelling proposal Cebadas-Ecuador: The organization of this system begins with an abstraction in the center, thus generating an internal courtyard that becomes the articulating void of the project, this central space serves as a starting point to which the other spaces are gradually added. Following these principles of organization, half of a central space is subtracted, creating a porch-like foyer that ends in the main entrance. Expanding to the upper floor, an addition is projected at the rear that functions as a balcony, redirecting views to the surrounding landscape. Ultimately, the project seeks to break with its formal orthogonality by projecting a set of heights through sloping roofs, as shown in Figure 5:\n\n3.2.4 Function\n\nThe parameter suggests posing a relationship and interconnection in the project spaces generating permeability and visual interconnection with the immediate surroundings.\n\nFlexible modular dwelling proposal Cebadas- Ecuador: The project establishes an axis to connect directly with the city, allocating the first floor to communal, public and semi-public spaces, and the upper floor to private spaces, ensuring a clear separation of uses. It employs a 1 m × 1 m modulation to provide the minimum essential space, complemented by 50 cm × 50 cm micro-modules for a flexible and functional distribution. The organization starts from a central internal courtyard, one half of which is subtracted to create a porch-like foyer to the main entrance. Upstairs, a rear balcony redirects the views to the landscape.\n\nThe project breaks the orthogonality with sloping roofs, creating a set of heights.\n\nIn terms of function, as shown in Figure 3, it is organized horizontally, with a central hierarchical axis where the greenhouse is located, which distributes the areas around it. This link leads to an exhibition gallery and a workshop, creating a community social space that integrates the production and sale of handicrafts and crops, promoting local identity.\n\nThe greenhouse acts as a key element, visually and spatially connecting the interior and exterior, functionally segmenting the house and guiding circulation in a coherent and efficient manner from the street to the rear cultivation area. The rear of the lot is transformed to enhance the landscape and encourage cultivation, recovering the identity of the sector. In addition, the design allows for the expansion of the dwelling into a duplex apartment, offering a new source of income. As shown in Figure 6:\n\n3.2.5 Materials\n\nThe project should integrate materials with insulating properties, both thermal and acoustic, as these materials help the project to air condition the spaces. It also favors the use of local, sustainable materials from renewable sources.\n\nFlexible modular dwelling proposal Cebadas- Ecuador: The project integrates materials with insulating properties, both thermal and acoustic, to air condition the spaces. The predominant materials are Compressed Earth Block (CEB) and steel. The CEB is used as an element of solar gain and thermal insulation to project them on most of the walls of the house. Wood, in the form of planks or boards, is mainly applied on the floor of the project to improve thermal gain as a support for the roof. The use of these local materials seeks to recover the identity and thermal characteristics of the sector’s dwellings, as shown in Figure 4. In addition, local materials are integrated with new systems such as steel, aluminum and glass. Steel and aluminum guarantee the flexibility of the spaces, while glass is used in the internal stained glass to create a suitable environment for both the landscape and the development of the internal vegetation. As shown in Figure 7.\n\n3.2.6 Bioclimatic\n\nThis indicator suggests maximizing solar and heat gain through passive and active strategies.\n\n• The project should be oriented towards the sun to obtain greater solar collection, which would allow greater thermal gain. It is important that the spatial distribution organizes the bedrooms and the social area towards the facades directly facing the sun, so that the other spaces receive indirect solar incidence.\n\n• Gain of natural lighting in all spaces of the project.\n\n• Thermal gain through central greenhouses that can act as multifunctional-bioclimatic-landscapes, such as internal courtyards, surrounded by social and private areas.\n\n• Regarding ventilation, cross ventilation strategies are suggested through large windows, but avoiding the prevailing winds of the sector.\n\n• Adaptation and use of the existing topography.\n\n• Wind protection through the modeling of the existing topography, vegetation curtains, use of surrounding vegetation.\n\n• Involvement of materials with high thermal inertia such as wood for the roof, handmade bricks for walls, stone for floors, etc., so that heat is transmitted to the interior of the house.\n\n• Use of colors that allow the sun’s rays to be reflected.\n\n• Bioclimatic strategies in the project design to increase the temperature of the building, such as the use of Trombe walls or heat traps.\n\n• The thickness of the perimeter walls allows keeping the heat inside the building, while the internal walls of lesser thickness allow a greater use and passage of heat, maintaining an adequate temperature inside the building.\n\n• It is suggested that the building’s electrical system be supported by a system of solar panels that capture sunlight and transform it into energy.\n\n• Making use of the collection and recycling system as an alternative source of energy income by being able to trade recycled materials.\n\n• Rainwater harvesting and reuse strategies, to be used as irrigation for greenhouse crops and green areas or as water reserve for the house.\n\nFlexible modular dwelling proposal Cebadas-Ecuador: The design of the lighting system focuses on providing direct light to the social and semi-social spaces of the project. Therefore, a greenhouse is projected in the central part, surrounded by curtain walls, thus allowing direct sunlight in these areas, as shown in Figure 8. This approach maximizes the entry of natural light, and also integrates the greenhouse element as a central component in the lighting distribution. Additionally, direct lighting is sought in the private spaces, specifically in the bedrooms, for which large floor-to-ceiling windows have been assigned on the side facades of the building, these windows provide an abundant entry of natural light, improving the quality of the interior lighting, as well as establishing a direct visual connection with the exterior environment. This lighting system design not only addresses practical considerations of efficient lighting, but also contributes to the thermal component of the building. As shown in Figure 8:\n\nThe analysis of natural lighting of the house is presented in percentage ranges from 0 to 100% with 0 being least illuminated spaces, where natural light does not shine directly, and 100 being the spaces that receive direct lighting. As can be seen in Figure 9 generated by Dynamic Daylighting Analysis, it is evident that the highest incidence of light is concentrated in the greenhouse, although it is at 50% because the stained glass and retractable roof strategies sift direct light to control the passage of illumination, this luminosity is distributed to the other spaces which added to the reduction in the thickness of the internal walls, makes effective the passage of heat to all spaces of the house, generating warm and well-lit spaces. The same happens on the upper floor, where the presence of openings and balconies on the level allow the entry of diffuse light, achieving uniform illumination in most of the spaces. As shown in Figure 9:\n\nFigure 10 clearly shows that the materials used in the construction of the house have had an impact on the reduction of the energy flow, which has contributed to maintaining a constant temperature in the interior spaces.\n\nThe materials used have proven to be effective in thermal regulation by limiting heat loss or gain, hence the thermal comfort inside the house is optimal. As shown in Figure 11 the internal temperature varies between 17 and 20 degrees, numbers that are within the habitable thermal standards proposed by Olgyay, V. (1963) and Givoni, B. (1969). As shown in Figure 11:\n\n\n4. Conclusions/Discussion\n\n\n\n• The research project on flexible modular dwelling for rural environments has explored the complex housing needs in the sector, drawing conclusions that highlight the relevance and potential of the proposal.\n\n• Flexibility and Adaptability: The introduction of a basic housing module with the capacity for future expansion effectively addresses the changing needs of users, allowing for continuous adaptation over time and anticipating the growth of families.\n\n• Additional Income Generation: The inclusion of a duplex apartment as part of the expansion of the project responds to the housing needs of the users, and presents an opportunity for the residents to generate additional income, thus contributing to the economy of the families.\n\n• Community and Cultural life: The incorporation of public spaces, stores and craft exhibitions promotes community life and rescues the cultural identity of the sector, contributing to the preservation of local traditions.\n\n• Tourism and Rural Development: The combination of landscape design with crops serves agricultural needs, promotes tourism and redefines the perception of rural life.\n\n• Bioclimatic and Sustainability: The implementation of bioclimatic strategies, such as the central greenhouse, efficiently addresses thermal problems, improving the habitability of the house. In addition, the use of local materials and sustainability strategies such as the reuse of rainwater for crop irrigation promotes responsible management of water resources, contributing to the sustainability and efficiency of the project.", "appendix": "Data availability statement\n\nZenodo: Flexible modular dwelling for rural environments; specific case: Cebadas – Ecuador, https://doi.org/10.5281/zenodo.12785571 (Cajamarca et al., 2024).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nCajamarca Dacto KE, Montero Riofrio JC, Nieto Páez EF, et al.: Flexible modular dwelling for rural environments; specific case: Cebadas – Ecuador. [Data set]. Zenodo. 2024. Publisher Full Text\n\nGarzón B: Arquitectura Sostenible. Bases, soportes y casos demostrativos. NOBUKO; 2010. Reference Source\n\nGivoni B: Man, Climate and Architecture. 1st ed.Elsevier Publising Company Limited; 1969. Reference Source\n\nMoncaleano A, Morales A: Vivienda digna para todos, manifiesto hacia la construcción de una política pública de vivienda social, democrática, equitativa e incluyente que Protegido un hábitat digno para los colombianos. 1st ed.Pontificia Universidad Javeriana of Colombia; 2006.\n\nOlgyay V: Arquitectura y clima, manual de diseño bio- climático para arquitectos y urbanistas. 1st ed.Gustavo Gili, SL, Barcelona; 1963. 1998 Reference Source\n\nPinto V, Ruiz S: La vivienda rural en el Ecuador: desafíos para procesos sustentables e incluyentes. 1st ed.Ciudad Research center: Paso a paso Program; 2009.\n\nSanchez E: Diseño Sostenible: Adaptabilidad y Deconstrucción [Trabajo de Fin de Master, Universidad Politécnica de Catalunya]. Institutional Repository - Polytechnic University of Catalunya; 2011." }	[ { "id": "333945", "date": "04 Nov 2024", "name": "Maria del Cisne Aguirre Ullauri", "expertise": [ "Reviewer Expertise Architecture", "historical materials", "stratigraphic muraria reading", "risk and management" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe initiative of the type of work presented is welcomed. At the same time, the following observations and comments are made: Of form: 1. Revise the spelling of proper nouns in their own language. 2. Revise the naming of paragraph 2.5 considering the naming of paragraph 2. 3.\n\nIn general, section 2 needs better structure and contextualization. For example, the macro and micro location of the object of study to enable understanding. 4.\n\nRevise the format of the textual citation, it is incomplete in the development of the text. 5.\n\nCheck the punctuation in the development of the work. 6.\n\nFigure 2, figure 5, figure 6, figure 8 and figure 9 should be relocated according to the development of the text and the first reference given for consultation. 7.\n\nThe use of subtitles should be reviewed to avoid those of the fourth order being more evident than those of the third order. 8.\n\nThe typeface should be standardized. Figures have a different typeface to the text in general. The size is larger. 9.\n\nThe wording should be revised; grammatical tenses are mixed up. 10.\n\nFigures should include graphic scale and orientation. 11.\n\nDiscussion should be separated from Conclusions, necessarily. 12.\n\nThe bibliography should be significantly improved in form and content. The sources consulted and used are limited and do not cover geographically the development of the subject and the contribution presented with the work in the world scenario. 13.\n\nTechnical revision of the language by a specialist is recommended. Background: 1.\n\nThe summary does not present how the research work is developed, i.e. the method used and its main technical resources. The content is generic and does not match what was developed in the work being presented. The results should be expanded at a technical level in the 6 stated guidelines. Review the correspondence of the conclusions and the initial focus of the summary; the topic of tourism generates noise due to the emphasis given. 2. It is suggested to change the keyword adaptable, it does not contribute by itself and there is another keyword (modular) that is already presented. 3.\n\nIn the third and fourth paragraph of the introduction there is a lack of reference to authors, necessarily. Other such cases are evident throughout the document. 4.\n\nThe introduction is weak, it does not evidence about the existing contribution to the knowledge generated by the research. 5.\n\nIn general, section 2 needs better structure and contextualization. For example, the macro and micro location of the object of study in order to understand it. 6.\n\nSection 2.1 is not clear about particulars such as: type of sources consulted, period of time during which the research was carried out, method of analysis of the documents, whether qualitative or quantitative. The same applies to sections 2.2 to 2.7, which are general and do not contribute to the research process developed. 7.\n\nSection 3.1 is introductory content, not a result, as stated in the work. It allows us to understand the situation of the place and the problems to be addressed, i.e. it is the state of the art, at least in the initial paragraphs. 8.\n\nFigure 1 refers to a specific methodology that is not indicated and explains how it was applied in the methodology section. In the following paragraph the case is repeated and extended to figure 2. 9.\n\nParagraph 5 of section 3.1 needs to be reviewed for coherence and consistency of content; possibly there are contradictions. 10.\n\nThe development of section 3.2 requires technical precision in each of the 6 components. The inclusion of renderings alone is deficient. If the context is rural, the architectural proposal may be aggressive. It is also suggested to mix conceptual descriptions with the proposal. 11.\n\nThe proposal is not clear on certain particulars, e.g. how many people is the building designed for? 12.\n\nDiscussion should be separated from Conclusions, necessarily. The current content is disjointed and needs more consistency. 13.\n\nThe bibliography should be significantly improved in form and substance. The sources consulted and used are limited and do not cover geographically the development of the topic and the contribution presented with the work on the world stage.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate? No\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No\n\nIs the case presented with sufficient detail to be useful for teaching or other practitioners? Partly", "responses": [ { "c_id": "13039", "date": "17 Jan 2025", "name": "Karina Elizabeth Cajamarca Dacto", "role": "Author Response", "response": "We have carefully reviewed the suggestions provided by the peer reviewer and would like to express our appreciation for their valuable comments. In response, we have made the necessary changes to the article to improve its clarity, content and academic rigor. Likewise, changes have been implemented in the content of the article to ensure that all modifications are consistent with the observations made, improving the quality of the work presented." }, { "c_id": "13074", "date": "17 Jan 2025", "name": "Karina Elizabeth Cajamarca Dacto", "role": "Author Response", "response": "Agradecemos los valiosos comentarios realizados por los revisores. Todas las sugerencias y comentarios han sido cuidadosamente revisados e incorporados al manuscrito, con el objetivo de mejorar su calidad y claridad. Los siguientes son los cambios realizados: - Sección de listado de autores: faltas de ortografía, tilde en el apellido de uno de los autores, Dany Marcelo Tasán Cruz, fueron corregidos. - Sección de palabras clave: La palabra clave adaptable se ha cambiado a modular porque se adapta mejor al contexto de la investigación. - Apartado Método: En el apartado 2 de Métodos, se han modificado los apartados correspondientes al Diseño de la investigación y al nivel de investigación con el fin de conseguir una mejor estructura, contextualización y comprensión del objeto de estudio. Estos cambios permiten una explicación más clara y precisa de la macro y micro localización del objeto de estudio. Asimismo, se ha cambiado el nombre de la sección 'Método' por el de 'Metodología', ya que el subtítulo tenía el mismo nombre. En cuanto a su contenido, se ha incorporado una explicación más clara de las seis pautas básicas que deben cumplir este tipo de viviendas: medio ambiente, visuales, forma, función, bioclimática y materiales. Con ello se pretende aportar mayor claridad a la metodología de esta investigación y al proceso que conduce a la propuesta arquitectónica. - Apartado Diagnóstico: En el apartado 3.1, correspondiente al diagnóstico del parámetro de resultados, se ha ajustado la ubicación de la figura N 2 para alinearla con el texto anterior, consiguiendo así un orden lógico y coherente del texto explicativo seguido de la figura. - Sección de Propuesta: En el apartado 3.2, correspondiente al parámetro de resultados, se ha incorporado la información sobre el número de personas que habitarán la propuesta arquitectónica, atendiendo a la sugerencia de uno de los pares evaluadores. - Función de sección: En el apartado 3.2.1, correspondiente al parámetro de la propuesta, se ha corregido el número de figura, cambiándolo de 3 a 6, para garantizar la coherencia con la materia. Asimismo, se ha ajustado la ubicación de la figura número 6 para alinearla con el texto anterior, consiguiendo así un orden lógico y coherente del texto explicativo seguido de la figura. - Figuras: Se ha modificado el contenido de las figuras N 5, 6, 7, 9, 10 y 11, añadiendo una escala gráfica que permite la representación visual y proporcional de la relación entre las dimensiones de un objeto o espacio en el mundo real y su representación en un plano o dibujo. Esto permite al observador del dibujo o plano interpretar correctamente las medidas y proporciones, facilitando su comprensión y análisis. Ya que la escala gráfica es especialmente útil en planos arquitectónicos, mapas y diagramas, ya que proporciona una referencia clara de tamaño y distancia. Y en cuanto a la figura N 8, se ha modificado su contenido, añadiendo la orientación solar para entender mejor el análisis bioclimático objeto de la presentación. - Bioclimática: En el apartado 3.2.6, correspondiente al parámetro de la propuesta, se ha ajustado la ubicación de las figuras del subapartado (figuras nº 8, 9, 10 y 11) para alinearlas con el texto anterior, consiguiendo así un orden lógico y coherente en el que al texto explicativo le siguen las figuras. - Conclusiones/Discusión: En la sección 4 del documento, en el título combinado, se ha eliminado el término \"Discusión\" porque genera confusión en relación con el tema de investigación. Estos son los cambios incorporados en la nueva versión del documento. Estamos profundamente agradecidos por todas las valiosas sugerencias proporcionadas por los revisores, que han sido fundamentales para mejorar el contenido de este artículo. Permanecemos atentos al proceso de actualización y al avance del respectivo proceso de publicación. Saludos y gracias." }, { "c_id": "13075", "date": "17 Jan 2025", "name": "Karina Elizabeth Cajamarca Dacto", "role": "Author Response", "response": "We are grateful for the valuable comments made by the reviewers. All suggestions and comments have been carefully reviewed and incorporated into the manuscript, with the aim of improving its quality and clarity. The following are the changes made: - List of authors section: spelling mistakes, tilde in the surname of one of the authors, Dany Marcelo Tasán Cruz, were corrected. - Key words section: The key word adaptable has been changed to modular because it is better suited to the context of the research. - Method section: In section 2 of Methods, the sections corresponding to the Design of the research and the level of research have been modified in order to achieve a better structure, contextualization and understanding of the object of study. These changes allow a clearer and more precise explanation of the macro and micro location of the object of study. Likewise, the name of the section 'Method' has been changed to 'Methodology', since the subtitle had the same name. As for its content, a clearer explanation of the six basic guidelines that this type of housing must comply with has been incorporated: environment, visuals, form, function, bioclimatic and materials. This is intended to provide greater clarity to the methodology of this research and the process leading to the architectural proposal. - Diagnosis Section: In section 3.1, corresponding to the diagnosis of the results parameter, the location of figure N 2 has been adjusted to align it with the preceding text, thus achieving a logical and coherent order of explanatory text followed by the figure. - Proposal Section: In section 3.2, corresponding to the results parameter, the information on the number of people who will inhabit the architectural proposal has been incorporated, attending to the suggestion of one of the peer reviewers. - Section Function: In section 3.2.1, corresponding to the proposal parameter, the figure number has been corrected, changing it from 3 to 6, to ensure consistency with the subject matter. Also, the location of figure number 6 has been adjusted to align it with the preceding text, thus achieving a logical and coherent order of the explanatory text followed by the figure. - Figures: The content of figures N 5, 6, 7, 9, 10 and 11 has been modified, adding a graphic scale that allows the visual and proportional representation of the relationship between the dimensions of an object or space in the real world and its representation in a plan or drawing. This allows the observer of the drawing or plan to correctly interpret the measurements and proportions, facilitating its understanding and analysis. Since the graphic scale is especially useful in architectural plans, maps and diagrams, as it provides a clear reference of size and distance. And as for figure N 8, its content has been modified, adding the solar orientation to better understand the bioclimatic analysis object of the presentation. - Bioclimatic: In section 3.2.6, corresponding to the proposal parameter, the location of the figures in the subsection (figures No. 8, 9, 10 and 11) has been adjusted to align them with the preceding text, thus achieving a logical and coherent order in which the explanatory text is followed by the figures. - Conclusions/Discussion: In section 4 of the document, in the combined title, the term “Discussion” has been removed because it generates confusion in relation to the research topic. These are the changes incorporated in the new version of the paper. We are deeply grateful for all the valuable suggestions provided by the peer reviewers, which have been fundamental to improve the content of this article. We remain attentive to the updating process and to the progress of the respective publication process. Greetings and thanks." }, { "c_id": "13086", "date": "17 Jan 2025", "name": "Karina Elizabeth Cajamarca Dacto", "role": "Author Response", "response": "We are grateful for the valuable comments made by the reviewers, which have been carefully reviewed and incorporated into the manuscript to improve its quality and clarity. The following are the changes made: - List of authors: the tilde in the surname of Dany Marcelo Tasán Cruz was corrected. - Key words: “adaptable” was replaced by “modular” to adapt it to the context of the research. - Methodology: In section 2, the sections on Design and Level of research were reorganized to improve the contextualization and understanding of the object of study. A more detailed explanation of the six basic guidelines (environment, visuals, form, function, bioclimatic and materials) was incorporated. - Diagnosis: In section 3.1, the location of Figure No. 2 was adjusted to align it with the preceding text. - Proposal: In section 3.2, information on the number of inhabitants of the architectural proposal was added, as suggested by the evaluators. - Function: In section 3.2.1, the figure number was corrected (from 3 to 6) and its location was adjusted for consistency. - Figures: Graphical scales were added to figures No. 5, 6, 7, 9, 10 and 11, and solar orientation was included in figure No. 8 to improve the bioclimatic analysis. - Bioclimatic: In section 3.2.6, figures were reorganized for consistency between explanatory text and images. - Conclusions: The term “Discussion” was removed from the title of section 4 to avoid confusion. We are deeply grateful for the valuable suggestions of the reviewers, which were essential to optimize this article. We remain attentive to the publication process." }, { "c_id": "13087", "date": "17 Jan 2025", "name": "Karina Elizabeth Cajamarca Dacto", "role": "Author Response", "response": "Dear Editor, I enclose the text in the requested number of words: We are grateful for the valuable comments made by the reviewers, which have been carefully reviewed and incorporated into the manuscript to improve its quality and clarity. The following are the changes made: - List of authors: the tilde in the surname of Dany Marcelo Tasán Cruz was corrected. - Key words: “adaptable” was replaced by “modular” to adapt it to the context of the research. - Methodology: In section 2, the sections on Design and Level of research were reorganized to improve the contextualization and understanding of the object of study. A more detailed explanation of the six basic guidelines (environment, visuals, form, function, bioclimatic and materials) was incorporated. - Diagnosis: In section 3.1, the location of Figure No. 2 was adjusted to align it with the preceding text. - Proposal: In section 3.2, information on the number of inhabitants of the architectural proposal was added, as suggested by the evaluators. - Function: In section 3.2.1, the figure number was corrected (from 3 to 6) and its location was adjusted for consistency. - Figures: Graphical scales were added to figures No. 5, 6, 7, 9, 10 and 11, and solar orientation was included in figure No. 8 to improve the bioclimatic analysis. - Bioclimatic: In section 3.2.6, figures were reorganized for consistency between explanatory text and images. - Conclusions: The term “Discussion” was removed from the title of section 4 to avoid confusion. We are deeply grateful for the valuable suggestions of the reviewers, which were essential to optimize this article. We remain attentive to the publication process." } ] }, { "id": "347420", "date": "28 Dec 2024", "name": "Tanya Veridiana Cueva Kean Chong", "expertise": [ "Reviewer Expertise Social and community architecture" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article addresses an important issue in sustainable architecture. However, to enhance its academic and practical impact, it would be beneficial to further explore the methods, data, and graphical representations, and to provide more detailed analysis of the socioeconomic and cultural aspects of the studied context.\nThe work is presented clearly and structured, using relevant citations, such as those of Garzón (2010), Sánchez (2011), Olgyay (1963), and Givoni (1969), to support its arguments on sustainability, bioclimatic design, and modularity. The literature review addresses principles of flexibility, sustainability, and adaptable design, essential for the topic discussed.\nThe study design is appropriate. It combines a qualitative-quantitative approach to address both the needs of the context and the technical diagnosis. Furthermore, the research has academic merit by integrating bioclimatic, sustainable, and social criteria into the modular housing proposal for a vulnerable rural area like Cebadas.\nThe methods and analyses are described in sufficient detail, including the site diagnosis, the use of tools such as bioclimatic charts and psychrometric diagrams, as well as software-assisted architectural design techniques. These elements enable other researchers to replicate or adapt the approach.\nA numerical statistical analysis is not directly mentioned; instead, bioclimatic graphs and tools (such as Olgyay and Givoni charts) are used to interpret climatic conditions. These tools are relevant to the architectural design context.\nThe article mentions the use of sources such as climatic data and site characteristics, but it does not include a repository or appendix with the source data used. To ensure full reproducibility, it would be ideal to provide direct access to the supporting data\nThe conclusions are well-founded on the analyses conducted and the results obtained. Flexibility, adaptability, sustainability, and income generation are ideas consistent with the data and proposals developed in the project.\nSuggestions:\nIt would be advisable to detail the numerical data used to assess the initial conditions or measure the effectiveness of the proposal. A deeper exploration of socioeconomic aspects is needed, as the article mentions the poverty conditions of rural housing in Cebadas, Ecuador. It would be interesting for the proposal to address issues related to the financing of these homes. The possible limitations of the study or challenges in implementing the proposal are not discussed, such as cultural acceptance, technical or logistical feasibility in rural contexts. To better communicate the key aspects of architectural design, 3D diagrams or renders would be useful.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes\n\nIs the case presented with sufficient detail to be useful for teaching or other practitioners? Yes", "responses": [ { "c_id": "13085", "date": "17 Jan 2025", "name": "Karina Elizabeth Cajamarca Dacto", "role": "Author Response", "response": "We are grateful for the valuable comments made by the reviewers, which have been carefully reviewed and incorporated into the manuscript to improve its quality and clarity. The following are the changes made: - List of authors: the tilde in the surname of Dany Marcelo Tasán Cruz was corrected. - Key words: “adaptable” was replaced by “modular” to adapt it to the context of the research. - Methodology: In section 2, the sections on Design and Level of research were reorganized to improve the contextualization and understanding of the object of study. A more detailed explanation of the six basic guidelines (environment, visuals, form, function, bioclimatic and materials) was incorporated. - Diagnosis: In section 3.1, the location of Figure No. 2 was adjusted to align it with the preceding text. - Proposal: In section 3.2, information on the number of inhabitants of the architectural proposal was added, as suggested by the evaluators. - Function: In section 3.2.1, the figure number was corrected (from 3 to 6) and its location was adjusted for consistency. - Figures: Graphical scales were added to figures No. 5, 6, 7, 9, 10 and 11, and solar orientation was included in figure No. 8 to improve the bioclimatic analysis. - Bioclimatic: In section 3.2.6, figures were reorganized for consistency between explanatory text and images. - Conclusions: The term “Discussion” was removed from the title of section 4 to avoid confusion. We are deeply grateful for the valuable suggestions of the reviewers, which were essential to optimize this article. We remain attentive to the publication process." } ] } ]	1	https://f1000research.com/articles/13-845
https://f1000research.com/articles/13-96/v1	15 Feb 24	{ "type": "Research Article", "title": "Sentiment analysis of internet posts on vaccination using ChatGPT and comparison with actual vaccination rates in South Korea", "authors": [ "Sunyoung Park" ], "abstract": "Background This study used ChatGPT for sentiment analysis to investigate the possible links between online sentiments and COVID-19 vaccination rates. It also examines Internet posts to understand the attitudes and reasons associated with vaccine-related opinions.\n\nMethods We collected 500,558 posts over 60 weeks from the Blind platform, mainly used by working individuals, and 854 relevant posts were analyzed. After excluding duplicates and irrelevant content, attitudes toward and reasons for vaccine opinions were studied through sentiment analysis. The study further correlated these categorized attitudes with the actual vaccination data.\n\nResults The proportions of posts expressing positive, negative, and neutral attitudes toward COVID-19 vaccines were 5%, 83%, and 12%, respectively. The total post count showed a positive correlation with the vaccination rate, indicating a high correlation between the number of negative posts about the vaccine and the vaccination rate. Negative attitudes were predominantly associated with societal distrust and perceived oppression.\n\nConclusions This study demonstrates the interplay between public perceptions of COVID-19 vaccines as expressed through social media and vaccination behavior. These correlations can serve as useful clues for devising effective vaccination strategies.", "keywords": [ "COVID-19", "vaccination", "ChatGPT", "sentiment analysis" ], "content": "Introduction\n\nThe exchange of opinions and information on social media platforms has become vital for social interaction and communication. This transformation has created an environment in which information and opinions about societal issues spread rapidly and are shared.1 In recent years, the global landscape has been significantly affected by the COVID-19 pandemic, leading to an abundance of Internet posts discussing various aspects of this crisis. Among these critical topics, vaccination has emerged as an indispensable tool for overcoming the challenges posed by the pandemic.2 Despite their importance, the distribution and vaccination rates vary significantly across nations, regions, and occupations,3 and these differences are closely related to individuals’ perceptions of and attitudes toward vaccines.4,5\n\nGathering public opinion on vaccination through Internet posts is anticipated to contribute to providing accurate information and obtaining insights for policy formulation in infectious disease prevention.6 Sentiment analysis is commonly employed to analyze extensive and diverse online content. It is a form of text classification that focuses on subjective statements and is often called opinion mining. The goal was to analyze opinions to gain insights into public perceptions.7 However, the complexity and necessity of meticulous processes to enhance accuracy pose challenges for sentiment analysis.8 Moreover, the language used on social media platforms can vary in style among users and may require understanding within the context. In such cases, existing sentiment-analysis models may find it challenging to adapt to diversity and changes.9\n\nTherefore, in this study, we employed ChatGPT, a state-of-the-art language model recognized for its natural language understanding capabilities, to explore the nuanced insights derived from the analysis.10 ChatGPT excels in contextual understanding, allowing comprehension of the nuanced meanings within the context of a conversation. This contextual awareness is particularly valuable in sentiment analysis, where the interpretation of sentiments often relies on an understanding of the surrounding text. In addition, ChatGPT is adaptable to diverse language nuances, capturing the intricacies of expression across different linguistic styles, cultural variations, and demographic factors.11 This adaptability can be crucial in sentiment analysis, especially when dealing with social media discourse, where language can be highly dynamic and varied.\n\nIn particular, the sentiment analysis conducted in this study using ChatGPT holds several strengths. Firstly, the objective was to compare the attitudes towards vaccines identified in online content with actual vaccination rates. While analyzing data extracted from internet posts through sentiment analysis contributes to understanding a multitude of opinions, there has been a limitation in verifying how these expressed opinions relate to real-world behavioral outcomes. Analyzing the relationship with societal behavioral outcomes, as reflected in actual vaccination rates, will aid in comprehending the results of sentiment analysis and considering future analytical directions.12 Secondly, sentiment analysis conducted in Korean, a relatively smaller cultural sphere, has encountered limitations despite various approaches. This study sought to explore the extent to which ChatGPT could contribute to understanding the subtle nuances in internet posts written by diverse individuals in the Korean language.13\n\nThis study aimed to conduct a sentiment analysis of Internet postings using OpenAI GPT-3.5-turbo model, exploring the potential associations between diverse opinions expressed on social media and actual vaccination rates. The goal was to investigate the causal relationship between sentiments observed through sentiment analysis and real-world behavior. We hypothesized that a higher prevalence of positive vaccine-related posts correlates with elevated vaccination rates. Additionally, the research intended to further analyze the reasons associated with attitudes toward vaccines as expressed in internet posts.\n\n\nMethods\n\nThis observational study analyzed users’ perceptions of the COVID-19 vaccine on Internet platforms targeting working individuals and their relationship with actual vaccination rates. This study, involving the collection and analysis of publicly available internet posts without containing personal information, received approval for a consent waiver and exemption from review through the National Health Insurance Service Ilsan Hospital Institutional Review Board (IRB) (NHIMC-2023-08-028).\n\nOn the Internet, there are cases in which individuals intentionally post multiple messages to emphasize their claims or engage in actions with specific intentions, such as marketing.14 To counteract this form of online manipulation, we utilized web crawling on the social network service (SNS) ‘Blind (https://www.teamblind.com/kr/),’ where individuals involved in employment, job-seeking, and workplace organizations actively participate and interact. Users join this SNS by using their individual email accounts associated with their respective workplaces, anonymously. The posts were web-scraped using the Python Selenium package, adhering to the Blind’s Access Restriction Protocol (robots. txt). The data collection period spanned between March 23, 2022, and May 16, 2023, totaling 60 weeks, and a total of 500,558 posts were gathered. Information such as post number, posting date, publicly available workplace information of the post author, post title, and content was collected through web scraping. To ensure the integrity of the dataset, we implemented a robust method for excluding duplicate posts. Each post was uniquely identified based on a combination of attributes, including post number, posting date, and author details. Posts sharing identical attributes were flagged as duplicates, and only the earliest occurrence was retained for analysis. This process aimed to eliminate redundancy and maintain the diversity of opinions within the dataset. After then, posts were filtered based on the presence of keywords associated with COVID-19, such as “COVID,” “coronavirus,” and vaccine-specific terms.scraping. To ensure the integrity of the dataset, we implemented a robust method for excluding duplicate posts. Each post was uniquely identified based on a combination of attributes, including post number, posting date, and author details. Posts sharing identical attributes were flagged as duplicates, and only the earliest occurrence was retained for analysis. This process aimed to eliminate redundancy and maintain the diversity of opinions within the dataset. After then, posts were filtered based on the presence of keywords associated with COVID-19, such as “COVID,” “coronavirus,” and vaccine-specific terms.\n\nAfter excluding duplicate posts and those less relevant to COVID-19, 4,419 posts were curated, with 854 posts specifically mentioning the vaccines chosen for the analysis. The posts underwent text preprocessing, involving UTF-8 encoding, stop word and URL removal, as well as the removal of emojis and special characters.\n\nSubsequently, the posts were analyzed using the OpenAI GPT-3.5-turbo model. This model, pretrained on a large corpus of language data by OpenAI, classified the attitude expressed in each post toward the vaccine as positive, negative, or neutral, following the criteria commonly used in the sentiment analysis of conditional statements, evaluating whether the sentiment toward a specific topic is positive, negative, or neutral.7 In cases where the model could not confidently assign an attitude, we instructed it to respond with ‘unclear’.\"\n\nUsing ChatGPT, we extracted the reasons for positive or negative attitudes toward vaccines from Internet posts. The system’s role was an AI assistant tasked with identifying the reasons behind the positive or negative views on COVID-19 vaccines in the given posts. The goal was to extract up to three reasons per post. Cases in which the reasons were unknown or difficult to classify were noted accordingly.\n\nCOVID-19 vaccination information was collected from the Korea Disease Control and Prevention Agency daily vaccination status (https://ncv.kdca.go.kr/vaccineStatus.es?mid=a11710000000). The counts for the first and second doses were collected over the 60-week research period, including additional winter booster vaccination counts for 31 weeks starting on October 11, 2022.\n\nConsidering the working patterns of employees and the lower frequency of vaccination on weekends, a correlation analysis was performed on the sum of the posts and weekly vaccination counts. Furthermore, an association analysis was conducted to explore relationships among the reasons mentioned in the posts, specifically focusing on understanding the relationships between key reasons behind positive and negative attitudes. All analyses were performed using R version 4.2.2.\n\n\nResults\n\nThe analysis used OpenAI’s gpt-3.5-turbo model, which yielded 851 emotional evaluations. In three cases, the model reported uncertainty; upon manual review, these instances were deemed uncertain and excluded from the analysis. Two psychiatrists evaluated 100 posts, resulting in 86% agreement with the results provided by the gpt-3.5-turbo model.\n\nOver the 60-week analysis period, the sentiment distribution was as follows: 44 positive (5%), 704 negative (83%), and 103 neutral (12%) posts. For posts collected over 31 weeks starting from October 11, 2022, and associated with additional vaccinations during the winter season, the sentiment distribution was 20 positive (6%), 254 negative (80%), and 43 neutral (14%) posts. The total vaccination counts, weekly vaccination averages, and weekly post-vaccination averages for each study period are presented in Table 1.\n\nPositive posts regarding vaccination attitudes showed a weak positive correlation with the first-dose vaccination counts. Negative posts on vaccines exhibited a moderately positive correlation with both first- and second-dose vaccinations. Posts expressing a neutral attitude showed a weak positive correlation with second-dose vaccinations (Table 2, Figure 1).\n\n** The correlation is significant at the 0.01 level (2-tailed).\n\n* The correlation is significant at the 0.05 level (2-tailed).\n\nRegarding the booster vaccination count during the winter season, a strong correlation was observed between positive and negative posts regarding vaccination attitudes.\n\nThe total counts of positive, negative, and neutral posts showed strong correlations with the counts of the first, second, and booster vaccinations. Table 2 presents the correlation results.\n\nUsing ChatGPT, we extracted the reasons for positive or negative attitudes toward vaccines from Internet posts. Among the 44 positive posts, the most prevalent (73%) was prevention, cited in 39 instances. For the 704 negative posts, the most common reason (28%) was distrust of the social system, which was mentioned in 194 cases. Two psychiatrists manually reviewed 100 posts and compared the outcomes in the extracted results. For the first reason per post, there were 58 instances of agreement, 37 for the second reason, and 14 for the third reason.\n\nAn association analysis was also conducted for the reasons mentioned in the postings. However, this aspect was excluded from further study because of the low agreement rate (14%) for the third reason per post during the manual review. Cases in which reasons showed a high frequency of repetition were classified into item categories. The positive reasons for vaccination include prevention, symptom alleviation, reduced mortality rate, effectiveness, safety, fewer side effects, containment of the spread of infection, and immune system reinforcement. Negative reasons for vaccination included six items: mistrust of the social system, antipathy toward social oppression, side effects, concerns about side effects, lack of information, and perception of insufficient efficacy. If the first and second reasons for a post fell under the aforementioned classification, they were included in the association analysis. In the study of positive posts, 36 groups were used to analyze positive posts, and 381 groups were analyzed.\n\nIn the analysis of positive reasons, “Decreasing mortality rate” is associated with “Symptom alleviation,” showcasing a support of 5.71%, confidence of 50.00%, and a lift of 2.92. Additionally, instances of “Post-recovery symptom alleviation” (support = 5.71%, confidence = 100.00%, lift = 1.21%), “Immune activity strengthening” (support = 17.14%, confidence = 100.00%, lift = 1.21%), “Inhibition of infection spread” (support = 31.43%, confidence = 100.00%, lift = 1.21%), and “Safety” (support = 14.29%, confidence = 83.33%, lift = 1.01%) are correlated with the item of “Prevention.”\n\nIn the analysis of negative reasons, ‘Antipathy to social oppression’ strongly correlates with ‘Mistrust’ (support = 21.78%, confidence = 94.32%, lift = 2.16). Conversely, ‘Mistrust’ is moderately associated with ‘Antipathy to social oppression’ (support = 21.78%, confidence = 50.00%, lift = 2.16). Instances involving concerns about underlying conditions were linked to side effects (support = 29.13%, confidence = 91.74%, lift = 1.26). Conversely, side effects were associated with concerns about the underlying conditions (support = 29.13%, confidence = 40.07%, lift = 1.26). The presence of “lack of information” was strongly associated with”unknown side effects” (support = 23.62%, confidence = 90.91%, lift = 1.25). The overall trends in the association analyses are shown in Figure 2.\n\n\nDiscussion\n\nThis study explored the relationship between professionals’ attitudes toward the COVID-19 vaccine as expressed in internet posts and actual vaccination rates. Additionally, it examined the positive and negative reasons associated with vaccine attitudes and investigated the relationships between them.\n\nThe sentiment analysis conducted using OpenAI’s gpt-3.5-turbo model demonstrated an 86% concordance rate when compared with evaluations by mental health specialists. This result indicates a substantial level of accuracy of the model and affirms the utility of automated analysis using natural language processing technology. Recent studies using deep-learning-based analysis models have reported sentiment analysis accuracies ranging from approximately 70% to 90%. These studies often evaluate sentiments in posts related to COVID-19 on major social media platforms, such as Twitter.15,16 The reasoning analysis in this study, which aimed at extracting the reasons behind positive or negative sentiments toward vaccines, showed a lower matching rate (58%). Compared to sentiment analysis, which gauges the overall sentiment, reasoning analysis delves into specific words or phrases that explain why a sentiment is expressed. This process involves a deeper understanding of language nuances and contextual cues, making it a more intricate task.17 Furthermore, ChatGPT tends to include irrelevant content when producing results for short posts, making it challenging to infer the reasons. This behavior is likely attributable to the generative nature of ChatGPT, a characteristic inherent in creative AI models.11\n\nIn this study, the correlation analysis between the number of posts and vaccine doses administered indicated a strong correlation between the total number of positive, negative, and neutral posts and the counts of the first, second, and additional vaccine doses. Numerous studies have explored the relevance of social media platforms to epidemiological patterns and medical information.18 For instance, even before the COVID-19 pandemic, research suggested a strong correlation between the regional distribution of social media posts related to infectious diseases and their actual spread.19 Additionally, studies on trend analysis using search queries have shown associations with the spread of infectious diseases.20 In this study, the diverse opinions expressed online before and after the vaccination could be considered a reflection of the various perspectives emerging on online platforms.\n\nIn this study, the number of posts with a negative attitude often showed a stronger correlation with vaccination rates than those with positive attitudes. According to previous studies on the attitudes of Korean adults toward the COVID-19 vaccine, the refusal or hesitation rate among Korean adults was approximately 39.8%, which is higher than in other countries.21 The actual vaccination rate reported by the Korea Disease Control and Prevention Agency is 96.9%. In this study, the percentage of negative opinions about vaccination was 82%, which was significantly higher than the survey results expressing vaccine hesitancy and the actual vaccination rate. The discrepancy between high actual vaccination rates and negative attitudes toward vaccines can be understood through the internet posts used as data in this study. The analysis of posts in this study revealed various attitudes, including cases where individuals voluntarily chose vaccination, cases where vaccination was chosen to reduce social discomfort or due to occupational relevance, and instances of choosing vaccination but with an unfavorable outlook. At times, there were also expressions of social discomfort and resentment caused by the refusal to vaccinate.\n\nThese results are associated with certain social phenomena in which negative or extreme online content is prevalent. Cyber venting22,23 is a phenomenon in which internet users express dissatisfaction, stress, or anger online, making it easy to express various negative emotions related to vaccination, discomfort about side effects, and social pressure. Moreover, the freedom to swiftly respond and exchange opinions through comments in anonymous online spaces can result in uninhibited emotional expressions.24,25 This phenomenon was evident in the posts analyzed in this study, in which various expressions of anxiety and discomfort regarding vaccine side effects, derogatory remarks about compliant attitudes toward vaccination, and rumors related to vaccines were observed.\n\nRegarding the number of posts with a positive attitude, there was a weak positive correlation with the first-dose vaccination count and a moderate positive correlation with additional vaccinations during the winter. Choosing to be vaccinated additionally during the winter season might indicate a more positive and proactive attitude toward vaccination than the foundational doses of the vaccine.\n\nIn this study, implications were derived by analyzing the underlying factors influencing attitudes toward vaccines. For positive attitudes toward vaccines, individuals expected preventive effects, personal relief from symptoms and after-effects, and societal benefits, such as preventing the spread of infection. In contrast, negative attitudes toward vaccines were associated with resentment and distrust toward social oppression. This aligns with discussions in numerous studies during the pandemic, indicating that public distrust of efforts to prevent epidemics at the societal level can lead to strong resistance.26–28 Concerns about physical health and side effects are closely related, with the latter linked to a lack of information. Information gaps in various media channels regarding vaccines can reinforce public anxiety and contribute to negative attitudes.29 Therefore, it is crucial to implement effective communication strategies and educational initiatives to address these concerns and promote a more informed perspective on vaccination.30,31\n\nThe limitations of this study include its focus on SNS users among employed individuals, warranting future research that encompasses diverse demographic groups and regions for a more comprehensive understanding. Furthermore, research incorporating various factors is essential to investigate the relationship between opinion formation on Internet platforms and vaccination behavior. While this study inferred the reasons behind attitudes toward vaccines within posts and conducted an association analysis, the matching rate, particularly for positive reasons, was very low compared with manual reviews. Additionally, the limited number of posts for positive reasons poses significant constraints on interpretation.\n\nMoreover, the analysis of sentiment analysis models, including the gpt-3.5-turbo model, reveals additional limitations. These models may not fully capture the subtle nature of emotions, and the interpretation of emotional expressions can vary among individuals.11 Therefore, involving a diverse range of reviewers across different age groups and backgrounds for manual review is crucial. Considering the gpt-3.5-turbo model, there is a limitation in fully understanding subtle nuances and cultural contexts. This is particularly evident in contexts like Korea, characterized by unique language styles, cultural norms, and demographic characteristics, where capturing emotional changes comprehensively may face constraints.13\n\nIn conclusion, this study revealed the interaction between the public’s perception of the COVID-19 vaccine expressed on social media and their actual vaccination behavior. The perception of risk and willingness to be vaccinated can be influenced by various mass media sources, such as the news. Opinions encountered on SNS, which people use, are also likely to significantly impact individuals’ perceptions of vaccines due to biased approaches to information and the phenomenon of conformity. Therefore, implementing social strategies that provide appropriate vaccine information in an accessible manner is crucial.\n\nThis study was exempted from review by the National Health Insurance Ilsan Hospital Institutional Review Board (NHIMC-2023-08-028) 04/09/2023.", "appendix": "Data availability\n\nZenodo: Korea Disease Control and Prevention Agency daily COVID19 vaccination status, https://zenodo.org/doi/10.5281/zenodo.10252895.\n\nVaccination data is accessible in the form of an Excel file. This file comprehensively includes vaccination rate information relevant to the research findings. COVID-19 vaccination information was collected from the Korea Disease Control and Prevention Agency daily vaccination status (https://ncv.kdca.go.kr/vaccineStatus.es?mid=a11710000000). For additional details or specific requests regarding data provision, feel free to contact us.\n\nThe data used for SNS crawling in this study, acquired through social media crawling, cannot be shared due to ethical and copyright restrictions related to social media content. A comprehensive description of the methodology is presented in the Methods section, along with the Python code below, facilitating the replication of the study. For inquiries concerning the methodology, please direct any questions to the corresponding author.\n\nhttps://github.com/bechungan/Scraping-and-Sentiment-Analysis-using-CGPT .\n\nZenodo: STROBE checklist for Sentiment analysis of internet posts on vaccination using ChatGPT and comparison with actual vaccination rates in South Korea, https://doi.org/10.5281/zenodo.10429910.\n\n\nAcknowledgments\n\nWe extend our sincere appreciation to G-J Park at Cheongdam SL Clinic for invaluable guidance and assistance in data scraping and analysis. 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Probl. 2023; spad006. Publisher Full Text\n\nLee W, Ahn S: Risk Perception and Vaccination Intention towards COVID-19 News. Korean Journal of Journalism & Communication Studies. 2022; 66(6): 388–425. Publisher Full Text\n\nPalmedo PC, Rauh L, Lathan HS, et al.: Exploring distrust in the wait and see: Lessons for vaccine communication. Am. Behav. Sci. 2022; 000276422110628. Publisher Full Text\n\nLarson HJ, Jarrett C, Eckersberger E, et al.: Understanding vaccine hesitancy around vaccines and vaccination from a global perspective: a systematic review of published literature, 2007–2012. Vaccine. 2014; 32(19): 2150–2159. PubMed Abstract \| Publisher Full Text" }	[ { "id": "284069", "date": "17 Jun 2024", "name": "Cihan Cilgin", "expertise": [ "Reviewer Expertise Machine Learning", "Deep Learning", "sentiment analysis" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study used ChatGPT to perform sentiment analysis on posts about Covid-19 vaccines.\n1. Within the scope of the study, many studies conducted within the same scope were ignored and the literature section was not given. However, the existing studies in the literature are very important to both reveal and support the current contributions of these studies. For example, the study given below is a direct alternative to this issue:\n>> Çılgın, C., Gökçen, H., & Gökşen, Y. (2023 [Ref -1]). Sentiment analysis of public sensitivity to COVID-19 vaccines on Twitter by majority voting classifier-based machine learning. Journal of the Faculty of Engineering and Architecture of Gazi University, 38(2)\n2. There are many repetitive sentences under the title of web crawling and data collection. This title should definitely be reviewed again.\n3. It is really interesting that only 854 relevant posts were confiscated out of approximately 500 thousand posts. Many studies in the literature used social media posts much higher than this number. The reader should be made more aware here by giving more details about this filtering process.\n4. Using a lexicon-based approach such as Vader or TextBlob in sentiment analysis, in addition to ChatGPT, may make the results of this study more valuable. In addition, a suitable data set is available for such a method comparison.\n5. Presenting a confusion matrix of the results obtained as a result of the 100 posts considered for the test data set is very important in terms of the consistency of the results.\n6. There are repetitive expressions, especially in the Discussion section of the study.\n7. There is no statement in the Discussion section that compares the findings of this study with the findings of other studies in the literature. As mentioned before, this is related to the lack of literature section. The similarity or difference of the findings with the existing literature is very important for the reader to evaluate the findings of this study. This study used ChatGPT to perform sentiment analysis on posts about Covid-19 vaccines.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "12156", "date": "02 Sep 2024", "name": "Sunyoung Park", "role": "Author Response", "response": "Thank you for your comment. I have revised this article as below. Please go through the respective Author responses for Reviewer Comments made. 1. As suggested, I have developed and included a comprehensive literature review related to the main topic of this study. Additionally, I have incorporated important insights from the paper you mentioned as an example, which have significantly contributed to the argument presented in my work. 2. Thank you for pointing this out. There was an error in the editing process of the Methods section, which led to the repetition of content. This has now been corrected. 3. Thank you for highlighting this critical point. The relatively small number of relevant posts collected in this study can be attributed to the characteristics of the website BLIND, from which the data was gathered, and the fact that data collection occurred some time after vaccines were a hot topic. I have added a detailed explanation to address this. Additionally, I have also enhanced and elaborated on the filtering process in the study. 4. Thank you for your insightful suggestion. It is true that most sentiment analysis studies utilize English data, and the lexicons you mentioned are indeed based on English. However, Korean, being a less commonly used language globally, presents challenges in applying these pre-established analytic methods directly. I believe this underscores the significance of using ChatGPT in our study, which is specifically adapted to handle Korean text. This point has been detailed in the literature review and discussed further in the discussion section of our paper. 5. I have added the results of the confusion matrix and included comments on the identified features in the discussion section. Additionally, while creating the confusion matrix, there were slight modifications to the previously manually evaluated accuracy results (from 86% to 85%). 6. I have revised the Discussion section to eliminate repetitive expressions and streamline the content. 7. Thank you for your meaningful feedback. Our study has notable differences from other studies, particularly due to the linguistic and sociocultural factors specific to Korea. I have addressed these differences and added a comparison of our findings with those in the existing literature in the Discussion section." } ] } ]	1	https://f1000research.com/articles/13-96
https://f1000research.com/articles/13-946/v1	21 Aug 24	{ "type": "Research Article", "title": "Genotoxic effects in island populations of Cartagena de Indias, Colombia due to environmental exposure to mercury and cadmium", "authors": [ "Eder Cano-Pérez", "Doris Gómez-Camargo", "Dacia Malambo-García", "Eder Cano-Pérez", "Doris Gómez-Camargo" ], "abstract": "Background Contamination of Cartagena Bay, Colombia with heavy metals such as mercury (Hg) and cadmium (Cd) presents a major environmental and public health concern, particularly for human communities residing on nearby islands and coastal areas. These populations face enhanced exposure risks owing to their traditional fishing practices and continuous interactions with polluted marine environments. This study aimed to evaluate the genotoxic effects of environmental exposure to Hg and Cd in populations from the island zone of the Cartagena district, Bolívar.\n\nMethods Ninety-four individuals from the four island communities (study group) and 30 individuals from the urban area of Cartagena (control group) participated in this study. The blood samples were collected to measure total mercury (T-Hg) and Cd concentrations, and a Buccal Micronucleus Cytome (BMCyt) assay was used to evaluate exposure effects.\n\nResults Cadmiun levels in the blood of the study group were within the normal range and comparable to those of the control group (p > 0.05). However, the study group exhibited significantly higher T-Hg levels (7.34 μg/L) compared to the control group (2.01 μg/L), surpassing the accepted limit. Moreover, the study group showed a higher incidence of DNA damage and cell death biomarkers (p < 0.05). Additionally, significant correlations were observed between total blood Hg levels and the frequencies of micronuclei, karyorrhexis, and karyolysis.\n\nConclusion These results suggest that island populations of Cartagena are exposed to high levels of Hg and exhibit genotoxic damage, indicating a problem that must be addressed.", "keywords": [ "Cadmium", "DNA damage", "Genotoxicity", "Mercury", "Heavy metals" ], "content": "1. Introduction\n\nThe significance of genotoxic biomonitoring studies lies in their ability to assess and reveal the harmful effects of various physical and chemical agents on population DNA. The most-studied genotoxic agents are pesticides,1 petroleum derivatives,2 drugs,3 and heavy metals.4 In particular, the genotoxic effects of heavy metals such as mercury (Hg) and cadmium (Cd) have been of special interest because of their known mutagenic effects on populations occupationally or environmentally exposed to these metals.4 These metals can directly or indirectly harm the structure of genetic material, leading to carcinogenic effects.4,5\n\nCytogenetic biomarkers have been used in environmental surveillance studies to evaluate human exposure to potentially genotoxic agents. The buccal micronucleus cytome assay (BMCyt) is a suitable and noninvasive method for quantifying DNA damage, chromosomal instability, and cell death in the mucosal tissue.6,7 Notably, biomarkers measured using this assay have been linked to a heightened predisposition to specific types of cancers.7\n\nThe Bay of Cartagena, Colombia, faces severe heavy metal contamination owing to the inflow of sediments from the Magdalena River through the Canal del Dique, which transports approximately 2000 tons of sediments daily from the vast mining and industrial areas within the country. This influx is the primary source of contamination in the Bay.8 Recent ecological studies conducted in this region have highlighted elevated levels of various metals, including Hg and Cd, in sediments of the Bay of Cartagena.8,9 Moreover, studies have reported elevated Cd levels in oysters10 and significant Hg levels in diverse marine and terrestrial organisms, such as fish,11,12 crustaceans,13 mollusks,14 and birds,15 within this water body.\n\nElevated levels of Hg have been detected in the hair and blood of residents of certain island communities in cartagena.13,14,16 Owing to their traditional fishing activities and constant interactions with affected marine areas, these populations face heightened risks of exposure to these agents, which enter the human body through the digestive, respiratory, and cutaneous pathways. However, there is a gap in the research regarding the effects of these metals on the genetic material of exposed populations. Therefore, this study assessed the genotoxic effects caused by the presence of Hg and Cd in the blood of coastal and island populations in the district of Cartagena, Colombia using the BMCyt assay.\n\n\n2. Methods\n\nThis study was conducted on the rural island communities of Ararca, Barú, Caño del Oro, and Tierra Bomba, which are traditional fishing communities located in the district of Cartagena de Indias, Colombia (Figure 1). Ararca, with a population of 900 inhabitants residing in 219 homes, is situated 15 km away from the urban area of Cartagena and maintains direct interaction with the Bay of Cartagena and Dique Canal; and Barú is a peninsula inhabited by 1922 people living in 448 homes, located 34 km from the urban area of Cartagena.17 Caño del Oro and Tierra Bomba are communities that are part of the island of Tierra Bomba, with populations of 1257 (326 homes) and 1472 inhabitants (298 homes), respectively.\n\nThe satellite images were obtained from Google Earth, Image © 2024 Maxar Technologies.\n\nThe population analyzed in this study consisted of individuals residing in the communities of Ararca, Barú, Caño del Oro, and Tierra Bomba (5551 inhabitants). To determine the sample size and proportion for each site, the formula for sample estimation was used within a defined population,18,19 where N represents the total population size (5551 inhabitants); p denotes the expected proportion of individuals with Hg and/or Cd-caused DNA damage, estimated at 50% (0.5); and d2 represents the maximum allowable error of 0.1 (10%).\n\nThe total estimated sample size was 94. Subsequently, this number was distributed among the four communities based on the contribution of each community to the total population size. Consequently, the numbers of individuals evaluated in each community were determined to be: 16 from Ararca, 31 from Barú, 22 from Caño del Oro, and 25 from Tierra Bomba, resulting in a combined sample size of 94. Additionally, a control group of 30 individuals residing in the city of Cartagena was included for comparative analysis.\n\nParticipants were registered using a comprehensive survey that collected information on various lifestyle factors, including alcohol and tobacco consumption, dietary habits, water source and treatment, occupational activities, duration of residence, and history of exposure to genotoxic agents, such as chemicals or radiation.\n\nBased on the survey data, individuals included in the study were required to have resided in the study area for more than three years, with no history of alcoholism, smoking, cancer, or chronic degenerative diseases within the six months prior to the survey. Additionally, they should not have undergone any pharmacological treatment and should not have a history of prolonged exposure to any other known chemical or physical genotoxic agent. Failure to meet any of these criteria was considered exclusion criterion.\n\nThe inclusion criteria for individuals in the control group were the same as those in the study group except that they should not belong to any of the communities under study. Therefore, individuals residing within the urban area of Cartagena were consulted to ensure a match in sex and age proportions with the study group.\n\nEvery participant, without exception, provided their consent by signing an informed consent form. The form outlined the objectives of the study and authorized the use of their biological samples for scientific purposes.\n\nThe blood samples and buccal mucosal cells were collected from all participants included in the study. To analyze the levels of Hg and Cd, 3–6 mL of the peripheral blood was drawn into EDTA-containing tubes and stored on ice. For the BMCyt assay, buccal mucosal cell samples were obtained by gently swabbing the inner cheeks with a cotton swab. These cells were then suspended in a cold saline solution (0.9%). Before sample collection, the participants were instructed to rinse their mouths with bottled drinking water provided by the researchers. Subsequently, the samples were transported to the UNIMOL Laboratory at the University of Cartagena for further analysis.\n\nTotal mercury (T-Hg) and Cd levels in the blood were determined at the Laboratory of Toxicology and Environmental Management at the University of Córdoba within the first 48 h. Two milliliters of blood were transferred to a 100 ml Teflon vessel, to which 8 ml of concentrated nitric acid and 2 ml of hydrogen peroxide (30%) were subsequently added. The vessels were sealed and digested in an Ethos Touch microwave oven at a temperature of 280 °C, with a pressure of 80 bars and a power of 1,400 W for 30 minutes. Once cooled, the sample volumes were adjusted with deionized water to a final volume of 70 ml for T-Hg analysis and 500 μl of the sample adjusted to a final volume of 1 ml for Cd analysis. T-Hg analyses in the blood were performed using Cold Vapor Atomic Absorption Spectrophotometry (CVAAS; Thermo Scientific TM, model iCE, series 3000) at a wavelength of 253.7 nm and detection limit of 0.40 μg/L.20 Blood Cd analyses were conducted using Graphite Furnace Atomic Absorption Spectrometry (GFAAS, Thermo Scientific iCE 3000 Series equipped with a graphite furnace) with a detection limit of 0.20 μg/L.21 Notably, Cd analysis was not possible for four individuals because of sample scarcity. Concentration units for both metals were determined in micrograms per liter. The exposure limits for T-Hg and Cd in the blood were established following the guidelines of the World Health Organization (WHO)22 and the Centers for Disease Control and Prevention (CDC),23 respectively; both of which specify an allowable limit of up to 5 μg/L in the blood for these metals.\n\nAfter buccal massage, the cells were suspended in 15-mL centrifuge tubes containing 5 mL of 0.9% saline solution (w/v). Upon arrival at the laboratory, samples were centrifuged at 1500 RPM for 10 min. The settled buccal cells were washed twice with saline solution and once with Carnoy’s fixative (methanol and glacial acetic acid, 3:1) under the same centrifugation conditions. Subsequently, 80–100 μL of cell suspension were carefully applied to angled slides to ensure optimal cell spreading.2 The fixed cells were stained using the Feulgen method, following the recommendations of Thomas et al.7 In summary, the slides were first treated in a 50% and 20% ethanol solution for 1 minute at room temperature, followed by immersion in distilled water for 2 minutes. Next, the slides were exposed to 5 M HCl for 30 minutes. A slide not treated with HCl served as a negative control during this step. After this treatment, the slides were rinsed with running water for 3 minutes and then immersed in Schiff’s reagent (Sigma-Aldrich, St. Louis, MO, USA) for 1 hour in complete darkness at room temperature. Following this, the slides were rinsed for 5 minutes with running water and then with distilled water. Finally, the slides were immersed in 0.2% (w/v) Light Green solution (Sigma-Aldrich, St. Louis, MO, USA) for 20 to 30 seconds, rinsed with distilled water, and allowed to air dry for 15 minutes at room temperature.\n\nStained slides were examined using an optical microscope (Leica Microsystems, Germany), with 1000 cells/individual visualized and analyzed at 100× magnification. Nuclear abnormalities such as DNA damage (micronuclei and nuclear buds), cell death indicators (condensed chromatin, pyknosis, karyorrhexis, and karyolysis), and cytokinesis defects (binucleated cells) were assessed following the recommendations of Thomas et al.7:\n\nMicronucleated cells: micronucleated cells possess a main nucleus as well as one or more micronuclei. Micronuclei are generally round or oval and exhibit a staining intensity comparable to that of the main nucleus. They typically measure between 1/3 and 1/16 the diameter of the main nucleus and are situated within the cellular cytoplasm (Figure 2a).\n\na) Micronucleus. b) Nuclear bud. c) Binucleated cell. d) Condensed chromatin. e) Karyorrhexis. f) Karyolysis. g) Pyknosis. Original Images from this study.\n\nNuclear buds: the main nucleus exhibits a sharp constriction that forms a bud, which remains attached to it. This bud has a staining intensity similar to that of the main nucleus and its diameter ranges from one-quarter to one-half of the nuclear diameter (Figure 2b).\n\nBinuclead cell: Cells contain two main nuclei of similar size and staining intensity. The nuclei are usually very close and may touch each other and usually have the same morphology as that observed in normal cells (Figure 2c).\n\nCondensed chromatin: the nucleus shows areas of aggregated chromatin, with distinct regions that are more intensely stained. Additionally, the nucleus exhibits a striated pattern (Figure 2d).\n\nKaryorrhexis: The nucleus exhibits extensive aggregation of chromatin, which can be observed in substantial clusters. Additionally, nuclear fragmentation may be evident (Figure 2e).\n\nKaryolysis: the nucleus is depleted of DNA, as indicated by its lack of staining with the Feulgen method (the nucleous apparent as a ghost-like image) (Figure 2f).\n\nPyknosis: the cell has a small, shrunken nucleus that is uniformly and intensely stained. The diameter of this nucleus is approximately 1/3 to 2/3 of the diameter of a normal nucleus (Figure 2g).\n\nThe normality of the variables was assessed using the Kolmogorov–Smirnov test or Shapiro–Wilk test to determine whether parametric or non-parametric analysis was appropriate. The Shapiro-Wilk test is more appropriate for small sample sizes (N ≤ 50), while the Kolmogorov-Smirnov test is used for larger sample sizes (N > 50). Both the Shapiro-Wilk and the Kolmogorov-Smirnov tests compare the scores in the study sample with a normally distributed set of scores with the same mean and standard deviation; their null hypothesis is that sample distribution is normal. Therefore, if the test is significant (p < 0.05), the sample data distribution is non-normal.25\n\nIn our study, the variables did not follow a normal distribution (p < 0.05). Therefore, the results are reported as medians and interquartile ranges (IQR: 25th–75th percentile). Significant differences between groups were examined using the Mann–Whitney U test or Kruskal–Wallis test for multiple comparisons, followed by post-hoc Dunn’s test for each pairing. The Mann-Whitney U test and the Kruskal-Wallis test are non-parametric tests that assume a non-normal distribution of data. The Mann-Whitney U test can only deal with the comparison between two samples, whereas the Kruskal-Wallis test can handle multiple samples. Furthermore, post-hoc tests such as Dunn’s test enable us to identify which specific groups exhibit statistical differences.26\n\nFinally, correlations among blood metal levels, quantitative demographic variables, and BMCyt parameters were assessed using Spearman’s coefficient (a non-parametric test for establishing correlations). All analyses were performed using the statistical software SPSS v.19.0 (IBM Corp, Armonk, NY, USA). Statistical significance was defined as p < 0.05.\n\n\n3. Results\n\nThe main demographic characteristics of the study population are summarized in Table 1. The median age of the study group was 31.5 years (IQR: 23–42.25), comprising 69 females (73.4%) and 25 males (26.6%). No significant differences in the median age were observed between the study and control groups (p = 0.178). Regarding education, four individuals in the study group were illiterate, 33% had not completed primary or secondary education, and only two held university degrees. In terms of occupation, 56.38% were homemakers, 30.85% were employed, 9.57% were students, and 3.19% were unemployed. Among those employed, 34.48% worked in tourism, 13.79% in commerce, and 6.89% were fishermen. Other occupations constituted the remaining 44.84%. Approximately 78.72% obtained water from rain or ponds because of the lack of access to a piped water supply system. In terms of diet, fish was the primary protein source, with 40.42% consuming it daily and 45.75% consuming it at least once per week. All individuals followed to a balanced diet consisting of rice, flour, legumes, fruits, and vegetables.\n\n* Non-alcoholic consumers with a low level of consumption according to the National Institute of Alcohol Abuse and Alcoholism - NIAAA.\n\nBlood concentrations of T-Hg and Cd are presented in Table 2. The median T-Hg level was significantly higher in the study group than in the control group (p < 0.001). Furthermore, the averages exceeded the permissible limits set by the WHO for populations environmentally exposed to Hg, both within communities and overall. When comparing different communities, Barú exhibited significantly higher levels as compared to Ararca and Caño del Oro.\n\nAnalysis of blood Cd levels revealed no significant differences between the study and control groups. Notably, 77.7% (70/90) of the examined individuals exhibited values below the detection limit for Cd in the blood, according to the employed methodology (0.2 μg/L). Among the 20 individuals in whom Cd was detectable, the levels ranged from 0.2 to 2.99 μg/L (median = 0.43 μg/L). This suggests that none of the participants exceeded the Cd limit set by the CDC (5 μg/L).\n\nComparisons of demographic variables potentially influencing the blood levels of T-Hg and Cd within the study group, such as sex, age, duration of residence in the area, fish consumption, and source of drinking water, are presented in the Supplementary Material (Tables S1 and S2). The analysis revealed that men and individuals consuming fish daily exhibited significantly higher blood T-Hg levels (p < 0.05) (Table S1). Spearman’s correlation analyses indicated significant associations between blood T-Hg levels and age (Rho = 0.260; p = 0.012), duration of residence in the area (Rho = 0.374; p < 0.001), and fish consumption (Rho = 0.415; p < 0.001). No differences between the groups or correlations between different variables and blood Cd levels were observed (p > 0.05) (Table S2).\n\nTable 3 presents a comparison of the BMCyt biomarkers between the control and study groups. Significantly higher frequencies of all BMCyt assay biomarkers (except pyknosis) were observed in the study group than in the control group (p < 0.05). Site-specific comparisons revealed that the frequency of nuclear alterations indicative of cell death (condensed chromatin, karyorrhexis, and karyolysis) was generally lower in the Ararca community than in the other communities. Figure 2 outlines each of the reported biomarkers.\n\nTable 4 shows the Spearman’s correlations between blood metal levels and BMCyt biomarkers. Significant positive correlations were observed between T-Hg levels and the frequencies of micronuclei, karyorrhexis, and karyolysis. Considering that sex and age might significantly influence the parameters measured by the BMN-cyt assay, we evaluated these factors as potential predictors of the frequency of these parameters. Our analysis found no differences between sexes and no significant correlation between age and the parameters tested by the BMCyt assay (Table S3 and S4).\n\n* Correlation is significant at the 0.05-level.\n\n** Correlation is significant at the 0.01-level.\n\n\n4. Discussion\n\nAssessment of the genotoxic effects associated with heavy metal concentrations in the blood plays a fundamental role in the primary monitoring of genetic material integrity and the well-being of populations. This study provides the first evidence related to the evaluation of genotoxic effects exerted by the environmental exposure to Hg and Cd using BMCyt assay in the communities of Ararca, Barú, Caño del Oro, and Tierra Bomba, rural island communities in the district of Cartagena de Indias, Colombia.\n\nOur findings revealed that the blood levels of Cd in the study group were within the normal range and comparable to those of the control group. In contrast, residents of these island communities exhibited significantly higher blood concentrations of T-Hg than the control group, surpassing the internationally accepted reference levels set by WHO (5 μg/L).22 Given the well-known mercury contamination issue in fish from the Bay of Cartagena,11,12 it is plausible that the high consumption of fish is the primary source of these metals in these communities. Accordingly, our analyses indicated that individuals who consumed fish daily had elevated blood Hg levels compared to those who consumed fish less frequently. A significant correlation between fish consumption and Hg concentrations was also identified. These findings are consistent with previous research that reported similar correlations between fish consumption frequency and Hg concentrations in hair and blood among populations in the Colombian Caribbean Coast and other regions of Colombia exposed to this metal.13,16,27–31\n\nThe BMCyt assay revealed significantly higher frequencies of micronuclei and nuclear buds (indicators of DNA damage and genetic instability) in the buccal cells of the study group than in those of the control group (p < 0.05). Additionally, a significant positive correlation was identified between the Hg concentration and micronucleus frequency. Similar findings have been reported for other Colombian populations environmentally exposed to Hg.32 Furthermore, studies utilizing the cytokinesis-block micronucleus assay (CBMNcyt) have reported correlations between micronucleus frequency in lymphocytes and the Hg concentration in the blood of environmentally exposed populations.33–35 In the current study, the CBMNcyt assay was not used; however, a close positive correlation between micronucleus frequency in BMCyt and CBMNcyt has been demonstrated.36,37 Therefore, despite methodological differences, our findings are generally similar and consistent with those of multiple reports in the literature, suggesting that Hg is a heavy metal associated with increased DNA damage in exposed populations.\n\nThe presence of nuclear buds indicates genetic amplification, implying an increase in the number of copies of specific genome sections.38,39 This amplification results in more intense expression of genes located in the amplified region. A significant biological implication of the increased frequency of nuclear buds concerning the health of the studied populations is the potential role of gene amplification in cancer development.40\n\nIn addition to the formation of micronuclei and nuclear buds, various biomarkers of cell death, including cells with condensed chromatin, karyorrhexis, karyolysis, pyknosis, and other nuclear anomalies, such as binucleated cells (indicative of cytokinesis defects), were assessed. Our findings revealed a significant increase in the frequencies of condensed chromatin, karyorrhexis, and karyolysis in the study group compared to those in the control group. Moreover, notable correlations were identified between T-Hg levels and the frequencies of karyorrhexis and karyolysis. These results align with those of Cruz-Esquivel et al.,32 who reported a significant increase in all biomarkers related to cell death and cytokinesis defects in BMCyt among Hg-exposed human populations, in contrast to the non-exposed group. The study also highlighted a significant positive correlation between Hg concentration and karyolysis.\n\nNuclear alterations indicative of cell death represent apoptotic or necrotic events. Some authors have noted that condensed chromatin and karyorrhexis accompany the early stages of apoptosis (which can lead to subsequent necrotic changes), whereas karyolysis is evident only in the necrotizing cells.41,42 Nuclear irregularities in oral tissue usually occur in the superficial cell layer as part of the natural process of cell renewal. However, excessive cell death events, particularly apoptosis, beyond normal levels can serve as an indicator of exposure to genotoxic agents.41\n\nIn buccal cells, alcohol intake may also be a risk factor for increased frequency of oral anomalies and the development of cancers in the oral cavity, pharynx, and larynx.43 However, our study found no influence of alcohol consumption on any of the BMCyt parameters evaluated. This finding was expected, given that the majority of both exposed and unexposed individuals reported not consuming alcohol, with only 10% being light consumers. Additionally, neither age nor sex influenced the frequency of micronuclei or cell death biomarkers in the studied communities. Similarly, various authors have noted that most human biomonitoring studies conducted using the BMCyt assay have not found a statistically significant influence of age or lifestyle on micronucleus frequency in the study populations.37,44\n\nLimitations of this study include several factors that may have influenced the interpretation of results. Firstly, the sample size, although calculated based on statistical power, may not fully represent the diversity within the island communities of Cartagena. Secondly, while efforts were made to control for confounding variables such as age, sex, and some habits, other environmental and genetic factors could have influenced the observed genotoxic effects. Additionally, the BMCyt assay, while effective for assessing buccal cell damage, provides a snapshot of genetic damage that may not capture long-term effects or variations in different cell types. Furthermore, the study’s cross-sectional design limits the ability to establish causal relationships between heavy metal exposure and genotoxic outcomes. Longitudinal studies would provide more robust evidence of the cumulative effects of chronic exposure to mercury on genetic integrity in these vulnerable populations.\n\n\n5. Conclusion\n\nIn summary, this study provides the first evidence related to the assessment of the genotoxic effects caused by environmental exposure to Hg and Cd using the BMCyt assay in the island communities of Cartagena de Indias, Colombia. The main findings revealed significantly higher levels of T-Hg in the studied communities than in the control population, which exceeded the established limits. Results from the BMCyt assay indicated a significantly higher frequencies of almost all biomarkers analyzed in the study population than in the control group. Furthermore, correlation analyses indicated an increase in the frequency of micronuclei, karyorrhexis, and karyolysis as blood Hg concentrations increased. These findings suggest that Hg is a potential genotoxic agent in the island populations of Cartagena de Indias, Colombia.\n\n\nEthics and consent\n\nThis study was conducted as part of the Basin Sea Interactions with Communities (BASIC-Cartagena) project, a multicenter applied research initiative on the interactions between basins, the sea, and communities in the coastal area of Cartagena.24 Participants from these communities were provided with their individual blood heavy metal results accompanied by pertinent recommendations explained by a healthcare professional. This study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of the Faculty of Medicine at the University of Cartagena in May of 2021 (Approval number 045-2021), adhering to the ethical requirements outlined in Resolution 08430 of 1993 by the Ministry of Health of Colombia.\n\nEvery participant, without exception, provided their consent by signing an informed consent form.", "appendix": "Data availability\n\nFigshare: Genotoxic effects in island populations of Cartagena de Indias, Colombia due to environmental exposure to mercury and cadmium Supplementary material and dataset, https://doi.org/10.6084/m9.figshare.26373451.v2. 45\n\nThis project contains the following underlying data:\n\n• Supplementary material (Tables S1, S2, S3 and S4)\n\n• Dataset (original raw data)\n\n• Participant registration form\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nWe express our gratitude to Dr. Cristiano Trindade for his valuable advice during the development of this work. We would also like to thank the professionals Mashiel Fernández, Katia Gazabón, and Yocelyn Cabarcas for their support and collaboration during the fieldwork stage, and Shellenia Monterroza for her collaboration during laboratory work. We also extend our thanks to all community leaders and residents of the Ararca, Barú, Caño del Oro, and Tierra Bomba communities for their cooperation and participation in this study.\n\n\nReferences\n\nBenedetti D, Nunes E, Sarmento M, et al.: Genetic damage in soybean workers exposed to pesticides: Evaluation with the comet and buccal micronucleus cytome assays. Mutation Research/Genetic Toxicology and Environmental. Mutagenesis. 2013; 752(1): 28–33. Publisher Full Text\n\nLeón-Mejía G, Luna-Rodríguez I, Trindade C, et al.: Cytotoxic and genotoxic effects in mechanics occupationally exposed to diesel engine exhaust. Ecotoxicol. Environ. Saf. 2019; 171: 264–273. 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Publisher Full Text" }	[ { "id": "317053", "date": "14 Sep 2024", "name": "Marina Piscopo", "expertise": [ "Reviewer Expertise Study of the molecular effect of heavy metals and other pollutants on the reproductive health of organism and on red cells" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the article titled “Genotoxic effects in island populations of Cartagena de Indias, Colombia due to environmental exposure to mercury and cadmium” the authors aimed to evaluate the genotoxic effects of environmental exposure to Hg and Cd in populations from the island zone of the Cartagena district, Bolívar. They found that cadmiun levels in the blood of the study group were within the normal range and comparable to those of the control group while significantly higher T-Hg levels were registered compared to the control group, surpassing the accepted limit. In addition, in this study a higher incidence of DNA damage and cell death biomarkers were revealed. Finally, significant correlations were observed between total blood Hg levels and the frequencies of micronuclei, karyorrhexis, and karyolysis. - I find it an interesting and very relevant work since environmental pollution is a major concern worldwide. I suggest a major revision, especially since the state of the art is not up-to-date and also to try to correlate the results obtained with each other for a better understanding of the paper.\nThe suggestions I would make are as follows:\nMajor point • There is a different degree of accumulation in blood and semen. I suggest to read and quote the following paper in order to amply the introduction or discussion[1] • Mercury have many effects on the reproductive health of human and marina organisms. I suggest to read and quote the following papers in order to amply the introduction or discussion[2],[3],[4]\n• Have the authors checked whether the effects of cadmium are seasonal? Because e.g. in mussels it is so. [5] • Mercury have many effects on hemoglobin and red cells. In addition, olive oil and other antioxidant prevent the effect of mercury in red cells. I suggest to read and quote the following papers in order to amply the introduction or discussion:[6],[7],[8]\n• The results must be commented on and an explanation must also be given for the effect of these pollutants on the alterations observed. A molecular mechanism must also be better hypothesized • try to correlate the results obtained with each other\n\nMinor point • ml must be changed in mL in all manuscript • µl must be changed in µL • I believe that to make the article more appealing you should include a nice color image that summarizes the results, the molecular mechanism and the message the authors want to give • Better define the limitations of this study • English revision required\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "12657", "date": "18 Oct 2024", "name": "Eder Cano Pérez", "role": "Author Response", "response": "General commentary: We appreciate the reviewer for each of the observations and recommendations provided. Overall, most of these suggestions have been addressed and taken into account to enhance the quality of our article. We hope that the modifications made meet the expectations of both the reviewer and the editorial team, facilitating a successful acceptance process for our manuscript. • There is a different degree of accumulation in blood and semen. I suggest to read and quote the following paper in order to amply the introduction or discussion[1] R/ We appreciate the reviewer’s recommendations. We have opted to include the suggested reference to enhance the introduction of our manuscript • Mercury have many effects on the reproductive health of human and marina organisms. I suggest to read and quote the following papers in order to amply the introduction or discussion[2],[3],[4] R/ We appreciate the reviewer’s recommendations. We have chosen to include some of the suggested references to enhance the introduction of our manuscript. • Have the authors checked whether the effects of cadmium are seasonal? Because e.g. in mussels it is so. [5] R/ We appreciate the reviewer’s observation. In our study, we aimed to assess the genotoxic effects of Hg and Cd in human populations exposed to environmental contamination. However, since our study was a cross-sectional observational cohort, we are unable to determine whether the effects of Cd on these populations vary seasonally. • Mercury have many effects on hemoglobin and red cells. In addition, olive oil and other antioxidant prevent the effect of mercury in red cells. I suggest to read and quote the following papers in order to amply the introduction or discussion:[6],[7],[8] R/ We appreciate the reviewer’s recommendations. We have chosen to include some of the suggested references to enhance the introduction of our manuscript. • The results must be commented on and an explanation must also be given for the effect of these pollutants on the alterations observed. A molecular mechanism must also be better hypothesized R/ We appreciate the reviewer’s recommendation. We have added a paragraph in the discussion of the manuscript outlining the mechanisms by which heavy metals such as Hg can cause DNA damage and lead to the alterations observed in our study (primarily micronuclei). For this, we have consulted relevant scientific literature. Minor point • “ml” must be changed in “mL” in all manuscript R/ We appreciate the reviewer’s detailed observation. We have made the correction from \"ml\" to \"mL\" throughout the entire document. • µl must be changed in µL R/ We appreciate the reviewer’s detailed observation. We have made the correction from \" µl\" to \" µL\" throughout the entire document • Better define the limitations of this study R/ We have revised several aspects of the limitations section to enhance clarity and better articulate our ideas. These improvements aim to provide a more precise understanding of the constraints of our study. • English revision required R/ This study was reviewed by English-speaking experts in the field of toxicology prior to its submission to the journal." } ] } ]	1	https://f1000research.com/articles/13-946
https://f1000research.com/articles/13-916/v1	12 Aug 24	{ "type": "Research Article", "title": "Examining the effects of anxiety and education level on mental health: The role of spiritual intelligence as an intervening variable in post COVID-19 patients in Indonesia", "authors": [ "Anis Ansyori", "Ahmad Yunus", "Sentot Imam", "Yuly Peristiowati", "Ahmad Yunus", "Sentot Imam", "Yuly Peristiowati" ], "abstract": "Background The COVID-19 pandemic has profoundly affected global health systems and daily life, exacerbating vulnerabilities, particularly in Indonesia. This study investigates the impact of anxiety and education level on mental health, with spiritual intelligence as an intervening variable among post-COVID-19 patients in Indonesia.\n\nMethods A cross-sectional design was employed, analyzing data from 390 post-COVID-19 patients in Indonesia. Structured questionnaires were used to assess anxiety, education level, spiritual intelligence, and mental health.\n\nResults The findings indicate that anxiety significantly affects both spiritual intelligence and mental health, with spiritual intelligence acting as a mediating factor. Additionally, higher educational attainment is positively associated with enhanced spiritual intelligence and improved mental health outcomes.\n\nConclusions The study underscores the importance of incorporating spiritual development practices into mental health interventions and educational programs to boost resilience and overall well-being in the post-pandemic era. These practices can help mitigate the adverse effects of anxiety and educational disparities on mental health.", "keywords": [ "anxiety", "education level", "spiritual intelligence", "mental health" ], "content": "1. Introduction\n\nThe COVID-19 pandemic has had a significant influence on worldwide health systems, economies, and daily life, dramatically altering the way societies function and interact (Clemente-Suárez et al., 2021; Onyeaka et al., 2021). In Indonesia, the impact has been particularly profound, as the pandemic has exposed and intensified existing vulnerabilities within the healthcare infrastructure. The country’s healthcare system, already facing challenges such as limited resources and uneven access to services, has been pushed to its limits by the demands of the pandemic. This strain has exacerbated pre-existing issues, leading to a widespread epidemic of mental health disorders that affect both healthcare professionals and the general public (Gupta & Sahoo, 2020; Søvold et al., 2021).\n\nAnxiety and depression have surged in Indonesia, mirroring a global trend of rising mental health concerns during the pandemic. Healthcare professionals, who are on the front lines, have faced immense pressure, dealing with overwhelming workloads, the risk of infection, and the emotional toll of patient care. This has resulted in increased levels of stress, burnout, and mental fatigue among medical workers. Similarly, the general public has experienced heightened anxiety and depression due to factors such as social isolation, economic instability, and fear of the virus (Alfadla et al., 2020; Kumar et al., 2022; Tolentino et al., 2022).\n\nThe pandemic has disrupted daily life, altering routines, and impacting economic activities, further compounding mental health issues. Lockdowns and restrictions have limited social interactions, leading to feelings of loneliness and uncertainty (Nitschke et al., 2021; Patulny & Bower, 2022). The economic downturn has resulted in job losses and financial insecurity, which have added to the psychological burden faced by many individuals (Dubey et al., 2020). As these stressors continue to affect the population, understanding and addressing the mental health challenges they present have become increasingly important for Indonesia’s recovery and resilience in the post-pandemic era.\n\nThere are particular difficulties that arise during the transition from acute illness to recovery that may have an impact on mental health. Among these difficulties, anxiety has emerged as a major problem due to persistent concerns about one’s health, unpredictability in the economy, and the pandemic’s wider effects. Anxiety disorders are the most common mental health conditions, significantly impacting quality of life and functioning (Minoletti et al., 2022). Increased anxiety can show up in a number of ways, such as physical symptoms, sleep difficulties, and overall psychological discomfort (Richards et al., 2020; Rowa et al., 2017), all of which have a substantial negative impact on mental health (Rathakrishnan et al., 2022).\n\nIn addition, educational level has a significant impact on mental health, influencing how individuals perceive and respond to stressors. Higher education levels are generally linked to improved coping strategies, increased access to resources, and greater resilience. Individuals with higher educational attainment are often better equipped to navigate complex challenges due to their enhanced problem-solving skills and access to information (Wu et al., 2013). This ability to effectively manage stress can lead to more positive mental health outcomes, as educated individuals may employ healthier coping mechanisms and utilize available support systems more effectively (Mirowsky, 2017).\n\nConversely, people with lower levels of education may face substantial barriers in accessing mental health resources and information. They might struggle to find or afford appropriate care, leading to delayed or inadequate treatment. This difficulty in obtaining help can exacerbate feelings of helplessness and stress, resulting in increased anxiety levels and poorer mental health outcomes. The lack of educational opportunities may also limit their awareness of effective coping strategies, further compounding their vulnerability to mental health issues.\n\nIn this situation, spiritual intelligence—which is described as the capacity to negotiate challenging emotional environments, remain adaptable, and rely on one’s own principles and beliefs to get through difficult times (Emmons, 2000; Hyde, 2004)—may be rather important. It has been proposed that spiritual intelligence guards against anxiety and other mental health issues (Tolentino et al., 2022). In the midst of the pandemic’s upheavals, it offers a framework for people to find purpose and stability, which may lessen the detrimental effects of anxiety and educational inequality on mental health.\n\nDespite the growing interest in spirituality as a factor in mental health, there remains a notable gap in the literature regarding the specific role of spiritual intelligence in the post COVID-19 context. Existing research has not fully explored how spiritual intelligence might mediate the relationship between anxiety, educational level, and mental health outcomes. This study aims to fill this gap by employing a cross-sectional design to assess the prevalence of anxiety and depression among post COVID-19 patients in Indonesia. It will investigate the extent to which spiritual intelligence serves as an intervening variable that mediated the effects of anxiety and educational level on mental health.\n\n\n2. Literature review and hypothesis development\n\nExcessive concern, trepidation, and fear are hallmarks of anxiety, a common mental health condition that can have a serious negative influence on a person’s ability to function in everyday life and overall quality of life. According to research on the subject, anxiety can result from a complex interaction of hereditary, environmental, and psychological factors (Barlow, 2002). Anxiety disorders are among the most prevalent mental diseases globally, affecting over 18% of adult Americans alone, according to Kessler et al. (2005). Numerous research showing heightened anxiety symptoms due to health worries, social isolation, and economic difficulties have documented how the COVID-19 pandemic has further exacerbated anxiety levels globally (Rajkumar, 2020). Anxiety can take on multiple forms, such as panic disorder, social anxiety disorder, and generalized anxiety disorder, each with its own set of symptoms and difficulties. Research has demonstrated that cognitive-behavioral therapy (CBT) is a successful treatment for anxiety disorders, as it can effectively reduce symptoms and enhance coping mechanisms (Hofmann et al., 2012). While they may have adverse effects and need to be closely monitored, pharmacological therapies, such as selective serotonin reuptake inhibitors (SSRIs), are also frequently used to treat anxiety symptoms (Baldwin et al., 2014). According to Hofmann et al. (2010), recent research has examined the potential of mindfulness and relaxation practices as supplemental therapies, with an emphasis on their effectiveness in reducing anxiety. For those seeking therapy for anxiety, obstacles to care such as stigma and a lack of resources persist despite improvements in treatment. Research on anxiety must continue as our understanding of the problem advances in order to create more approachable and efficient interventions for those who suffer from this widespread illness.\n\nIt has long been known that an individual’s educational level has a substantial impact on their resilience, coping mechanisms, and resource accessibility, all of which are related to their mental health. Higher educational level is regularly linked to better mental health outcomes because it frequently gives people the tools they need to think critically, solve problems more effectively, and comprehend a wider range of health-related information (Mirowsky & Ross, 2003). These abilities can improve a person’s capacity to deal with difficult situations and find resources, which can result in an increase in psychological well-being (Ross & Wu, 1995). Additionally, education gives people access to social and economic possibilities that might lower stress and anxiety, which promotes an atmosphere that is more stable for mental health (Burgard & Lin, 2013). On the other hand, those with less education could have trouble getting mental health care because they don’t know about or comprehend the resources that are accessible to them. This can make them feel even more stressed and helpless (Zajacova et al., 2015). These differences have been brought to light even more by the COVID-19 pandemic, as people with lower educational level have found it more difficult to adjust to distant work and learning environments, which has led to an increase in mental health stresses (Patrick et al., 2020). Comprehending the influence of educational level on mental health is crucial in order to formulate focused measures and regulations that tackle these discrepancies and encourage fair and equal availability of mental health services to individuals from diverse educational backgrounds.\n\nThe ability to find meaning, purpose, and connection in life is referred to as spiritual intelligence, and it has come to be recognized as a significant element impacting mental health. The capacity to uphold inner calm, exhibit empathy, and exhibit perseverance in the face of difficulty are characteristics of this type of intellect (Zohar & Marshall, 2000). Studies reveal that people with high spiritual intelligence typically have lower rates of anxiety and depression because they are better able to handle stress and difficulties because they have a stronger sense of purpose and connectivity (Vaughan, 2002). A holistic perspective of life’s experiences is facilitated by spiritual intelligence, which enables people to see challenges as chances for personal development rather than insurmountable roadblocks (Emmons, 2000). Additionally, research has demonstrated that spiritual intelligence can increase emotional regulation, which can minimize unpleasant feelings and improve psychological well-being (King & DeCicco, 2009). Spiritual practices that are components of spiritual intelligence, such mindfulness and meditation, have been demonstrated to considerably reduce stress and produce a positive mental state in the context of mental health (Seybold & Hill, 2001). Growing research on spiritual intelligence and its advantages provide a possible path for creating therapies that integrate existential and spiritual elements into therapeutic modalities to address mental health concerns.\n\nAn essential part of total wellbeing, mental health includes social, psychological, and emotional dimensions that affect people’s thoughts, feelings, and behaviors. It is essential for managing stress, interacting with people, and making decisions at different phases of life (World Health Organization, 2001). Millions of people worldwide suffer from mental health illnesses, which can have a significant negative influence on an individual’s productivity and quality of life. These disorders include conditions like depression, anxiety, and schizophrenia (Kessler et al., 2005). The stigma attached to mental illness frequently prevents people from getting treatment, which increases the burden of these disorders (Corrigan, 2004). Prevention, early intervention, and access to suitable treatment services are all essential components of a comprehensive strategy for providing effective mental health care (Patel et al., 2016). Various mental health issues have been demonstrated to be effectively managed by psychotherapy, medication, and lifestyle therapies such exercise and mindfulness techniques (Cuijpers et al., 2016). Furthermore, a growing body of research underscores the significance of socioeconomic determinants, including wealth, education, and community support, in shaping mental health outcomes and stresses the necessity of policies that take these elements into account (Marmot, 2005). There is a growing need for comprehensive strategies that integrate mental health into public health agendas in order to improve mental health outcomes worldwide and lessen the stigma and barriers associated with seeking care, as awareness and understanding of mental health issues continue to rise.\n\nPervasive sensations of anxiety and fear are the hallmark of anxiety, which can have a major impact on mental health and spiritual intelligence, among other elements of psychological functioning. Studies have indicated a correlation between elevated anxiety levels and heightened mental health conditions, including emotional discomfort and depression (Rathakrishnan et al., 2022). Furthermore, spiritual intelligence—which includes the ability to find purpose in life, preserve inner calm, and demonstrate empathy—can be impacted by anxiety.\n\nThe relationship between anxiety and mental health may be mediated by spiritual intelligence. People who possess strong spiritual intelligence may be better able to control their anxiety because of their increased emotional intelligence, resilience, and capacity to find purpose in difficult circumstances. The detrimental effects of anxiety on mental health may be lessened by this buffering effect. According to Rathakrishnan et al. (2022), spiritual intelligence can improve mental health outcomes by reducing the negative impacts of anxiety.\n\nAnxiety has a significant effect on spiritual intelligence.\n\nAnxiety has a significant effect on mental health.\n\nAnxiety has a significant effect on mental health with spiritual intelligence as a mediation.\n\nHigher levels of spiritual intelligence can be attributed to improved cognitive and emotional growth, which is correlated with educational level. Putra’s (2016) research revealed a favorable correlation between parents’ educational level and their children’s spiritual intelligence, implying that education can promote spiritual development and comprehension. Higher education can give people the skills and understanding needed to develop spiritual practices and awareness.\n\nFurthermore, there is a strong correlation between mental health outcomes and educational level. Better employment opportunities, financial security, and access to healthcare are all benefits of higher education that can enhance mental health. According to studies by Taple et al. (2022), Raghupathi & Raghupathi (2020), and Namira & Yuliawati (2021), having more education is associated with improved mental health since it gives one access to more resources and support networks. On the other hand, a lack of education can limit one’s ability to utilize these resources, which can result in more stress and worse mental health consequences.\n\nEducational level has a significant effect on spiritual intelligence.\n\nEducational level has a significant effect on mental health.\n\nEducational level has a significant effect on mental health with spiritual intelligence as a mediation.\n\nSpiritual intelligence, which involves the ability to find meaning and purpose in life, maintain inner peace, and exhibit empathy and compassion, is proposed to influence mental health outcomes. The relationship between spiritual intelligence and mental health has been explored in various studies, revealing both supportive and conflicting results. Research by Rathakrishnan et al. (2022) and Wahyuni & Bariyyah (2019) suggests that higher levels of spiritual intelligence are positively associated with better mental health. These studies indicate that spiritual intelligence can help individuals manage stress, anxiety, and other mental health challenges by providing a sense of purpose and resilience.\n\nIn contrast, Furqani (2021) found that spiritual intelligence did not have a significant relationship with mental health, highlighting a potential discrepancy in the literature. This conflicting result underscores the need for further investigation into how spiritual intelligence may affect mental health and whether this relationship varies across different contexts or populations. The research gap identified from these differing findings suggests that while spiritual intelligence may generally support mental health, the effect might not be uniform across all studies. Thus, we hypothesize:\n\nSpiritual intelligence has a significant effect on mental health.\n\n\n3. Methods\n\nThis study investigates post-COVID-19 patients in Indonesia, with the primary focus on those who have recovered from the virus. The research population includes all post-COVID-19 patients in Indonesia, while the sample is specifically drawn from those residing in Indonesia. To be included in the study, participants must have been diagnosed with COVID-19 by a medical doctor, have recovered from the illness, be at least 18 years old at the time of diagnosis, consent to participate, and have been residing in Indonesia during their illness. Exclusion criteria are applied to ensure the validity of the study: patients with chronic illnesses affecting physical and psychological health, those unable to provide accurate health information, individuals who cannot adhere to the study’s lifestyle requirements, those who have undergone significant additional medical treatments post-recovery, and individuals who are deceased or unreachable are excluded.\n\nThe sample size was calculated using the Slovin formula, which resulted in a required sample of 390 respondents. This calculation ensures a representative sample size with a margin of error of 5%. The study employs a non-probability sampling technique, specifically purposive sampling, allowing the researcher to select participants based on the defined inclusion criteria. Primary data is collected through structured questionnaires and semi-structured interviews, providing both quantitative and qualitative insights. The Likert scale ranging from 1 to 4 is used for measurement, capturing participants’ responses on anxiety, spiritual intelligence, educational level, and mental health. To eliminate the chance of bias, the questionnaire was carefully designed and thoroughly evaluated before being circulated. Data were analyzed using Structural Equation Modeling (SEM) with SmartPLS 3.2.4 to address the research objectives and test the hypotheses (Ringle et al., 2014).\n\nIn this study, various measurement scales are employed to accurately assess the variables of anxiety, educational level, spiritual intelligence, and mental health, ensuring a comprehensive evaluation of each construct.\n\nFor anxiety (X1), the scale is based on Storer et al. (2024) and includes dimensions such as feelings of anxiety, fear, sleep disturbances, somatic symptoms, and respiratory symptoms. This scale captures a broad spectrum of anxiety-related experiences, from emotional and psychological aspects to physical manifestations.\n\nThe educational level (X2) is measured according to Tirtarahardja (2005). This scale evaluates educational level, relevance of the field of study, and competency. It assesses the impact of an individual’s educational background, including their level of education, how relevant their field of study is, and the competencies they have developed.\n\nSpiritual intelligence (Z) is assessed using the framework from Organ (2006). This scale includes dimensions such as the ability to be flexible, a high level of awareness, the ability to cope with and utilize suffering, the relation to faith, and strong empathy. It measures various aspects of spiritual intelligence, capturing how flexibility, awareness, coping abilities, faith, and empathy contribute to an individual’s spiritual capacity.\n\nLastly, mental health (Y) is evaluated using the scale developed by Veit and Ware (1983). This includes experiencing depression, loss of control over emotional behavior, the presence of general positive affect, emotional bonding, and overall life satisfaction. This scale addresses different facets of mental health, providing insights into emotional states, positive feelings, and general contentment with life.\n\nThe conceptual model for this study, which illustrates the relationships between anxiety, educational level, spiritual intelligence, and mental health, is depicted in Figure 1. This model guides the analysis and interpretation of the data, providing a visual representation of the hypothesized relationships among the study variables.\n\n\n4. Results\n\nDemographic data in Table 1 provides a detailed breakdown of the participants’ characteristics, allowing for a comprehensive understanding of the diverse group surveyed. The data spans various categories including gender, age, education, the year of infection with COVID-19, and employment status, offering insights into the demographic distribution and contextual background of the individuals involved.\n\nThe demographic data presented offers a detailed overview of the participants’ characteristics across various categories including sex, age, education, the year of infection with COVID-19, and occupation. The sample consists of 390 participants with a distribution skewed towards female respondents, who make up 73% of the total (286 individuals), compared to 27% male participants (104 individuals). Age-wise, the group is mostly concentrated between 23 and 37 years, with 59 participants (15%) aged 23-27 years, 85 participants (22%) aged 28-32 years, and 95 participants (24%) aged 33-37 years. The remaining age groups gradually decrease in representation with the lowest numbers in the 53-67 years range.\n\nEducational levels among the participants vary, with the majority holding a Senior High School diploma (230 participants, 59%), followed by those with a Bachelor’s degree (112 participants, 29%). Fewer participants have attained a Master’s (17 participants, 4%) or Doctoral degree (3 participants, 1%). Regarding the year of COVID-19 infection, a significant number were infected in 2021 (192 participants, 49%), followed closely by those infected in 2020 (97 participants, 25%) and 2019 (95 participants, 24%).\n\nOccupationally, the participants are diverse, with factory workers and homemakers each comprising 19% of the total. Other notable occupations include self-employed (35 participants, 9%), students (19 participants, 5%), and private sector employees (25 participants, 6%). The rest are distributed among various jobs including teachers, freelancers, and civil servants, reflecting a wide range of employment statuses within the group. This diverse demographic composition provides a rich dataset for analyzing the impacts and correlates of various socio-economic factors.\n\nThe measurement model evaluates the reliability and validity of the constructs: Anxiety (X1), Educational Level (X2), Spiritual Intelligence (Z), and Mental Health (Y). Each construct is measured using specific scales, and the reliability and validity of these measurements are tested through various criteria.\n\nThe measurement model analysis in Table 2 demonstrated that the constructs used in the study—Anxiety, Educational Level, Spiritual Intelligence, and Mental Health—are both reliable and valid. Each construct showed high internal consistency, with Cronbach’s alpha values exceeding 0.70 and composite reliability values above 0.80. The Average Variance Extracted (AVE) for all constructs surpassed the 0.50 threshold, indicating adequate convergent validity. Moreover, discriminant validity was confirmed as the square root of the AVE for each construct was greater than its highest correlation with any other construct, ensuring distinctiveness among the constructs. These results confirm that the measurement scales used for Anxiety, Educational Level, Spiritual Intelligence, and Mental Health are robust, providing a reliable and valid foundation for further analysis in the structural model.\n\nThe structural model presented in the Figure 2 and Table 3 illustrates the relationships among Anxiety (X1), Educational Level (X2), Spiritual Intelligence (Z), and Mental Health (Y). The model employs path coefficients to demonstrate the strength and direction of these relationships.\n\nAnxiety (X1) has a significant positive direct effect on Spiritual Intelligence (Z), with a path coefficient of 0.561, a T-Statistic of 4.742, and a p-value of 0.000. This indicates that higher levels of anxiety are significantly associated with higher levels of spiritual intelligence. However, Anxiety has a significant negative direct effect on Mental Health (Y), with a path coefficient of -0.249, a T-Statistic of 3.999, and a p-value of 0.000. This suggests that higher anxiety levels are associated with poorer mental health outcomes.\n\nEducational Level (X2) has a moderate positive effect on Spiritual Intelligence (Z), with a path coefficient of 0.242, a T-Statistic of 2.667, and a p-value of 0.010. This indicates that higher educational levels are significantly associated with higher spiritual intelligence. Educational Level also positively affects Mental Health (Y), with a path coefficient of 0.332, a T-Statistic of 2.597, and a p-value of 0.013. This shows that higher educational levels are associated with better mental health outcomes.\n\nSpiritual Intelligence (Z) has a strong positive effect on Mental Health (Y), with a path coefficient of 0.734, a T-Statistic of 5.342, and a p-value of 0.000. This underscores the crucial role of spiritual intelligence in enhancing mental health, indicating that individuals with higher spiritual intelligence tend to have better mental health outcomes.\n\nThe model also examines the indirect effects of Anxiety (X1) and Educational Level (X2) on Mental Health (Y) through Spiritual Intelligence (Z). The indirect effect in Table 4 of Anxiety on Mental Health through Spiritual Intelligence is significant, with a calculated effect of 0.412 (0.561 * 0.734), indicating that higher levels of anxiety contribute to better mental health indirectly by enhancing spiritual intelligence. Similarly, the indirect effect of Educational Level on Mental Health through Spiritual Intelligence is also significant, with a calculated effect of 0.178 (0.242 * 0.734), suggesting that higher educational levels improve mental health indirectly by increasing spiritual intelligence. These significant indirect effects highlight the mediating role of spiritual intelligence in the relationship between anxiety, educational level, and mental health.\n\nThe summary Table 5 below presents the direct, indirect, and total effects of the variables on each other within the model:\n\nThe direct effect of Anxiety (X1) on Spiritual Intelligence (Z) is 0.561, while the direct effect of Educational Level (X2) on Spiritual Intelligence is 0.242. Both of these effects are significant, indicating that higher anxiety and higher educational levels lead to increased spiritual intelligence. For the relationship between Anxiety and Mental Health (Y), the direct effect is -0.249, suggesting a negative impact. However, when considering the indirect effect through Spiritual Intelligence (0.412), the total effect of Anxiety on Mental Health is 0.163, highlighting a net positive impact due to the mediation by spiritual intelligence.\n\nEducational Level (X2) has a direct positive effect on Mental Health (0.332), and with an additional indirect effect through Spiritual Intelligence (0.178), the total effect on Mental Health is 0.510, emphasizing the substantial positive influence of education on mental health. Lastly, the direct effect of Spiritual Intelligence on Mental Health is notably strong at 0.734, reaffirming its crucial role in promoting better mental health outcomes.\n\n\n5. Discussion and implication\n\nOur findings support the hypothesis that anxiety has a major impact on spiritual intelligence and mental health. Higher degrees of anxiety are linked to higher levels of spiritual intelligence, which suggests that people who are anxious could look for a deeper sense of meaning and purpose in life as a coping mechanism. This result is consistent with the findings of Rathakrishnan et al. (2022), who suggested that anxiety may cause people to become more spiritually intelligent in an attempt to cope with their emotional pain and melancholy. But anxiety’s deleterious impacts are further highlighted by the actual harm it causes to mental health. The idea that spiritual intelligence improves emotional resilience and gives a sense of purpose, hence lowering the deleterious consequences of anxiety, is supported by the fact that spiritual intelligence reduces some of the negative effects of anxiety on mental health.\n\nThese results suggest that programs for treating anxiety should take into account the inclusion of spiritual development practices in mental health therapies. By helping people discover meaning and purpose, practices like mindfulness, meditation, and spiritual counseling may be able to lessen the detrimental effects of anxiety on mental health. This strategy is consistent with the buffering theory put forth by Rathakrishnan et al. (2022), according to which spiritual intelligence increases emotional resilience and lessens the negative consequences of anxiety.\n\nSpiritual intelligence and mental health are strongly influenced by educational level. Increased cognitive and emotional growth is probably the reason why higher educational attainment is associated with increased spiritual intelligence. This confirms Putra’s (2016) findings that learning promotes understanding and spiritual growth. Additionally, studies by Taple et al. (2022), Raghupathi and Raghupathi (2020), and Namira and Yuliawati (2021) that highlight the advantages of higher education in providing access to better employment opportunities, financial security, and healthcare, tend to support the idea that people with higher educational levels also tend to have better mental health outcomes. A supportive framework for mental health is provided by the development of spiritual intelligence as a result of higher education. This suggests that education gives people the knowledge and abilities needed to cultivate spiritual practices and awareness, which in turn has a positive impact on mental health.\n\nThe relevance of educational policies and programs in improving mental well-being is shown by the enormous influence that educational attainment has on both spiritual intelligence and mental health. Curricula that support spiritual development in addition to cognitive and emotional development should be incorporated into educational institutions. Programs that promote empathy, ethical reasoning, and critical thinking may raise students’ spiritual intelligence and improve their mental health. This strategy backs up the findings of studies by Taple et al. (2022), Raghupathi and Raghupathi (2020), and Namira and Yuliawati (2021), which show how education can enhance mental health outcomes by giving people better access to resources and support systems.\n\nImproving mental health outcomes requires a high level of spiritual intelligence. Higher spiritually intelligent people are better able to control their stress and anxiety, which benefits their general mental health. This result is consistent with studies by Wahyuni and Bariyyah (2019) and Rathakrishnan et al. (2022), which indicate that spiritual intelligence supports people in exhibiting empathy and compassion, finding meaning and purpose in life, and preserving inner peace—all of which are factors that positively impact mental health. Furqani (2021) did not find a significant correlation between spiritual intelligence and mental health, which suggests that there may be variation in this relationship among groups or circumstances. This is an essential point to remember.\n\nThe substantial positive correlation between spiritual intelligence and mental health bears important implications for interventions aimed at promoting mental health. Policymakers and mental health professionals should think about integrating spiritual intelligence development into their initiatives. Mental health initiatives can help people manage stress and anxiety more effectively by providing courses and materials on finding meaning in life, preserving inner calm, and developing empathy. This is consistent with the favorable results reported by Wahyuni and Bariyyah (2019) and Rathakrishnan et al. (2022), which suggests that spiritual intelligence can be an effective means of fostering mental wellness. Notwithstanding the inconclusive results reported by Furqani (2021), it is imperative to customize these initiatives to particular cultural and demographic settings in order to guarantee their efficacy.\n\n\n6. Conclusion\n\nComprehending the intermediary function of spiritual intelligence in the associations of anxiety, level of education, and mental health has pragmatic consequences for formulating all-encompassing mental health remedies. Programs that tackle anxiety reduction, educational success, and spiritual growth all at the same time are probably going to be more successful in enhancing mental health results. Individuals will profit from the direct and indirect paths found in this study thanks to the comprehensive approach. In order to develop integrated support systems, mental health policy should encourage interdisciplinary collaborations between educators, mental health practitioners, and spiritual counselors.\n\nHowever, there are limitations to this study. First, the cross-sectional design restricts the ability to infer causality between the variables. Second, the sample is limited to post-COVID-19 patients in Indonesia, which may affect the generalizability of the findings to other populations or settings. Finally, while the study highlights the importance of spiritual intelligence, it does not fully explore how different aspects of spiritual intelligence contribute to mental health outcomes.\n\nNevertheless, these results offer insightful information for both scholarly study and real-world interventions meant to improve mental health. Putting a strong emphasis on the growth of spiritual intelligence may be a calculated move to lessen the negative effects of anxiety and maximize the benefits of education. To validate and build on these findings, future studies should investigate these correlations in a variety of demographics and circumstances.\n\n\nEthics and consent\n\nAll procedures involving human participants in this study were conducted in accordance with the institutional ethical standards of Institut Ilmu Kesehatan Strada Indonesia, which received approval under number 000986/EC/KEPK/I/03/2024 on March 7, 2024. The health and well-being of the participants were prioritized throughout the study, in line with the commitment to ensuring their safety and ethical treatment.\n\nInformed consent was obtained from all participants. Written consent was provided by each participant, who received comprehensive information about the study’s purpose, procedures, potential risks, and benefits. Participants voluntarily agreed to participate in the study based on this information.", "appendix": "Data availability statement\n\nThe data presented in this study are available on request from the corresponding author due to confidentiality agreements with the participants involved in the research. Our data statement is complete and adheres to the journal’s guidelines. Access to the data is restricted to protect participant privacy. Researchers wishing to access the data must submit a formal request to the corresponding author, detailing the purpose of their research, the specific data needed, intended use, and measures for ensuring data security and participant confidentiality. Requests will be evaluated on a case-by-case basis, and access will be granted under specific conditions approved by our Institutional Review Board (IRB). For further inquiries, please contact anisansyori@itsk-soepraoen.ac.id.\n\nFigshare: Questionnaire for “Examining the Effects of Anxiety and Education Level on Mental Health: The Role of Spiritual Intelligence as an Intervening Variable in Post COVID-19 Patients in Indonesia”, DOI: https://doi.org/10.6084/m9.figshare.26422345.v1 (Ansyori A, et al., 2024a).\n\nSTROBE checklist for “Examining the Effects of Anxiety and Education Level on Mental Health: The Role of Spiritual Intelligence as an Intervening Variable in Post COVID-19 Patients in Indonesia”, DOI: https://doi.org/10.6084/m9.figshare.26422324.v1 (Ansyori A, et al., 2024b).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgements\n\nThe authors would like to express their sincere gratitude for the support and resources provided during the course of this research.\n\n\nReferences\n\nAlfadla MT, Hanafi H, Rahman DH, et al.: Anxiety Management for New Normal Era: Hermeneutic Studies of Kitab Kuning. 1st International Conference on Information Technology and Education (ICITE 2020). 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Bloomsbury Publishing; 2000." }	[ { "id": "314076", "date": "12 Sep 2024", "name": "M Arli Rusandi", "expertise": [ "Reviewer Expertise My areas of expertise include Education", "Counseling", "Digital Health", "Information Technology Education", "Higher Education", "and Artificial Intelligence in Education." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary of the Article: The article investigates the relationships among anxiety, education level, spiritual intelligence, and mental health in post-COVID-19 patients in Indonesia. Utilizing a cross-sectional design and Structural Equation Modeling (SEM), the study analyzes data collected from 390 participants. The findings reveal that anxiety significantly influences both spiritual intelligence and mental health, with spiritual intelligence serving as a mediating factor. Moreover, the study demonstrates that higher educational attainment is positively correlated with enhanced spiritual intelligence and better mental health outcomes. The article concludes by highlighting the significance of incorporating spiritual development practices into mental health interventions and educational programs to enhance resilience and overall well-being in the post-pandemic context.\nEvaluation Based on Questionnaire: 3. Are sufficient details of methods and analysis provided to allow replication by others? Answer: Partly, Although the methods section is comprehensive and notes the use of established measurement scales, the manuscript would benefit from further elaboration on the validation or adaptation of these scales for the Indonesian context. Providing these additional details would enhance the study's replicability, particularly for researchers operating in different cultural settings. 5. Are all the source data underlying the results available to ensure full reproducibility? Answer: Partly, the manuscript discusses the availability of data, with some restrictions due to participant confidentiality. While the data availability statement is clear, these restrictions may limit the ability to fully reproduce the study's findings. The authors might consider offering anonymized data or providing further details on how the data can be accessed by qualified researchers.\nReviewer Comments to Author To ensure comprehensiveness, I will organize my comments according to the manuscript's structure. Introduction Major Comments: 1. The introduction provides a solid foundation by addressing the impact of the COVID-19 pandemic on mental health, particularly within the Indonesian context. However, the research aim or question could be articulated more explicitly earlier in the introduction. This would help orient the reader and clarify the study's purpose from the outset. 2. The rationale for exploring the role of spiritual intelligence as a mediator between anxiety, education, and mental health is well-founded and relevant. However, consider summarizing the existing literature more concisely to avoid redundancy and maintain a sharper focus on the specific research gap your study aims to address. Minor Comments: 1. Ensure consistent use of terminology when discussing mental health. The text occasionally shifts between general references to mental health and specific conditions such as anxiety and depression. It may be beneficial to clarify early in the manuscript whether the study focuses broadly on mental health or specifically on conditions like anxiety and depression. 2. The transitions between paragraphs could be smoother, especially when shifting from the general discussion of the pandemic’s impact to the specific focus on spiritual intelligence. Consider adding transitional sentences to enhance the narrative flow.\nMethodology Major Comments: 1. The use of purposive non-probability sampling is appropriate given the specific population targeted by the study. However, this approach introduces potential biases that should be acknowledged. It would be beneficial to discuss how these biases might impact the generalizability of the findings and whether any measures were taken to mitigate them. 2. The measurement tools selected for the study appear well-chosen and likely valid. However, it would be advantageous to provide additional details regarding how these tools were adapted or validated for the Indonesian context, particularly considering potential cultural differences in the interpretation of survey items. Minor Comments: 1. The inclusion and exclusion criteria are clearly articulated and well-defined. However, the exclusion of patients with chronic illnesses could limit the generalizability of the findings. A brief discussion of this limitation would enhance the transparency of the study. Ethical Considerations: 2. While the methodology section is comprehensive, including a brief mention of the ethical considerations or approval process in this section, in addition to the detailed explanation in the conclusion, would further underscore the study's ethical integrity.\nResults Major Comments: 1. The results are presented with clarity, and the significant findings effectively support your hypotheses. However, the positive relationship observed between anxiety and spiritual intelligence is somewhat counterintuitive. It would be beneficial to explore alternative explanations for this finding or to consider the possibility of reverse causality, either within the results section or in greater detail in the discussion. 2. The significant indirect effects mediated by spiritual intelligence are a crucial aspect of the study's findings. It is important to ensure that these effects are clearly interpreted, particularly in terms of their practical implications for mental health interventions. Minor Comments: 1. While the demographic data provided is comprehensive, the skew towards younger, female participants should be addressed. Consider discussing how this demographic imbalance might affect the generalizability of your findings to a broader population. 2. The results section could benefit from a brief summary at its conclusion, linking the findings back to the original research questions or hypotheses. This would reinforce the narrative and help ensure that the reader fully grasps the significance of the results.\nDiscussion and Conclusions Major Comments: 1. The discussion successfully connects your findings to the existing literature, especially in emphasizing the role of spiritual intelligence. However, the counterintuitive result that anxiety positively influences spiritual intelligence warrants a more thorough exploration. Consider addressing any conflicting literature or offering theoretical explanations to better contextualize this finding. 2. The discussion of limitations is appropriately transparent, particularly with regard to the cross-sectional design and the specificity of the population sample. Expanding on how these limitations could be addressed in future research—such as through longitudinal studies or more diverse sampling—would enhance the robustness of your recommendations. Minor Comments: 1. The discussion of integrating spiritual intelligence into mental health interventions is well-argued. However, providing additional concrete examples or recommendations for implementation in educational or clinical settings could strengthen this section. 2. The conclusion effectively summarizes the study’s contributions and acknowledges its limitations. Including a final sentence that emphasizes the broader impact of your findings on mental health policy or practice would create a stronger and more impactful closing statement.\nAbstract Major Comments: The abstract is well-organized and effectively summarizes the study. However, including a brief mention of the study’s limitations or the need for further research would provide a more comprehensive overview. Additionally, specifying the statistical methods used, such as Structural Equation Modeling (SEM), could add depth and clarity. Minor Comments: Keywords: The keywords are appropriate, but you might consider adding terms like \"post-pandemic\" or \"cross-sectional study\" to improve searchability and relevance.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "12783", "date": "11 Nov 2024", "name": "Anis Ansyori", "role": "Author Response", "response": "Thank you for your thorough review and valuable feedback on our manuscript. We appreciate the time and expertise you dedicated to enhancing the quality of our study. Below, we address each of your comments and outline the corresponding revisions we have made to the manuscript. Introduction Research Aim/Question: We have revised the introduction to state the research aim more explicitly at the beginning to improve clarity and orientation for readers. Concise Literature Summary: We have streamlined the literature review to maintain focus on the specific research gap related to the role of spiritual intelligence, reducing redundancy as suggested. Terminology Consistency: We have ensured consistent terminology when discussing mental health, specifying whether we refer to mental health in general or specific conditions such as anxiety and depression. Paragraph Transitions: Transitional sentences have been added to create a smoother flow, particularly when moving from the pandemic’s impact to the focus on spiritual intelligence. Methodology Sampling and Potential Biases: We have acknowledged potential biases from using purposive non-probability sampling and discussed how these biases might impact generalizability. Adaptation/Validation of Tools: Additional details have been added regarding the adaptation and validation of measurement tools for the Indonesian context, with consideration of cultural factors in interpreting survey items. Inclusion and Exclusion Criteria: We have discussed how excluding patients with chronic illnesses may limit the generalizability of findings, as recommended. Ethical Considerations: We have briefly mentioned ethical considerations, including the approval process, in the methodology section to emphasize the study’s ethical integrity. Results Anxiety and Spiritual Intelligence: In response to the counterintuitive positive relationship between anxiety and spiritual intelligence, we have expanded the discussion to include possible explanations, such as coping mechanisms and reverse causality, and referenced relevant literature to contextualize this finding. Interpretation of Indirect Effects: We have clarified the interpretation of significant indirect effects mediated by spiritual intelligence, particularly regarding their practical implications for mental health interventions. Demographic Data: We have addressed the demographic skew towards younger, female participants and discussed how this may affect the generalizability of our findings. Summary of Results: A brief summary has been added at the end of the results section to link the findings back to the research questions, reinforcing the significance of the results. Discussion and Conclusions Counterintuitive Finding on Anxiety and Spiritual Intelligence: We have provided a more detailed exploration of the unexpected positive relationship between anxiety and spiritual intelligence, referencing possible explanations and conflicting literature. Discussion of Limitations and Future Research: We have expanded on how limitations, such as the cross-sectional design and specific sample population, could be addressed in future research, including suggestions for longitudinal studies and broader sampling. Concrete Examples for Interventions: In the discussion on integrating spiritual intelligence into mental health interventions, we have added practical recommendations for implementation in educational and clinical settings. Final Impact Statement: We have strengthened the conclusion with a closing statement that highlights the broader impact of our findings on mental health policy and practice. Abstract and Keywords Limitations and Future Research: We have updated the abstract to briefly mention the study’s limitations and the need for further research. Statistical Methods: We have included the statistical method used (Structural Equation Modeling) to add clarity. Keywords: Terms like “post-pandemic” and “cross-sectional study” have been added to improve searchability and relevance. Once again, we thank you for your constructive feedback, which has greatly helped us refine and strengthen our manuscript. We hope that our responses and revisions meet your expectations and enhance the scientific quality and clarity of our study. Sincerely, Authors" } ] } ]	1	https://f1000research.com/articles/13-916
https://f1000research.com/articles/13-990/v1	02 Sep 24	{ "type": "Research Article", "title": "Impact of public health expenditure on malnutrition among Peruvians during the period 2010-2020: A panel data analysis", "authors": [ "Percy Junior Castro Mejía", "Rogger Orlando Morán Santamaría", "Yefferson Llonto Caicedo", "Francisco Eduardo Cúneo Fernández", "Nikolays Pedro Lizana Guevara", "Milagros Judith Pérez Pérez", "Lindon Vela Meléndez", "Percy Junior Castro Mejía", "Yefferson Llonto Caicedo", "Francisco Eduardo Cúneo Fernández", "Nikolays Pedro Lizana Guevara", "Milagros Judith Pérez Pérez", "Lindon Vela Meléndez" ], "abstract": "Background The study analyzes the impact of public health spending on malnutrition among Peruvians, using data from the National Household Survey, the Central Reserve Bank of Peru, the National Institute of Statistics and Informatics and the Ministry of Economy and Finance from 2010. -2020. Previous studies have revealed the existing relationship of health spending with the reduction of malnutrition.\n\nMethods A quantitative approach is considered, with an explanatory type of research using panel data methodology considering the bidimensionality of the data, which allows quantifying this effect for the Peruvian case using the National Household Survey, data from the Central Reserve Bank of Peru, as well as information from the National Institute of Statistics and Informatics and the Transparency Portal of the Ministry of Economy and Finance in the period 2010-2020.\n\nResults The results show that public expenditure on health has a negative relationship with malnutrition; the rural sector has a positive relationship with malnutrition given the limitations present for access to adequate food. Similarly, the unemployment rate shows a positive relationship with malnutrition, given that being unemployed leads to a higher cause of malnutrition in the population, and the gross domestic product has a negative relationship with malnutrition, given that greater economic growth produces an impact on reducing malnutrition, with the greatest impact being on the rural population and the gross domestic product.\n\nConclusions In the analysis period 2010-2020 in Peru, based on the panel data analysis, the impact of public health expenditure on reducing malnutrition is observed in 10 departments, achieving a reduction in malnutrition; while in 14 departments, this indicator has not been reduced.", "keywords": [ "public health expenditure", "malnutrition", "economy", "panel data." ], "content": "Introduction\n\nThe fight against hunger is considered a persistent problem for various countries around the world. According to the United Nations Food and Agriculture Organization (2021) even before the coronavirus pandemic, it was projected that the sustainable development goal of ending hunger and malnutrition by 2030 would not be achieved (Bhuyan et al., 2020; Ritchie et al., 2018).\n\nCasado et al. (2021) projected that between 2019 and 2020, nearly 657 million people, representing 8% of the world’s population, would be undernourished by 2030. This led to an increase in the prevalence of undernourishment from 8.4% to 9.9%, primarily concentrated in the regions of Asia (418 million), Africa (282 million), and Latin America and the Caribbean (14 million) (United Nations Food and Agriculture Organization, 2021).\n\nThe average public health expenditure in Latin America and the Caribbean is 3.8%, showing an increasingly unequal situation. Countries like Paraguay, Costa Rica, Ecuador, and Nicaragua allocate over 9% of their gross domestic product (GDP) to health, while countries like Peru, Jamaica, and Guyana do not exceed 6% of their GDP (Haldane et al., 2022; Pan American Health Organization, 2018).\n\nIn Peru, the problem is no different. The Pan American Health Organization (2018) states that despite favorable economic growth conditions in recent decades, this has not been reflected in higher health expenditure, barely surpassing 3% of GDP in the last ten years. In an optimistic scenario, it would only grow by one percentage point in the next seven years (Vázquez-Rowe & Gandolfi, 2020).\n\nThe National Institute of Statistics and Informatics (2020) analysis revealed that the Peruvian population had a food intake below the required minimum, with a national caloric deficit incidence of 26.8% and a growing trend during the 2016-2019 period, causing malnutrition issues. Vázquez-Rowe & Gandolfi (2020) consider that Peruvian nutrition is subject to an average monthly income of 1,400 soles, which is below a healthy basic basket of 1,515 soles for a household of four.\n\nIn urban areas, the daily diet consists of 1,161 grams of food products, resulting in a 22% caloric deficit among the urban population. In rural areas, the daily diet is 938 grams, with a 40.2% caloric deficit, evidencing inadequate nutritional intake due to low incomes that do not allow for the purchase of a basic food basket, with severe consequences in the fight against poverty and malnutrition (Velásquez et al., 2021).\n\nCalva & Ruiz (2020) state that there is still scant evidence of the relationship between health expenditure and malnutrition, with malnutrition being one of the social problems that directly impacts a country’s economic development (Caballero & Sánchez, 2021; Leung & Wolfson, 2019; Mogues & Billings, 2019).\n\nFor this reason, the research is justified by its practical contribution in revealing the relationship between health expenditure and malnutrition during the analysis period 2010-2020, considering the critical aspect Peru faces in its latest figures of increasing poverty and inequality, which indicate failure to meet the sustainable development goal of ending poverty and inequality.\n\n\nLiterature review\n\nAt the international level, Bernet et al. (2018) considers that the effectiveness of public health expenditure shows the challenges of aggregate public health expenditures and the problem of endogeneity and serial correlation between expenditures and outcomes; finding the inverse association between public health spending and the infant mortality rate.\n\nSimilarly, Calva & Ruiz (2020) showed that in countries in Latin America and Sub-Saharan Africa, public spending on health has a negative relationship with malnutrition; considering that in the rural sector, given the characteristics they face, they have a greater impact on malnutrition, showing a positive relationship; while unemployment has a positive relationship with malnutrition, just as inflation has a positive relationship with malnutrition.\n\nEdney et al. (2018) in their study carried out in Australia shows that a 1% increase in public health spending is associated with a 2.2% reduction in the number of years lost, showing that the marginal effects of public health spending are more effective in those areas where there are weak health systems.\n\nOn the other hand, Antelo et al. (2017) analyzes unemployment and its relationship with food spending in Spanish households, showing that unemployment has a negative impact on malnutrition, the greatest intensity of which is seen in economic crises; socioeconomic households being those that have the greatest impact on lower food consumption. Hence Bernet et al. (2018) points out that high levels of unemployment and poverty are the main causes of food insecurity, having an environment of complex causality structure in the design of policies for food assistance.\n\nGuo et al. (2019) points out that education also has an impact on reducing malnutrition, given that when the rural population migrates to urban areas they have a greater probability of better education, since Deller et al. (2019) points out that the rural population has important impact results in terms of education compared to the urban population.\n\nFallah et al. (2021) points out that the double burden of malnutrition has become a growing health problem, given the dynamics of energy imbalance that causes public health interventions to be oriented towards a reduction in energy imbalance, mainly by slowing down the prevalence of obesity and overweight. However (Velásquez et al., 2021) considers that in the Peruvian case, the diet in six regions shows a high consumption of carbohydrates and an unbalanced diet that leads to a critical state of nutrition because low income does not It allows them to purchase the basic food basket, showing greater growth in morbidity and mortality.\n\nFor Huaripuma (2022); Vera (2019) and Guzmán (2021) demonstrate in their research in Peru the indirect relationship between public spending on health and the decrease in the percentage of chronic malnutrition in children under five years of age. The challenge being to improve the indicators in terms of indicators of prenatal health, child health or chronic malnutrition given that the three impact evaluations of social programs using the family visiting service\n\n\nMethods\n\nFrom the review of the literature it is observed that the importance of public health spending in reducing malnutrition has been methodologically addressed by the vast majority of studies using the quantitative method and based on regressions of socioeconomic and macroeconomic variables (Bernet et al., 2018; Calva & Ruiz, 2020; Edney et al., 2018; Antelo et al., 2017; Guo et al., 2019; Fallah et al., 2021; Huaripuma, 2022; Vera, 2019; Guzmán, 2021)\n\nThe methodological approach considers the traditional quantitative approach and correlational type of research, given that it analyzes the impact of public health spending on malnutrition among Peruvians, using data from the National Household Survey, the Central Reserve Bank of Peru, the National Institute of Statistics and Informatics and the Ministry of Economy and Finance from 2010-2020.\n\nThe data comprises a total of 2,112 observations covering the 24 departments of Peru during the period 2010-2020. The dependent variable is malnutrition, measured by caloric deficit, while the independent variable is public health expenditure, incorporating control variables such as inflation, rural population, unemployment, education, exports, and gross domestic product. The analysis was conducted over the 2010-2020 period based on data availability, considering inclusion and exclusion criteria.\n\nThe inclusion criteria were Peruvian households experiencing a caloric deficit. We defined caloric deficit according to the methodology used by Herrera (2001), which establishes a caloric norm for Peru of 2,318 calories per capita per day. This caloric norm is derived from data from the National Household Survey conducted by the National Institute of Statistics and Informatics between the years 2010 and 2020.\n\nWhile the exclusion criteria is peruvian households not experiencing a caloric deficit according to the methodology used by Herrera (2001) which defines the caloric norm for Peru as a total of 2,318 calories per capita per day, based on data from the National Household Survey by the National Institute of Statistics and Informatics for the years 2010 to 2020.\n\nThe sample consists of a total of 2,112 observations covering the 24 departments of Peru during the period 2010-2020.\n\nThe sampling method is non-probabilistic as it addresses the entirety of the data, totaling 2,112 observations, involving departmental analysis for the period 2010-2020.\n\nThe unit of analysis comprises each department, totaling 24 departments in Peru.\n\nDocument analysis was used as the technique for measuring the variables, and the observation guide was employed as the instrument. This tool is used to systematically and structurally collect data during an observation or study.\n\nData were obtained from the microdata database of the National Household Survey for the years 2010 to 2020. The data were extracted from module 01 and 02 (Household Member Characteristics), module 03 (Education), module 04 (Health), module 05 (Employment and Income), module 07 (Food and Beverage Expenditures), and module 08 (Charitable Institutions) published on the website of the National Institute of Statistics and Informatics. This annual survey allows for the tracking of indicators on living conditions and is conducted nationwide across the 24 departments of the country.\n\nAdditionally, data on the percentage variation of the price index by department for the period 2010-2020 and the gross value added by department at constant prices from 2007, compiled by the National Institute of Statistics and Informatics, were used and published in its economic statistics section.\n\nFor the collection of public health expenditure data, departmental data reflecting the amount spent in millions of soles were obtained from the Economic Transparency Portal of the Ministry of Economy and Finance for the period 2010-2020.\n\nFinally, the database of the value of all goods and other market services exported to the rest of the world by department, measured in FOB value in millions of dollars, from the Central Reserve Bank of Peru for the period 2010-2020 was used. This data reflects the registration of sales abroad of goods and services by a resident company in Peru, including both traditional and non-traditional products.\n\nThe estimation of malnutrition is based on the estimation of the caloric deficit and the basal metabolic rate using the methodology by Herrera (2001) which defines the caloric norm for Peru as a total of 2,318 calories per capita per day. This is based on the data from the National Institute of Statistics and Informatics, considering the average weight estimates by sex and age, classified for children under 10 years and those over 10 years by FAO (Swindale & Ohri, 2004).\n\nFor calculating the basal metabolic rate (BMR) for those over 10 years old, corrections were made based on estimates for Latin American countries (Bengoa et al., as cited in Herrera, 2001). Two options were considered: moderate activity for those over 10 years old in urban areas and intense activity for those over 10 years old in rural areas.\n\nThe panel data model, based on Mushkin’s theory, will be used for the estimation, showing the relationship between malnutrition behavior explained by public health expenditure (Calva & Ruiz, 2020). The model utilizes two equations.\n\nThrough this model, the impact of public health expenditure on the malnutrition of Peruvians is quantified. Malnutrition, measured by caloric deficit, is the dependent variable, while public health expenditure is the independent variable. Control variables include inflation, rural population, unemployment, education, exports, and gross domestic product.\n\nTo ensure consistent estimations and an adequate analysis, variables such as public health expenditure, rural population, education, exports, and gross domestic product have been transformed into logarithms. Additionally, to estimate the regression with control variables, the structural equations of the variables under analysis are used (Wooldridge, 2010).\n\nEquation 1 establishes the relationship between the dependent variable malnutrition and public health expenditure by department 𝑖=1,2, …, 24i=1,2, …, 24 in the year t=2010−2020 t=2010−2020.\n\nOn the other hand, the incorporation of control variables for the robustness of the model includes variables such as inflation, rural population, unemployment, education, exports, and gross domestic product, which are reflected in the following equation:\n\nIn Equation 2, structural equations will be used to evaluate the interdependencies, expressing the mentioned interrelationship in four equations:\n\nGiven the presence of heteroscedasticity and autocorrelation in the structural equations, confirmed by Breusch and Pagan (1979) tests for heteroscedasticity and Wooldridge (2010) tests for autocorrelation, a Generalised Least Squares (GLS) model was employed. The GLS estimator accounts for these violations of classical linear regression assumptions, providing more efficient and unbiased estimates. Additionally, a Hausman (1978) specification test was conducted to determine the appropriateness of fixed or random effects.\n\nThe variables used for the model estimation are detailed in Table 1.\n\nFor the estimation of the undernutrition variable, the National Household Survey database for the period 2010-2020 was considered. Eviews 12 is used for the estimation of the panel data model, considering the control variables that are subjected to the proposed equations to analyze the interrelationship between the variables. This allows for both descriptive statistical treatment and the estimation of the proposed panel data model and the Generalized Least Squares (GLS) model. An academic license for the use of Eviews 12 software is available, registered under the name Lindon Vela Meléndez. The license details are as follows: Serial number: Q1208886 - D49010AF - 9D854485. The software can be downloaded from the following link: http://www.eviews.com/download/student12.\n\nAutocorrelation detection was performed using the Lagrange multiplier tests of Breusch & Pagan (1979) and Wooldridge (2010). In addition, the Hausman (1978) test was used to choose between a fixed or random effects model.\n\nWe assessed the presence of autocorrelation in the model residuals using two statistical tests. First, the Breusch and Pagan (1979) Lagrange multiplier test was applied, which examines the null hypothesis of no autocorrelation against the alternative of autocorrelation up to a specified order. Second, the Wooldridge (2010) test, designed specifically to detect first-order autocorrelation in panel data, was used.\n\nTo determine the appropriate specification of the model, we perform a Hausman (1978) specification test. This test compares fixed and random effects estimators under the null hypothesis that individual specific effects are uncorrelated with the explanatory variables.\n\nData for this study were obtained from the National Household Survey (ENAHO) conducted by the National Institute of Statistics and Informatics (INEI). The ENAHO, as a publicly available and freely accessible dataset on the INEI website, adheres to rigorous ethical standards to protect the confidentiality of participants.\n\nFurthermore, ENAHO data by INEI are anonymised before being made publicly available. This ensures that individual responses cannot be linked to specific participants.\n\nAlthough we cannot provide specific details about the consent process for each individual participant in the ENAHO survey, INEI, as a reputable government institution, is committed to ethical research practices and to obtaining informed consent.\n\nIn the ethical use of public data obtained by the INEI in the ENAHO, we adhere to the principles of intellectual honesty, truthfulness, transparency, human integrity, respect for intellectual property, justice and responsibility, the study aims to comply with the “Code of Ethics in Research of the Universidad César Vallejo, version 01; by University Council Resolution N° 0340-2021-UCV”.\n\nWe have used the data for research purposes only, as permitted by INEI’s terms of use. We have not attempted to re-identify any individual, and our analysis does not include any personally identifiable information.\n\nBy using publicly available anonymised data and adhering to ethical principles in our research, we aim to minimise any potential ethical concerns while leveraging valuable information for the benefit of public health research.\n\n\nResults\n\nThe results of the estimated regressions, considering the Wooldridge test (2010), indicate the presence of autocorrelation in the various panels. Additionally, the Breusch and Pagan (1979) Lagrange Multiplier test shows that the estimates presented heteroscedasticity issues. These issues have been corrected using Generalized Least Squares (GLS) to address the problems of heteroscedasticity and autocorrelation.\n\nTable 2 shows the results of the panel data estimation, where it is observed that public health expenditure, rural population, unemployment, and gross domestic product are statistically significant at the 5% level, considering Equation 2.\n\n* Significance p<0.05.\n\nIt is observed that for each 1% increase in public health expenditure, malnutrition decreases by 2.6%. Conversely, a 1% increase in the rural population leads to a 4.6% increase in malnutrition. Additionally, a 1% increase in the unemployment rate results in a 2.3% increase in malnutrition, while a 1% increase in gross domestic product leads to a 4.3% decrease in malnutrition. The variables with the most significant impact during the analysis period 2010-2020 are the rural population and the gross domestic product.\n\nTable 3 shows the analysis of public health expenditure considering structural Equation 3. The results indicate that chronic malnutrition and unemployment are significant at the 5% confidence level. It explains that malnutrition has a negative effect on public health expenditure due to the limited importance given to public malnutrition policies, with public budgets being prioritized for other sectors.\n\n* Significance p<0.05.\n\nIt was observed that for each 1% increase in the malnutrition rate, public health expenditure decreases by 0.16%. Meanwhile, a 1% increase in the unemployment rate leads to a 0.40% increase in malnutrition.\n\nTable 4 shows the analysis of the rural population considering structural Equation 4. The results indicate that education is significant at the 5% confidence level, explaining that education has a negative effect on the rural population. This is mainly due to the trend that as the human capital of the population increases, there is a migration from rural to urban areas, moving to central zones to improve their income levels.\n\n* Significance p<0.05.\n\nIt was observed that for each 1% increase in the average years of education, the malnutrition rate decreases by 1.46%.\n\nTable 5 shows the analysis of unemployment considering structural Equation 5. The results indicate that chronic malnutrition, inflation, and education are significant at the 5% confidence level. It explains that malnutrition has a positive effect on unemployment, as do education and inflation. This shows that high levels of malnutrition lead to high unemployment rates, indicating that nutritional imbalance causes problems in performing physical or intellectual labor, affecting worker productivity.\n\n* Significance p<0.05.\n\nAdditionally, the positive relationship between education and unemployment is explained by the excess accumulation of human capital in Peru, which exceeds the available job opportunities due to limited positions. Regarding inflation, the positive relationship with unemployment contradicts the Phillips Curve theory (1958) which suggests an inverse relationship between inflation and unemployment. According to Campoverde et al. (2016) this positive relationship depends on the economic context of each country. In Peru, the loss of purchasing power and delayed investment due to price fluctuations result in a decline in business confidence, creating an uncertain climate that impacts higher unemployment rates.\n\nIt was observed that for each 1% increase in the malnutrition rate, unemployment increases by 0.01%. Additionally, a 1% increase in the average years of education leads to a 1.80% increase in unemployment, and a 1% increase in inflation causes unemployment to rise by 0.01%.\n\nTable 6 shows the analysis of gross domestic product (GDP) considering structural Equation 6. The results indicate that exports, unemployment, and inflation are significant at the 5% confidence level. The findings explain that exports have had a positive effect on GDP during the analyzed period, as higher exports result in a positive balance of payments, impacting foreign exchange and terms of trade, thereby fostering GDP growth. Conversely, unemployment shows a negative relationship with GDP due to the still high unemployment rates in Peru, which negatively affect economic growth by reducing private investment and capital attraction. Inflation also shows a negative relationship with GDP, as the inflationary spiral leads to a loss of purchasing power, consequently affecting economic growth. This is consistent with Fernando (2016), who evidenced the negative relationship between inflation and economic growth for Honduras, and Uribe (2006), who noted that demand shocks negatively affect GDP and prices in Bolivia, while supply shocks have had a positive long-term impact on GDP and a decline in price levels.\n\n** Significance p<0.05.\n\nIt was detailed that for each 1% increase in the value of exports, GDP increases by 9.5%. Meanwhile, for each 1% increase in the unemployment rate, GDP decreases by 4.3%, and a 1% increase in inflation would cause GDP to decrease by 0.32%.\n\nIn the analysis of the impact of public health expenditure on the reduction of malnutrition by department shown in Figure 1, it is observed that the greatest impact is in the Ucayali department, which reduced the malnutrition rate by 19.17%, followed by Madre de Dios with a reduction of 12.62%, and Ica with a reduction of 12.97%. Conversely, in Pasco, public health expenditure led to an increase in malnutrition by 17.61%, in Arequipa by 15.18%, in Lima by 9.85%, and in Cajamarca by 8.53%. This variability in the impact of public health expenditure on malnutrition during the period 2010-2020 indicates differing efficiencies and effectiveness of public health spending across departments. In 14 departments, including Pasco, Arequipa, Cajamarca, La Libertad, and Lima, public health expenditure did not achieve a reduction in the malnutrition indicator, with the population not meeting the minimum required caloric intake during the period 2010-2020.\n\nNote. The abbreviations of the regions of Peru are AM (Amazonas), AN (Ancash), AP (Apurímac), AR (Arequipa), AY (Ayacucho), CA (Cajamarca), CU (Cusco), HU (Huánuco), HV (Huancavelica), IC (Ica), JU (Junín), LA (Lambayeque), LL (La Libertad), LI (Lima), LO (Loreto), MD (Madre de Dios), MO (Moquegua), PA (Pasco), PI (Piura), PU (Puno), SM (San Martín), TA (Tacna), TU (Tumbes), and UC (Ucayali).\n\nFigure 2 shows the interrelationship of the variables in the proposed structural equations, where it has been evidenced that public health expenditure has not had the expected impact, as malnutrition levels have increased in Peru. The rural sector shows the most significant relevance with malnutrition due to limitations in accessing adequate food because of low incomes. Thus, the unemployment rate has a positive relationship with malnutrition, demonstrating that the unemployed population would have lower adequate calorie consumption, highlighting a positive association with malnutrition. Meanwhile, the sustained growth of gross domestic product (GDP) produces a negative effect in reducing malnutrition, with the most significant impact being related to the rural population and GDP.\n\nNote. Result of the interactions of regressions in the identified structural equations in the departments of Peru\n\nAdditionally, it is observed that exports have positively influenced GDP, being considered a pillar of the Peruvian economy’s growth through the diversification of the productive matrix, which leads to a negative relationship with unemployment. Inflation, on the other hand, shows a negative relationship with GDP, as the inflationary spiral causes a loss of purchasing power, thereby affecting economic growth.\n\n\nDiscussion\n\nThe analysis of the impact of public health expenditure on the malnutrition of Peruvians during the years 2010-2020 shows a negative effect of public health expenditure on malnutrition. These results align with Huaripuma (2022), Vera (2019), and Guzmán (2021), who detailed in their research in Peru the indirect relationship between public health expenditure and the reduction of the chronic malnutrition percentage in children under five years old.\n\nIt is essential to highlight the interrelation with other variables observed in the proposed structural equations. Literature has evidenced that exports have had a positive effect on GDP during the analyzed period. Higher exports result in a positive balance of payments, impacting foreign exchange and terms of trade, thereby fostering GDP growth. In contrast, unemployment shows a negative relationship with GDP due to the still high unemployment rates in Peru, which negatively affect economic growth by reducing private investment and capital attraction. Inflation also shows a negative relationship with GDP, as the inflationary spiral leads to a loss of purchasing power, consequently affecting economic growth. This is supported by Bhuyan et al. (2020) who found that despite high economic growth in India, the country still faces the global problem of nutritional deficit, with the poor and very poor facing food insecurity alongside the middle class, causing issues among disadvantaged groups.\n\nHowever, Bernet et al. (2018) consider that the effectiveness of public health expenditure shows the challenges of aggregated public health spending, the problem of endogeneity, and the serial correlation between expenditures and outcomes, finding an inverse association between public health expenditure and the infant mortality rate. Similarly, Biadgilign et al. (2019) evidence that child malnutrition remains a significant problem in low- and middle-income countries, with adequate governance, urbanization, and public health expenditure having effects on child malnutrition.\n\nPeru is considered an upper-middle-income country that has been implementing public policies to reduce poverty through various social programs. According to Brar et al. (2020) a notable reduction in malnutrition has been observed in the Central and Western regions, involving multiple factors such as socioeconomic indicators, reductions in inequalities, and greater access to health services. The latter is a key element in reducing health, water, and sanitation gaps, resulting from better economic conditions due to Peru’s economic growth exceeding 5% of GDP. This regional analysis has allowed for greater public resources via public investment, reducing basic infrastructure gaps and contributing to the fight against malnutrition, corroborating the importance of public expenditure in various basic sectors.\n\nHowever, Peru faces a double burden of malnutrition, as stated by Quinteros et al. (2024) where not only prioritizing policies on malnutrition due to historically high levels is necessary, but also considering impacts related to intrafamily distribution and food quality used in regional programs like Qaliwarma. Another state program in Peru’s fight against poverty is Juntos, but in terms of cost-effectiveness, it still faces regional challenges, as indicated by Brar et al. (2020). Addressing the underlying causes of household targeting for active policy implementation requires leadership and effectiveness from policymakers and program leaders against malnutrition in the context of a politically uncertain agenda in Peru. This leads to an increased gap between the poor and the rich, as well as between rural and urban areas, and highlights the need for basic health and sanitation infrastructure to support a multidimensional approach beyond just conditional cash transfers.\n\nThus, the institutional capacity to ensure a common good for the population, such as food and nutritional security, remains critical, especially exacerbated by the global health crisis. However, it involves a multidimensionality of factors connecting various variables in a spiral, with the performance of health establishments as the coordinating axis developing initiatives to combat malnutrition in the country.\n\n\nConclusions\n\nDuring the period 2010-2020 in Peru, the impact of public health expenditure on the reduction of malnutrition shows that in 10 departments, malnutrition was reduced; while in 14 departments, this indicator was not reduced. The most notable increases were in Pasco, where public health expenditure led to an increase in malnutrition by 17.61%, in Arequipa by 15.18%, in Lima by 9.85%, and in Cajamarca by 8.53%.\n\nPublic health expenditure has a negative relationship with malnutrition, while the unemployment rate shows a positive relationship with malnutrition, as being unemployed leads to a higher cause of malnutrition in the population due to lower income.\n\nMalnutrition has a negative effect on public health expenditure, as little importance is given to public malnutrition policies, and public budgets are prioritized for other sectors.\n\nEducation has a negative effect on the rural population, mainly explained by the trend that as the human capital of the population increases, there is a migration from rural to urban areas, moving to central zones to improve their income levels.\n\nMalnutrition has a positive effect on unemployment, as do education and inflation. High levels of malnutrition generate high unemployment rates, while the positive relationship between education and unemployment is explained by the excess accumulation of human capital exceeding job opportunities. The positive relationship between inflation and unemployment reflects the loss of purchasing power and delayed investment due to price fluctuations, leading to a decline in business confidence.\n\nExports have had a positive effect on GDP during the analyzed period, as higher exports result in a positive balance of payments, impacting foreign exchange and terms of trade, fostering GDP growth. Conversely, unemployment shows a negative relationship with GDP due to the still high unemployment rates in Peru, which negatively affect economic growth by reducing private investment and capital attraction. Inflation also shows a negative relationship with GDP, as the inflationary spiral leads to a loss of purchasing power, consequently affecting economic growth.", "appendix": "Data availability statement\n\nZenodo. Impact of public health expenditure on malnutrition among Peruvians during the period 2010-2020: A panel data analysis. 10.5281/zenodo.12736705 (Castro et al., 2024).\n\nThis project contains the following underlying data:\n\n• Final results Panel data.xlsx\n\nThis project contains the following extended data:\n\n• Stata Commands.pdf\n\n• Figure 1.Impact of Public Health Expenditure on Malnutrition by Department.png\n\n• Figure 2.Dynamics of the Identified Structural Equations in the Departments of Peru.jpg\n\n• Rectoral Resolution N° 760-2007_UCV_Code Of Ethics (1).pdf\n\n• STROBE_checklist_v4_combined.pdf\n\nCreative Commons Zero v1.0 Universal (CC0 License)\n\n\nReferences\n\nAntelo M, Magdalena P, Reboredo JC: Economic crisis and the unemployment effect on household food expenditure: The case of Spain. Food Policy. 2017; 69: 11–24. Publisher Full Text\n\nBernet PM, Gumus G, Vishwasrao S: Effectiveness of public health spending on infant mortality in Florida, 2001–2014. Soc. Sci. Med. 2018; 211: 31–38. PubMed Abstract \| Publisher Full Text\n\nBhuyan B, Sahoo BK, Suar D: Nutritional status, poverty, and relative deprivation among socio-economic and gender groups in India: Is the growth inclusive? World Development Perspectives. 2020; 18: 100180. Publisher Full Text\n\nBiadgilign S, Ayenew HY, Shumetie A, et al.: Good governance, public health expenditures, urbanization and child undernutrition Nexus in Ethiopia: An ecological analysis. BMC Health Serv. Res. 2019; 19(1): 40. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBrar S, Akseer N, Sall M, et al.: Drivers of stunting reduction in Senegal: a country case study. Am. J. Clin. Nutr. 2020; 112: 860S–874S. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBreusch TS, Pagan AR: A Simple Test for Heteroscedasticity and Random Coefficient Variation. Econometrica. 1979; 47(5): 1287. Publisher Full Text\n\nCaballero FE, Sánchez GS: Vista de Análisis del impacto social y económico de la desnutrición en países como Chile, México, Ecuador y Paraguay durante el periodo 2001 al 2030. Kera Yvoty: Reflexiones Sobre La Cuestión Social. 2021; 6: 89–97. Publisher Full Text\n\nCalva J, Ruiz Y: Incidencia del gasto público en salud en la desnutrición para América Latina y África Subsahariana durante 2000-2015, utilizando técnicas de datos de panel. Revista Económica. 2020; 8(2): 1–13.\n\nCampoverde A, Ortiz C, Sánchez V: Relación entre la inflación y el desempleo: Una aplicación de la curva de Phillips para Ecuador, Latinoamérica y el Mundo. Revista. Económica. 2016; 1(1): Article 1. https://revistas.unl.edu.ec/index.php/economica/article/view/200\n\nCasado A, Rodriguez B, Perez M, et al.: Global Hunger Index. El Hambre y los sistemas alimentarios en situaciones de conflicto.2021.\n\nCastro P, Morán R, Llontop Y, et al.: Impact of public health expenditure on malnutrition among Peruvians during the period 2010-2020: A panel data analysis. [Data set]. Zenodo. 2024. Publisher Full Text\n\nDeller S, Kures M, Conroy T: Rural entrepreneurship and migration. J. Rural. Stud. 2019; 66: 30–42. Publisher Full Text\n\nEdney LC, Haji Ali Afzali H, Cheng TC, et al.: Mortality reductions from marginal increases in public spending on health. Health Policy (Amsterdam, Netherlands). 2018; 122(8): 892–899. PubMed Abstract \| Publisher Full Text\n\nFallah-Fini S, Ikeda N, Nishi N: Trends in energy imbalance gap and body weight status in the japanese adult population: A system dynamics approach. J. Epidemiol. 2021; 31(5): 335–342. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nFernando F: Inflación y crecimiento económico: Umbral para Honduras; 2016. https://www.secmca.org/DOCUMENTOS/10ForoInvestigadores/DOC5.pdf\n\nGuo Y, Song Y, Chen Q: Impacts of education policies on intergenerational education mobility in China. China Econ. Rev. 2019; 55: 124–142. Publisher Full Text\n\nGuzmán YV: Gasto público en salud y la desnutrición crónica infantil de la región Ancash, 2012-2019. Universidad Cesar Vallejo; 2021.\n\nHaldane V, Morales-Vazquez M, Jamieson M, et al.: Learning from the first wave of the COVID-19 pandemic: Comparing policy responses in Uruguay with 10 other Latin American and Caribbean countries. Health Policy OPEN. 2022; 3(August): 100081. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHausman JA: Specification Tests in Econometrics.1978; 46(6): 1251–1271.\n\nHerrera J: Food requirements and deficits Peru 1997-2000.2001.\n\nHuaripuma JA: Gasto público del programa articulado nutricional en la desnutrición infantil del Perú: 2015-2020. Universidad Cesar Vallejo; 2022.\n\nLeung C, Wolfson J: Perspectives from Supplemental Nutrition Assistance Program Participants on Improving SNAP Policy. Health Equity. 2019; 3(1): 81–85. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMogues T, Billings L: The making of public investments: The role of champions, co-ordination, and characteristics of nutrition programmes in Mozambique. Food Policy. 2019; 83: 29–38. Publisher Full Text\n\nPan American Health Organization: Espacio fiscal para la salud en América Latina y El Caribe.2018.\n\nQuinteros C, Seferidi P, Guzman-Abello L, et al.: Mapping food system drivers of the double burden of malnutrition using community-based system dynamics: a case study in Peru. BMC Glob. Public Health. 2024; 2(1): 15. Publisher Full Text\n\nRitchie H, Reay D, Higgins P: Sustainable food security in India—Domestic production and macronutrient availability. PLoS One. 2018; 13(3): e0193766. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSwindale A, Ohri P: Measuring Household Food Consumption: A Technical Guide. Food and Nutrition Techical Asistance. 2004; pp. 1–93.\n\nNational Institute of Statistics and Informatics: Perú: Encuesta Demográfica y de salud familiar. ENDES; 2020; vol. 2020. .\n\nUnited Nations Food and Agriculture Organization: The state of food security and nutrition in the world. Summary version of The state of food security and nutrition in the world 2021. FAO, IFAD, WHO, WFP and UNICEF; 2021; Vol. 1. . Publisher Full Text\n\nVázquez-Rowe I, Gandolfi A: Peruvian efforts to contain COVID-19 fail to protect vulnerable population groups. Public Health Pract. 2020; 1(June): 100015–100020. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nVelásquez LS, Ortiz CA, Calizaya UG, et al.: Energética nutricional en tiempos de pos COVID-19 en el Perú. Enfoque UTE. 2021; 12(4): 1–28. Publisher Full Text\n\nVera JE: Evidencia empírica sobre el impacto de la inestabilidad política sobre la eficiencia y productividad del gasto público asignado a nutrición infantil en las regiones de Perú. Universidad de Piura; 2019.\n\nWooldridge JM: Introducción a la econometría. Un enforque moderno.2010; 1." }	[ { "id": "321092", "date": "09 Sep 2024", "name": "Om Raj Katoch", "expertise": [ "Reviewer Expertise Nutrition" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReview Report on the Research Paper: \"Impact of Public Health Expenditure on Malnutrition Among Peruvians During the Period 2010-2020\"\nI have reviewed your research paper and would like to provide feedback to help you enhance the quality and clarity of your work. Please consider the following points as you revise your manuscript:\n1. Background and Literature Review The topic you address is highly relevant and significant in the field of public health. However, I recommend that you expand the literature review to include more recent studies. This will help you establish a stronger foundation for your research question and contextualize your findings within the current body of knowledge. Incorporating recent literature will also demonstrate the relevance and timeliness of your study. Cite these articles: Om Raj Katoch (2022 [Ref - 1]) https://doi.org/10.1016/j.nut.2021.111565 Om Raj Katoch et al. (2024 [Ref - 2]) https://doi.org/10.1108/IJESM-10-2022-0007 Om Raj Katoch (2024 [Ref - 3]) https://doi.org/10.1108/NFS-03-2023-0055\n2. Methodology The methodology section requires further elaboration to improve both clarity and comprehensibility. While the current draft mentions the use of structural equations and regression analysis, it is essential to provide detailed explanations to support the robustness of your approach. Specifically, you should clearly specify the data sources used in your analysis, discussing their reliability and relevance to the study. Additionally, clarifying the sample size and justifying its adequacy for the conducted analysis is crucial to ensure the validity of your results. Moreover, a detailed description of the specific statistical techniques employed, along with an explanation of why these techniques were chosen, will help readers understand the analytical framework. It is also important to offer a clearer explanation of how control variables were selected and discuss their relevance to the model. Finally, addressing the assumptions made during the analysis and explaining how potential biases were mitigated will further enhance the methodological rigor of your paper. By incorporating these elements, you will provide a more comprehensive and transparent account of your research methodology.\n3. Policy Implications The policy implications you discuss are crucial and well-founded. However, to make this section more impactful, consider providing more concrete recommendations for policymakers. For instance, elaborate on how increased investment in health services can be implemented effectively, particularly in rural areas. Additionally, consider discussing how these findings might be applied in other developing countries facing similar malnutrition challenges, thereby broadening the applicability of your research.\n4. Grammatical and Formatting Errors The manuscript contains several grammatical errors and awkward phrasings that need to be addressed. A thorough proofreading is essential to correct these issues and ensure that your paper meets academic standards for publication and indexing. Additionally, pay attention to consistent formatting throughout the manuscript, including citation styles and headings\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [] } ]	1	https://f1000research.com/articles/13-990
https://f1000research.com/articles/14-98/v1	16 Jan 25	{ "type": "Research Article", "title": "Assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B: a pilot case-control study", "authors": [ "Jihene Bergaoui", "Imed Latiri", "Sawssen MRAD", "Houda Chaouch", "Salma Amous", "Jihene Ben Abdallah", "Samia Ernez Hajri", "Helmi Ben Saad", "Jihene Bergaoui", "Imed Latiri", "Sawssen MRAD", "Houda Chaouch", "Salma Amous", "Jihene Ben Abdallah", "Samia Ernez Hajri" ], "abstract": "Background Studies assessing sub-maximal aerobic capacity in non-cirrhotic chronic hepatitis B (CHB) patients are scarce. This study aimed to evaluate sub-maximal aerobic capacity in CHB patients compared to apparently healthy participants (control-group).\n\nMethods A 6-min walk test was performed. The 6-min walk distance (6MWD) was recorded, along with heart-rate, oxygen hemoglobin saturation (SpO2), blood pressure, and dyspnea ( ie ; visual analogue scale) at rest (Rest) and at the end (End) of the test. Additionally, 6-min walk work (6MWW), “6MWD × body mass index (BMI), “6MWD × SpO2End”, and “estimated cardiorespiratory and muscular chain age” were calculated. Signs of physical intolerance were determined including abnormal 6MWD ( ie ; 6MWD < lower limit of normal), chronotropic insufficiency ( ie ; heart-rateEnd < 60% of maximal predicted heart-rate), high dyspnea ( ie ; dyspneaEnd > 5), and desaturation ( ie ; drop in SpO2 > 5 points).\n\nResults Compared to the control-group (n=28), the CHB-group (n=26) exhibited significantly lower 6MWD by 61 meters (13%), lower 6MWW by 5266 m.kg, lower “6MWD × BMI” by 1498 m.kg/m2, lower “6MWD × SpO2End” by 5650%, and lower heart-rateEnd by 26 bpm (12% predicted). The CHB-group included higher percentages of participants with chronotropic insufficiency (23.08% vs. 3.57% in the CG) and abnormal 6MWD (34.61% vs. 3.57% in the CG). CHB accelerated the aging of the “cardiorespiratory and muscular chain” by 11 years.\n\nConclusion Non-cirrhotic CHB may contribute to reduced submaximal aerobic capacity and acceleration of “cardiorespiratory and muscular chain” aging. A regular physical activity program could be a valuable intervention to mitigate these effects.", "keywords": [ "Aerobic Capacity", "Aging", "Chronic Disease", "Exercise Test", "Physical Fitness", "Physical Intolerance" ], "content": "Introduction\n\nViral hepatitis B (VHB) induces significant morbidity and mortality in the general population.1 VHB can progress to chronicity if it persists for more than six months and can induce systemic manifestations.1–3 In addition to hepatic conditions such as cirrhosis or hepatocellular carcinoma, chronic hepatitis B (CHB) causes extrahepatic effects, which can impact exercise capacity [ eg ; myocardial damage and alterations in pulmonary and muscle function]4–8 and significantly worsen the morbidity and mortality associated with CHB,2 with potential social disadvantages.6,8,9 Some studies have reported the harmful impacts of CHB on the main elements of the chain involved during adaptation to both maximal ( eg ; oxygen consumption ( V̇O2 ))9,10 and sub-maximal ( eg ; 6-min walk test (6MWT))10,11 aerobic exercise, namely the cardiorespiratory and muscular chain (CRMC).3,4,8,10 First, it “seems” that the resting cardiovascular system of CHB patients is altered, with 3% of them having cardiovascular disease.12 Second, CHB induces a decrease in resting lung function, such as the forced vital capacity and/or forced expiratory volume in one second.8 Third, CHB causes weakness of respiratory muscles with low maximal inspiratory and expiratory pressures,8 and can affect muscle fibres leading to muscle injuries.5,13\n\nExercise tolerance is commonly quantified through the measurement of V̇O2 during a cardiorespiratory test, which necessitates advanced and expensive equipment, highly skilled personnel for its operation, and substantial financial resources.14 These limitations have led to the adoption of simpler assessments, such as the 6MWT.15,16 The latter offers several advantages including enhanced safety, ease of administration, closer alignment with everyday activities, cost-effectiveness, and ready implementation on a large scale.15,16 Over the past two decades ( ie ; 2004-2024), the 6MWT has been extensively utilized in assessing functional exercise performance across diverse populations, including those with pulmonary, cardiac, and neuromuscular diseases.17–20 Studies assessing CHB-related incapacity in terms of maximal and sub-maximal aerobic exercise impairment are scarce.9–11 As of late December 2024, it “seems” that only two studies have assessed V̇O2 in CHB patients,9,10 and only one Saudi study has compared the 6MWT data of CHB patients to those of healthy participants.11 On the one hand, V̇O2 at peak of exercise ( V̇O2peak ) was a predictor of mortality, as patients with a low V̇O2peak ( ie ; < 17 ml/kg) had a survival rate of 55%,10 and it is significantly correlated with maximal inspiratory pressure (r = 0.64) and with the Model for End-Stage Liver Disease (r = 0.91).9 On the other hand, the authors of the Saudi study reported that compared to healthy participants (n=45), patients with CHB (n=49) had a significantly lower 6-min walk distance (6MWD) by 31 m.11 The Saudi study had some methodological weaknesses that can “slightly” modify the findings.11 First, the inclusion of patients with diverse liver diseases ( eg ; non-cirrhotic chronic hepatitis B (NC-CHB) or C, cirrhotic), is a source of ‘perplexity’ since the clinical outcomes are different.6 Second, the absence of sample size determination is a statistical flaw.21 Third, the expression of the main outcome ( ie ; 6MWD) only in absolute value, and the lack of its standardization according to participants’ characteristics ( eg ; sex and anthropometric data), could lead to misinterpretation.8,10,11 The standardized 6MWD allows a more objective comparison between the diverse groups.22 Fourth, the use on the quantitative significance approach with a “p value” < 0.05 is criticized, and the qualitative significance approach is recommended in medical exercise research.23\n\nTo the finest of the authors’ knowledge, no previous study has explored the incapacity via the 6MWT in a homogeneous group of NC-CHB patients compared to “apparently” healthy participants. The main aim of this case-control study was to compare the 6MWT data of the two groups. The null hypothesis was that the two groups would have comparable 6MWD ( ie ; the main outcome).\n\n\nMethods\n\nThe present study is part of a larger project, involving two groups (CHB patients and “apparently” healthy controls) and comprising three parts. The project’s methodology was published as a “protocol in progress”.6 The first part of the project evaluated muscle mass and strength in CHB patients.7 The main conclusion was that NC-CHB does not affect muscle mass and strength.7 The second part, which is the focus of this study, examines sub-maximal aerobic capacity. The third and fourth parts will evaluate the quality-of-life and oxidative status of the two aforementioned groups, respectively.\n\nThis project is a case-control study conducted during the decline of the coronavirus disease (COVID-19) pandemic in Tunisia ( eg ; September 2020). The study was conducted in collaboration with the department of physiology at the faculty of medicine of Sousse (Sousse, Tunisia) and three departments from Farhat HACHED hospital in Sousse ( ie ; infectious diseases, biochemistry, and hematology). The study was conducted following the guidelines established by the STROBE statement.24\n\nEach participant received comprehensive information about the study’s objectives, procedures, potential risks, and other pertinent details. After this thorough briefing, we obtained written informed consent from all participants, confirming their voluntary involvement in the study. Additionally, each participant was provided with a report of his/her individual evaluations.\n\nTwo groups of participants ( ie ; cases and controls) were recruited ( Figure 1).\n\nCHB: chronic hepatitis B. M: man. W: woman.\n\nCases were selected from patients followed for VHB infection, who had undergone histological evaluation by liver biopsy (LB) or fibroscan within the last four years prior to inclusion in the study at the above infectious diseases department. Diagnosis of hepatitis B virus (HBV) infection was based on a positive result for hepatitis B surface antigen (HBsAg) for at least six months. Patients were eligible for inclusion if they were aged between 25 and 55 years, had an HBV-DNA viral load higher than 2000 IU/ml confirmed at least one year prior to inclusion, and showed no significant pathological fibrosis, as indicated by a fibroscan score less than 6 kPa and/or a “meta-analysis of histological data in viral hepatitis” score less than A2F2. Exclusion criteria were as follows: physical or mechanical impairments that could interfere with the 6MWT such as a history of orthopedic or rheumatologic diseases, contraindications for the 6MWT like signs of unstable angina or myocardial infarction within the previous month, resting heart-rate (HR) higher than 120 bpm, systolic blood pressure higher than 180 mmHg, or diastolic blood pressure hgher than 100 mmHg),16 comorbidities such as respiratory or cardiovascular diseases, systemic conditions that could influence blood test results like diabetes mellitus or renal failure, consumption of alcohol, co-infection with other viruses, liver damage, or the requirement for CHB treatment during the study period.\n\nControls were “apparently” healthy participants, non-alcohol consumers, aged between 25 and 55 years, without any chronic disease, physical problems, COVID-19 infection, or 6MWT contraindications.16\n\nParticipants from both groups with missing biological data were excluded from the final statistical analysis.\n\nThe sample size was calculated using this equation25:\n\n• “N” is the the required number of participants (N = n1 + n2, such as n1 and n2 are the sample sizes for the case and control groups);\n\n• “Z α/2” is the normal deviate at a level of significance (1.96for a 5% level of significance);\n\n• “Z 1-β” is the normal deviate at 1- β% power with β% of type II error (1.28 at 90% statistical power);\n\n• “r” (= n1/n2) is the ratio of sample sizes required for the two groups (r = 1 gives a 1:1 sample size distribution for the two groups); and\n\n• “s” and “d” are the pooled standard-deviation (SD) and difference of 6MWD means between the two groups. These values were derived from a previous Saudi case-control study comparing the 6MWD of CHB patients to healthy participants.11 The controls and cases had 6MWD means of 421 and 390 m, respectively, with a mean SD of 50 m.\n\nInserting these values into the predictive equation resulted in a total sample size of 54 participants (27 in each group). Assuming a 10% loss of biological data, a revised sample size of 60 participants was determined (60 = 54/(1-0.10)).\n\nThe explorations were conducted indoor between 8:00 AM and 12:00 PM, with four participants examined per day, and an average time of 60 minutes per participant. The study protocol included the following steps:\n\n• Signing of consent and completion of medical questionnaires.\n\n• Collection of anthropometric data and blood samples.\n\n• Bioelectrical impedance analysis.\n\n• Consumption of a food snack of choice.\n\n• Measurement of handgrip-strength.\n\n• Performance of the 6MWT.\n\nA questionnaire comprising three parts was administered by one qualified examiner ( JB in the authors’ list). The mean duration of the questionnaire was approximately 20 minutes.\n\nThe first part was a standard medical questionnaire (widely used in the infectious diseases and physiology departments) aiming at collecting clinical and socioeconomic data. Questions were asked in Arabic. Clinical histories, such as previous hospitalization, comorbidities, and viral co-infections were recorded. Cigarettes smoking was evaluated in pack-years, and participants were classified into two groups (non-smoker: <5 pack-years; smoker3: 5 pack-years).6 Depending on alcohol consumption habits, participants were classified into two groups (consumer/non-consumer).6 Socioeconomic-level was determined according to the participant’s profession, with two levels defined ( ie ; unfavorable and favorable).6 Schooling level was arbitrarily defined as low and high.6 Parity (the number of children born to a woman) was noted. Since the 2023 Tunisian global fertility rate was 2.09 children per woman, a parity greater than two was considered “high”.26,27\n\nThe second part of the questionnaire was linked to the physical-activity level, which was estimated using the Voorrips questionnaire.28 This questionnaire is reproducible, and its score is positively related to the 24-hour measurement of the physical-activity as assessed by a pedometer.28 While the Arabic version is not validated, it has been widely used in previous studies.29–31 This questionnaire contains 51 items assessing various scores, which are divided into three categories of physical-activity ( ie ; daily, sports, and leisure activities). The sum of the three scores represents the total physical-activity score. According to the total score, participants were divided into two groups: sedentary (score <9.42) and active (score ≥9.42).28\n\nThe third part of the questionnaire is related to the evaluation of quality-of-life using the Chronic liver diseases questionnaire.32 Data from this part will be analyzed in a subsequent study.\n\nAge (in years) and sex and were documented for each participant. Height was measured in centimeters using a Siber Hegner® standing stadiometer, with participants standing upright, without shoes, heels together, and back straight. Weight (in kilograms), muscle mass (in percentage), and body fat (in percentage) were assessed using a Beurer BF-600 (Beurer GmbH, Germany) bioelectrical impedance analyzer in the morning after an overnight fast, with participants in a standing position.33 Body mass index (BMI, kg/m2) was determined. Participants corpulence status was categorized based on BMI as follows: underweight (BMI < 18.5 kg/m2), normal weight (BMI: 18.5–24.9 kg/m2), overweight (BMI: 25–29.9 kg/m2), and obesity (BMI ≥ 30 kg/m2). All measurements were conducted by a single qualified examiner ( JB in the authors’ list).\n\nSome biological data ( eg ; hemoglobin, erythrocyte-sedimentation-rate, C-reactive-protein, interleukin-6, alkaline-phosphatase, alanine-aminotransferase, aspartate-aminotransferase, gamma-glutamyl-transpeptidase, total-bilirubin, non-conjugated bilirubin, ( ie ; antioxidant stress marker),35 albumin ( ie ; antioxidant stress marker),36,37 and uric-acid ( ie ; oxidant-antioxidant balance marker)38 were collected by a nurse. Some of these biological data and their technical aspects were detailed elsewhere.6,7\n\nHandgrip-strength, the technique and findings of which were detailed elsewhere,6,7 was performed by one qualified examiner ( JB in the authors’ list). For this study, the highest absolute handgrip-strength value (kg) between the two hands of each participant was retained.\n\nSub-maximal aerobic capacity was evaluated using the 6MWT, supervised by one qualified examiner ( IL in the authors’ list). Participants were asked to wear comfortable clothing and appropriate footwear for walking, and to avoid strenuous exercise in the two hours preceding the 6MWT.16 A single 6MWT was performed in a 40 m flat corridor indoor ( ie ; physiology department), which was marked every meter with start and end indicators.39 Instructions given before the 6MWT followed the most updated guidelines,16,39 which included “walk as far as possible for 6 minutes”. Participants were informed that they could slow down, stop, rest as needed, and resume walking when able.16,39 They were instructed not to run under any circumstances, and no encouragement or walking aids were provided during the 6MWT.16,39 The remaining time was announced every minute ( eg ; you have × minutes left).16,39 The examiner did not walk with the participants to avoid influencing their walking speed.\n\nThe following 6MWT data were recorded: HR [bpm, % of maximal predicted HR (MPHR (bmp) = 208-0.7×Age (year))],40 dyspnea (absolute value), blood-pressure (mmHg), oxy-hemoglobin saturation (SpO2, %), number of stops while walking, and 6MWD (m, %). Additional relative 6MWD indices, including the product between 6MWD and weight ( ie ; 6-min walk work (6MWW, m.kg)),41 BMI (m.kg/m2), muscle-mass (m.kg), body-fat (m.kg), and SpO2End (%m) were calculated. HR, SpO2, blood-pressure, and dyspnea were measured while the participant was seated at rest (Rest) and immediately at the end (End) of the 6MWT.16,39 HR and SpO2 were measured using a handheld pulse oximeter (M700, Biolight CO., LTD. China), and blood-pressures were measured using a manual tensiometer and a stethoscope. Delta (∆) HR and SpO2 ( ie ; ∆HR (bpm) = HREnd – HRRest, ∆SpO2 = SpO2End - SpO2Rest) were calculated. Dyspnea was measured on a visual analog scale (VAS) ranging from 0 (no dyspnea) to 10 (maximum dyspnea).42\n\nThe 6MWD was expressed both in absolute value (m) and as a percentage of the predicted 6MWD.22,43 For participants under 40 years of age, the following predictive equation for 6MWD specific to the North African population was applied: 6MWD (m) = 800.05-64.71 × Sex (0: Man; 1: Woman) - 10.23 × BMI (kg/m2) - 1.63 × Age (years) + 2.05 × Weight (kg).43 For this group, the lower limit of normal (LLN) was calculated by subtracting 74.31 m from the predicted 6MWD value.43 For participants older than 40 years of age, the following predictive equation for 6MWD specific to the North African population was applied: 6MWD (m) = 720.50-160.27 × Sex (0: Man; 1: Woman) - 5.14 × Age (years) - 2.23 × Weight (kg) + 271.98 × Height (m).22 For this group, the LLN was calculated by subtracting 89 m from the predicted 6MWD value.22\n\nSince the 6MWT assesses the integrated response of the CRMC,39,44 its estimated age (ECRMC) was calculated using the following formulas: ECRMC (years) = 184.25-0.36 × measured 6MWD (m) + 44.39 × Height (m) - 13.87 × Sex (0: Man; 1: Woman); for participants under 40 years of age45; and ECRMC (years) = 140.17-0.19 × measured 6MWD (m) - 31.18 × Sex (0: Man; 1: Woman) - 0.43 × Weight (kg) + 52.91 × Height (m); for participants aged 40 years and more.45\n\nThe following definitions were applied based on previous studies22,46,47:\n\ni) Signs of walking intolerance: abnormal 6MWD ( ie ; 6MWD < lower limit of normal), stopping while walking, high dyspnea ( ie ; dyspneaEnd >5/10);\n\nii) Clinically significant desaturation: ∆SpO2 >5 points; and\n\niii) Chronotropic insufficiency: HREnd <60%.\n\nThe distribution of quantitative data was analyzed using the Shapiro-Wilk W test. Data were expressed as means±SD (and 95% confidence intervals) when the normality test was met. If not, data were presented as medians (interquartile range). The Wilcoxon matched-pairs test was used to compare chronological and ECRMC ages within each group. Two significant approaches were applied: i) Quantitative (statistical) approach: The Mann-Whitney U and Chi-2 tests were used to compare quantitative and categorical data, respectively, between the two groups; and ii) Qualitative (clinical) approach: The percentages of participants with walking intolerance signs, desaturation, chronotropic insufficiency were compared using the 2-sided Chi-2 test. Hedge’s unbiased d value was used to measure the effect size of the main outcome (6MWD).48 The effect size was described as small (≤0.2), medium (around 0.5), large (around 0.8), or very large (31.30).48\n\nAll statistical procedures were performed using. STATISTICA (data analysis software system, version 12. www.statsoft.com, RRID: SCR_014213). The significance level was set at p<0.05.\n\n\nResults\n\nOut of the 128 participants assessed, data from 54 participants [26 cases (15 men) and 28 controls (15 men)] were retained for the final dataset ( Figure 1).\n\nTable 1 presents the characteristics of the two groups of participants. Compared to the control-group, the CHB-group was ≈5 years older and had higher percentages of participants with low schooling-level, and unfavorable socioeconomic-level. The two groups had comparable handgrip-strength values and physical-activity scores, and included comparable percentages of smokers and sedentary participants. No participant consumed alcohol.\n\na Mean±standard deviation (95% confidence interval);\n\nb Number (%);\n\nc Median (interquartile).\n\n* p-value < 0.05 (Mann-Whitney U test or 2-sided Chi-2): CHB group vs. CG.\n\n# p-value < 0.05 (Wilcoxon matched pairs test): Chronological age vs. ECRMC for each group.\n\nα Liver biopsy puncture was performed in 13 patients.\n\nβ Fibroscan score was performed in 21 patients.\n\nThe CHB-group and the control-group had comparable values of hemoglobin (14.51±1.92 vs. 14.54±1.79 g/dL, respectively), erythrocyte-sedimentation-rate (6.96±7.13 vs. 7.36±6.95, respectively), CRP (5.39±0.98 vs. 5.93±1.54 mg/L, respectively), alkaline-phosphatase (50.61±16.60 vs. 41.64±16.07 UI/L, respectively), alanine-aminotransferase (16.26±6.58 vs. 16.89±11.54 UI/L, respectively), aspartate-aminotransferase (21.77±5.09 vs. 20.89±13.02 UI/L, respectively), gamma-glutamyl-transpeptidase (15.54±9.55 vs. 15.46±10.76 UI/L, respectively), non-conjugated bilirubin (12±16 vs. 9±5 μmol/L, respectively), total-bilirubin (14±16 vs. 10±5 μmol/L, respectively), albumin (44±3 vs. 44±3 g/L, respectively), uric acid (258±82 vs. 253±60 μmol/L, respectively), and interleukin-6 (1.7±0.9 vs. 1.9±1.7, respectively.\n\nTable 2 presents the 6MWD data and its relative indices, and Figure 2 exposes the 6MWD values for the two groups. Regarding the 6MWD, compared to the control-group, the CHB-group covered a statistically significantly shorter distance by ≈61 m (702±60 vs. 641±57 m, respectively) ( Figure 2A, Table 2) and by ≈8% (103±8 vs. 95±12%, respectively ( Figure 2B, Table 2). The Hedge’s unbiased d for the 6MWD (m, %) were small at -1.026 and -0.980, respectively. In terms of the relative 6MWD indices, compared to the control-group, the CHB-group had statistically lower 6MWW by 5266 m.kg, “6MWDxBMI” by 1498 m.kg/m2, and “6MWDxSpO2End” by 5650 %m. The “6MWDxmuscle-mass” and “6MWDxbody-fat” were comparable between the two groups.\n\n* p-value < 0.05 (Mann-Whitney U test or 2-sided Chi-2): CHB group vs. CG.\n\nA. 6MWD expressed as absolute value (m) B. 6MWD expressed as percentage of predicted values. Data were mean (●) and 95% confidence interval ().\n\nCompared to the control-group, the CHB-group had statistically lower HREnd by 26 bpm and 12% of MPHR, and DHR by 26%, and included a higher percentage of participants with chronotropic insufficiency ( Table 3).\n\na Mean±standard deviation (95% confidence interval) .\n\nb Number (%).\n\n* p-value < 0.05 (Mann-Whitney U test or 2-sided Chi-2): CHB group vs. CG.\n\nThe two groups had comparable blood-pressure, SpO2, and dyspnea, and included comparable percentages of participants with desaturation and high dyspenaEnd ( Table 4). Compared to the control-group, the CHB-group had a statistically higher DSpO2 by 1% and included a significantly higher percentage of participants with an abnormal 6MWD ( Table 4). All participants completed the 6MWT and none stopped during the test.\n\na Mean±standard deviation (95% confidence interval).\n\nb Number (%).\n\n* p-value < 0.05 (Mann-Whitney U test or 2-sided Chi-2): CHB group vs. CG.\n\nCompared to the control-group, the CHB-group had a higher ECRMC age by 28 years (25±28 vs. 53±26 years, respectively) ( Table 1). The comparison of chronological and ECRMC ages revealed accelerated aging of the CRMC by 11 years in the CHB-group, and decelerated aging in the control-group by 12 years ( Table 1).\n\n\nDiscussion\n\nThis case-control study reveals that CHB impacts sub-maximal aerobic capacity. Specifically, the CHB-group demonstrated statistically significant reductions in several parameters compared to the control-group: a decrease of 61 m (13%) in the 6MWD, lower 6MWW by 5266 m.kg, lower “6MWDxBMI” by 1498 m.kg/m2, lower “6MWDxSpO2End” by 5650 %m, and lower HREnd by 26 bpm and 12% of MPHR. Additionally, the CHB-group had higher percentages of participants with chronotropic insufficiency (23.08% vs. 3.57%) and abnormal 6MWD (30.76% vs. 3.57%). Consequently, the null hypothesis that the two groups would have comparable 6MWD was rejected. Furthermore, was found to accelerate the aging of the CRMC by 11 years.\n\nAs of late 2024, and to the best of the authors’ knowledge, only one Saudi study,11 detailed in Appendix 1 has compared 6MWT data of patients with hepatic pathologies, including 49 CHB patients, to those of a control-group.\n\nThe CHB-group had a lower 6MWD by approximately 61 m compared to the control-group, aligning with the Saudi study,11 which reported a difference of about 41 m. Additionally, the CHB-group exhibited an approximately 8% lower 6MWD expressed as a percent of predicted value (Appendix 1). No previous study have expressed the 6MWD as a percent of a predicted value. Relative 6MWD indices in CHB patients have not been previously evaluated. Compared to the control group, the CHB group had lower 6MWW by ≈5266 m.kg, “6MWDxBMI” by ≈1498 m.kg/m2, and “6MWDxSpO2End” by ≈5650 %m, while “6MWDxmuscle-mass” and “6MWDxbody-fat” values were comparable between the groups. There are no prior case-control studies evaluating these indices in chronic disease patients. The 6MWW, reflecting the work done during the 6MWT, has been assessed in conditions such as HIV infection and chronic obstructive pulmonary disease, which reported lower 6MWWs in chronic patient.49–51\n\nNo previous studies have compared HR, SpO2, blood-pressure, and dyspnea data between CHB and control groups. Compared to the control-group, the CHB-group had lower HREnd (bpm and %PMHR) by ≈26 and ≈12, respectively, and ΔHR by ≈26 bpm, with a higher percentage of patients exhibiting chronotropic insufficiency (4% vs. 23%) (Appendix 1). Despite being “apparently” free from cardiovascular diseases, chronotropic insufficiency in CHB patients could be a preclinical sign of incipient cardiovascular pathology, as 3% of CHB patients are reported to develop cardiovascular diseases.12\n\nCompared to the control-group, the CHB-group had a higher ΔSpO2, but comparable SpO2Rest and SpO2End (Appendix 1). The higher ΔSpO2 observed in our CHB-group lacks clinical significance as both groups had comparable SpO2 values, and no participant experienced “clinically significant desaturation”. This suggests that the alveolo-capillary membrane remains intact.\n\nBoth groups had comparable blood-pressure and VAS dyspnea (Appendix 1), indicating that CHB does not significantly affect blood-pressure or dyspnea.\n\nCompared to the control-group, the CHB-group had a higher ECRMC’ age by ≈23 years ( Table 1). The ECRMC age for the CHB and control groups was higher by ≈11 years and lower by ≈12 years compared to chronological age, respectively. This indicates accelerated CRMC aging, similar to findings reported in diabetic patients.52\n\nFactors explaining the decline in 6MWD and acceleration of CRMC aging in NC-CHB patients\n\nSeveral factors may explain the decline in 6MWD and the acceleration of CRMC aging in NC-CHB patients, including comorbidities ( eg ; cardiac, respiratory, and/or muscular diseases), patient characteristics ( eg ; age, corpulence status, schooling-level, socioeconomic-level, sedentarily lifestyle), parity, and smoking habits.\n\nChronotropic insufficiency may partly explain the 6MWD decrease, as seen in previous studies involving obstructive sleep apnea-hypopnea-syndrome (OSAHS) patients,45 diabetic patients,52 or narghile-smokers.31 Although the impact of CHB on sinus node activity during walking was not documented, it affects sinoatrial node function.53 Concerning the respiratory system, possible explanations for the 6MWD decrease include alterations in the alveolo-capillary membrane, bronchial airway, and respiratory muscle strength. The absence of SpO2 alterations suggests that the alveolo-capillary membrane is intact ( Table 4). However, lung function data alteration and respiratory muscle weakness indicate that these factors may contribute to the 6MWD decrease.8 Muscle function was not a factor in our study, as both groups had comparable muscle-mass and handgrip-strength ( Table 1). Previous studies have reported no impairment in muscle strength in CHB patients,54,55 but handgrip-strength is a strong predictor of 6MWD,56 and CHB can cause muscle injuries.5,13\n\nThe 5-year age gap between the CHB and control groups is unlikely to account for the differences in 6MWD and HR, as adjustments were made for age. Literature presents conflicting results regarding the effect of age on 6MWD.22,31,45,52 While age has been identified as an independent predictor of 6MWD in diabetic patients,52 it is a non-independent predictor in OSAHS patients45 and narghile-smokers.31 In healthy adults, age is a dependent predictor of 6MWD.22\n\nThe corpulence status was not a factor in our study, as the two groups had comparable BMI values and comparable corpulence statuses ( Table 1). Literature also provides conflicting conclusions about the effect of BMI and corpulence status on 6MWD.22,31,45,52 While some studies consider BMI an independent predictor of 6MWD in OSAHS patients,45 narghile-smokers,31 and healthy adults,22 others do not.52 While some studies consider corpulence status an independent 6MWD predictor in diabetic patients,52 others do not in OSAHS patients,45 narghile-smokers,31 and healthy adults.22\n\nIn our study, the CHB-group encompassed higher percentages of participants with lower schooling-level and unfavorable socioeconomic-level ( Table 1). The effect of schooling-level and socioeconomic-level on 6MWD is also controversial in literature.22,31,52,56,57 Schooling-level was an independent predictor in some studies of healthy adults,57 but not in others.22,31,45,52,56 Socioeconomic-level was an independent predictor in healthy adults22 and diabetic patients,52 but not in others including OSAHS patients45 or narghile-smokers.31 In, the socioeconomic-level was identified as a dependent 6MWD predictor.\n\nSince the two groups were matched for physical-activity ( Table 1), physical-activity levels cannot explain the 6MWD decrease. Literature on physical-activity’s effect on 6MWD is mixed.22,31,45,52 While one study considered physical-activity an independent 6MWD predictor in diabetic patients,52 two others considered it a non-independent 6MWD predictor in OSAHS patients45 or narghile-smokers.31 In healthy adults,22 the physical-activity level was identified as a dependent 6MWD predictor.\n\nSince the women of both groups were matched for parity data ( Table 1), the latter cannot explain the 6MWD decrease. In literature, parity is recognized as a 6MWD influencing factor in healthy adults,22,58 and patients with chronic conditions.45,52\n\nThe matched smoking status ( Table 1), also eliminates smoking as a cause for the 6MWD decrease, with conflicting literature results,45,52 While one study considered it an independent 6MWD predictor in diabetic patients,52 but not in others including OSAHS patients.45\n\nPathophysiological mechanisms explaining 6MWD decline and CRMC aging acceleration\n\nSeveral mechanisms may explain the 6MWD decline and CRMC aging acceleration in NC-CHB patients, including anemia, inflammation, liver dysfunction, oxidative stress, and apoptosis.59–69\n\nAnemia,59 inflammation,60,61 and certain liver function markers (aspartate-aminotransferase, alkaline-phosphatase, and bilirubin)62,63 are associated with exercise capacity. Nonetheless, since both groups were matched for hemoglobin, inflammation, and liver function data, these factors alone do not fully explain the 6MWD decline.\n\nCHB interferes with apoptosis signaling pathways,64,65 and oxidative stress may contribute to liver disease progression in CHB patients.66–68 Similar to chronic obstructive pulmonary disease, apoptosis in the quadriceps of CHB patients might impair muscle function,69 while oxidative stress could affect functional capacity.30,60 Although albumin, non-conjugated bilirubin, and uric-acid values were comparable between groups, suggesting maintained oxidant-antioxidant balance, the oxidative stress factor cannot be completely ruled out in explaining the 6MWD decline.\n\nSeveral methodological points including, which may influence our results, require discussion. The following paragraphs will discuss the sample and effect sizes, participants’ characteristics, statistical analysis approaches, recruitment methods, 6MWT practice, and data collection.\n\nSample and effect sizes\n\nIn contrast to the Saudi study,11 we calculated both sample and effect sizes. Determining an adequate sample size is crucial for ensuring sufficient power to detect statistical effects.70 The effect size provides a quantitative measure of the strength and magnitude of the observed association between exposure and outcome variables.48 Unlike p-values, which indicate only whether an association is statistically significant, the effect size offers a more comprehensive understanding of the practical significance of the relationship.48 Our calculated sample size ( ie ; CHB-group = 26, control-group = 28) was smaller than that of the Saudi study ( ie ; CHB-group = 49, control-group = 45),11 and the effect size for the 6MWD was small.\n\nParticipants’ characteristics\n\nSeveral factors can influence the 6MWD, including anthropometric data ( eg ; age, height, weight, BMI, corpulence status, and muscle-mass), sex, biological data ( eg ; hematological, inflammatory, and biochemical data), parity, schooling-level, socioeconomic-level, physical-activity level, and muscle strength. The influence of these factors will be discussed below.\n\nAge, height, weight, BMI, corpulence status, muscle-mass, and sex are known independent predictors of 6MWD.71–74 Compared to our study, the Saudi study11 included participants with a broader age range (25-55 vs. 18-80 years), which could introduce confusion, as 6MWD is negatively correlated with age.71–73 In our study, the control-group was younger than the CHB-group by ≈5 years. To account for this, we applied two corrective actions. We used North African 6MWD reference equations to standardize 6MWD by age,22,43 and we expressed HR as a percentage of MPHR, accounting for age.40 Anthropometric data ( ie ; height, weight, BMI, corpulence status, and muscle-mass), and sex were comparable between our two groups. The Saudi study11 reported comparable age, height, and weight but did not compare BMI or corpulence status (Appendix 1). This omission could lead to misinterpretation, as high BMI is associated with reduced functional capacity75 and 6MWD.22 Additionally, muscle-mass, an important factor influencing 6MWD74 was comparable between groups. As done by Alameri et al.,11 comparable percentages of men and women were included in our study. Sex also influences 6MWT results, with women generally showing lower 6MWD than men.76\n\nThe two groups were matched for all biological data. Our sample of CHB patients represents a real-life cohort. For instance, the mean hemoglobin value in our study (14.51±1.92 g/dL) is similar to that reported by Alameri et al.11 (12.87±4.41 g/dL).\n\nWe reported data on parity, which was comparable between the two groups, with no women having high parity. Parity negatively correlates with 6MWD, with multiparous women showing lower 6MWD compared to nulliparous women.22 This effect may be due to hormonal changes, biochemical modifications, or respiratory muscle impairment.22\n\nWe reported schooling-level and socioeconomic-level data for our participants ( Table 1). The unfavorable socioeconomic-level among our NC-CHB patients reflects findings in African CHB patient.77\n\nWe assessed physical-activity level and handgrip-strength, finding comparable data between the two groups. In our study 96% of the CHB-group had a sedentarily status ( Table 1), which aligns with a study reporting 60% of CHB patients as sedentary.78 Reduced physical-activity often leads to altered muscle metabolism, decreased muscle-mass, and reduced physical capacity.74 Handgrip-strength is a strong, independent predictor of 6MWD.56\n\nWhile the Saudi study.11 employed only a quantitative approach to compare measured data, our study utilized both quantitative and qualitative approaches. The qualitative approach, such as comparing percentages of patients with abnormal 6MWD, is recommended in medical exercise research.23\n\nRecruitment methods of the two groups\n\nLike what has been done by Alameri et al.,11 our CHB patients were recruited from those followed at outpatient clinics. The main limitation of such method is the potential for selection bias.79 Outpatient clinics typically serve individuals with less severe or milder forms of illness compared to those admitted to hospitals.80 This bias may affect the generalizability of the results to the broader population, including those not seeking regular medical care or those treated in other healthcare settings.79\n\nContrary to the Saudi study,11 where healthy participants were recruited from hospital employees and medical students, in our study, the “apparently” healthy participants were recruited from relatives of CHB patient and from the announcement on social media account. On the one hand, the method applied by Alameri et al.11 may consist of more highly educated individuals with a higher socioeconomic-levels, which are more likely to come from the broader general population. On the other hand, some relatives of CHB patients could be unknowingly carrying HBV.\n\n6MWT practice\n\nSince the information about 6MWT practice and data collection during the test allow better interpretation and comparison of results among different studies, many details such as applied guidelines, corridor length, place, number of tests, day-time, encouragement and walking aids during the 6MWT, and number of investigators need to be discussed. First, as done in Saudi study,11 we applied the most updated available guidelines ( ie ; 2002,39 and 2014 guidelines, respectively).15,16 Using updated guidelines in medical research lies in the promotion of scientific rigor, patient safety, relevance, consistency, regulatory compliance, and improved clinical decision-making. Second, as done in Saudi study,11 we reported the corridor’ length ( ie ; 30 and 40 m, respectively). The corridor length is essential for precise comparisons of 6MWT results81 and can influence performance.15,39 Although it was recommended that the walking course must be 30 m in length,39 research has shown that there are no significant differences in outcomes when tracks of lengths ranging from 15 to 50 m are used.81 Third, unlike the Saudi study,11 we reported the 6MWT practice place ( ie ; indoor as recommended).39 Research has indicated that there is little difference in 6MWD ( ie ; mean difference 4 m) between indoor and outdoor courses.82 Fourth, as done by Alameri et al.11 we performed only one 6MWT. Although repeated testing is recommended to account for the familiarization effect on 6MWD,22,71,73,83–86 the 6MWT is more appropriate for clinical settings, where the test is typically performed once.87 Fifth, contrary to the Saudi study,11 we reported the day-time of the 6MWT ( ie ; between 8 and 11 am).22,84 This period is characterized by a stable ambient temperature and humidity which can minimize the intraday effects.88 Intraday variability can be a source of biased data.39 Sixth, contrary to the Saudi study,11 we mentioned that no encouragement or walking aids during the 6MWT was given to participants. The latter can influence the 6MWD.15,16,89,90 Finally, contrarily to the Saudi study,11 where 6MWT was supervised by several investigators, only one investigator was implicated in our study. In patients with chronic conditions, the 6MWT data can be compared when conducted by different investigators.91\n\nSimilar to the Saudi study,11 we reported the main outcome of the 6MWT ( ie ; 6MWD) (Appendix 1). Contrary to the Saudi study, we reported additional 6MWT data (Appendix 1).\n\nThe 6MWT main outcome, which is the 6MWD, is reported frequently in meters,15,16 which could be a source of misinterpretation.8,10,11 In our study, 6MWD was expressed as percentage of predicted 6MWD, and the LLN was calculated from predicted values. Comparing measured 6MWD to predicted values derived from norms is an important point since norms are essential to guide the diagnostic and prognostic use of the 6MWT and the success in medical decision-making depends as much on selecting and properly using norms and their limits.15,39\n\nIn our study, we reported some 6MWT secondary outcomes, including HR, SpO2, BP, dyspnea, ECRMC’ age, and 6MWD relative indices. The following sentences will discuss their clinical importance. First, HR was reported in pbm and as % of MPHR in order to avoid the age effect, and ΔHR was calculated. Expressing HR as % of MPHR accommodates individual variations in fitness levels and age, allowing for personalized exercise intensity assessment.41 ΔHR calculation is essential since it correlated with 6MWD.86,92,93 Second, SpO2 and ΔSpO2 were reported. Oxygen desaturation during a 6MWT provides information regarding exercise-induced desaturation, disease severity and disease progress.15,16 Third, BP was mentioned. Measuring BP during the 6MWT is valuable for assessing cardiovascular health, exercise responses, and overall patient safety.22,45,94 It can aid in diagnosis, risk assessment, exercise prescription, and patient care in cardiovascular conditions.22,45,94 Fourth, dyspnea was evaluated. On the one hand, dyspnea is a clinical sign of walking intolerance.22,46,47 On the other hand, it reflects both the physiology of exercise limitation, and the impact of exercise limitation on daily life.15,16 Fifth, we estimated the ECRMC’ age, which reflects acceleration of ageing.39,44 Finally, we calculated some 6MWD relative indices ( eg ; 6MWW, “6MWDxBMI”, “6MWDxmuscle-mass”, “6MWDxbody-fat” and “6MWDxSpO2End”) in order to better estimate the work required to perform the 6MWT than 6MWD alone.41 For example, since weight directly affects the energy required to complete the 6MWT, the 6MWW can offer valuable insights into patients’ functional capacity.15,16 The 6MWW correlates strongly with V̇O2peak and is suggested as a parameter of patients’ fitness evaluation when gas exchange measurements are unavailable.95 In addition, as weight is not the only and best tool reflecting the body composition, and as the adiposity has a key position in the beginning of inability,75 we had multiplied the 6MWD by BMI, muscle-mass and body-fat. Moreover, since a positive and significant correlation was observed between 6MWD and SpO2End,96 we had multiplied the 6MWD by the SpO2End.\n\nStudy limitations\n\nThis study has two major limitations. First, the “apparently” healthy group did not undergo HBV-DNA testing or fibroscan to confirm the absence of HBV infection and hepatic fibrosis, respectively. These tests were challenging to perform due to economic constraints and ethical considerations. Second, the study did not include spirometry testing, despite its known predictive value for 6MWD.22,39,56,83,84,93 Spirometry tests were not feasible due to the COVID-19 pandemic and the associated restrictions.97\n\n\nConclusion\n\nCHB may alter sub-maximal aerobic capacity and accelerate CRMC aging, reflecting a broader phenomenon. To enhance functional capacity, a key determinant of quality-of-life, the study suggests incorporating regular physical-activity in addition to antiviral treatment. Regular physical-activity is significantly associated with a lower risk of hepatocellular carcinoma in CHB patients,98 making the development of physical-activity policies and their impact on CHB populations a recommended area for future research.\n\n\nEthical approval\n\nThis study was approved by the ethics committee of Farhat HACHED Hospital (Approval number FH/3010/2020) on August 15, 2020. All procedures in the study adhered to the ethical standards of the 1964 Helsinki Declaration.\n\n\nInformed consent\n\nWritten informed consent was obtained from all patients after receiving an explanation of the study.", "appendix": "Data availability\n\nZenodo: Excel data of the 54 participants (26 patients and 28 controls) included in the pilot case-control study titled “Assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B”, https://doi.org/10.5281/zenodo.14542662.99\n\nThe project contains the following underlying data:\n\n- [Excel data of the 2 groups (26 patients and 28 controls).xlsx] (Excel file including the numerical data of the 54 participants).99\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nZenodo: Appendix 1: Methodologies and results of studies comparing 6-min walk test (6MWT) data of chronic hepatitis B (CHB) patients and healthy participants, https://doi.org/10.5281/zenodo.14584968.100\n\nThe project contains the following extended data:\n\n• [Appendix 1: Methodologies and results of studies comparing 6-min walk test (6MWT) data of chronic hepatitis B (CHB) patients and healthy participants].100\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nZenodo: STROBE checklist for ‘[Assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B: A pilot case-control study]. https://doi.org/10.5281/zenodo.14542795.101\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nAuthors want to thank Prs. Salima FERCHICHI, Khalifa LIMEM, and Mondher KORTAS for their invaluable contribution to the analysis of biochemical and haematological markers. In preparing this paper, the authors used ChatGPT ephemeral on November 2024, to revise some passages of the manuscript, to double-check for any grammar mistakes or improve academic English only. After using this tool, the authors have reviewed and edited the content as necessary and take full responsibility for the content of the publication. The primary findings of this paper were showcased as a poster at the 5th International Congress of Physiology and Integrative Biology Society, held in June 2022 in Lyon, France. A revised abstract entitled “The assessment of submaximal aerobic capacity in North African patients with chronic hepatitis B (CHB): A case– control study” derived from this work was subsequently published in the Journal of Acta Physiologica.102\n\n\nReferences\n\nBerk PD, Popper H: Fulminant hepatic failure. Am. J. 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Publisher Full Text" }	[ { "id": "363568", "date": "08 Feb 2025", "name": "Khadija Ayed", "expertise": [ "Reviewer Expertise exercise physiology and pulomonary functionnal testing" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a rare and original study, focusing on The assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B (CHB) through a case-control study. This is a study that could provide a great benefit to the management of chronic diseases, but also to the importance of integrating adapted physical activity as an effective and promising therapeutic means in these diseases. However, this scientific work requires a review at certain points : In the introduction : Page 2 : Some studies have reported the harmful impacts of CHB on the main elements of the chain involved during adaptation to both maximal (eg; oxygen consumption ( _VO2)) and sub-maximal (eg; 6-min walk test (6MWT)) aerobic exercise…..\nThis example is not suitable, it is the maximal oxygen consumption (V'O2 max) which rather evaluates the tolerance to maximum effort\nPage 3 : Exercise tolerance is commonly quantified through the measurement of _VO2 during a cardiorespiratory test (à cardiopulmonary exercise testing CPET) Page 3 : (On the one hand, _VO2 at peak of exercise ( _VO2peak) was a predictor of mortality, as patients with a low _VO2peak (ie; < 17 ml/kg) had a survival rate of 55%,10 and it is significantly correlated with maximal inspiratory pressure (r = 0.64) and with the Model for End-Stage Liver Disease (r = 0.91).9 On the other hand, the authors of the Saudi study reported that compared to healthy participants (n=45), patients with CHB (n=49) had a significantly lower 6-min walk distance (6MWD) by 31 m.11 The Saudi study had some methodological weaknesses that can “slightly” modify the findings.11 First, the inclusion of patients with diverse liver diseases (eg; non-cirrhotic chronic hepatitis B (NC-CHB) or C, cirrhotic), is a source of ‘perplexity’ since the clinical outcomes are different.6 Second, the absence of sample size determination is a statistical flaw.21 Third, the expression of the main outcome (ie; 6MWD) only in absolute value, and the lack of its standardization according to participants’ characteristics (eg; sex and anthropometric data), could lead to misinterpretation.8,10,11 The standardized 6MWD allows a more objective comparison between the diverse groups.22 Fourth, the use on the quantitative significance approach with a “p value” < 0.05 is criticized, and the qualitative significance approach is recommended in medical exercise research.23)\nThis whole part should be mentioned in the discussion and not in the introduction\nIn the methods\nPage 4 : To the finest of the authors’ knowledge, no previous study has explored the incapacity (aerobic capacity) via the 6MWT in a homogeneous group of NC-CHB patients…. Page 5 : co-morbidities such as respiratory or cardiovascular diseases, systemic conditions that could influence blood test results like diabetes mellitus or renal failure, consumption of alcohol….\n\nWhy did you exclude diabetics from this study knowing that diabetes does not contraindicate 6MWT?\nPage 6 : (non-smoker: <5 pack-years; smoker3: 5 pack-years or over )\nThere is a mistake in the formula for the predicted value of the 6-minute walking distance for subjects under 40 years old\nFor patients under 40 years of age, you used the following formula: 6MWD (m) = 800.05-64.71 x Sex (0: Man; 1: Woman) - 10.23 x BMI (kg/m2) - 1.63 x Age (years) + 2.05 x Weight (kg) But, according to reference 43 The formula which allows the theoretical DM6 to be calculated is as follows: 6MWD (m) = 800.05 + 64.71 x Sex (men:1/women:0) - 10.23 x BMI (kg/m2) - 1.63 x Age (years) + 2.05 x Weight (kg). So you need to correct your formula and precise coefficient for gender. Page 7 : For the ECRMC, reference 45 only contains the formula for calculating this parameter in patients over 40 years old, so it is necessary to specify the reference of the other formula which allows the calculation of the ECRMC for patients under 40 years old. In the Statistical analysis: In this study it was necessary to calculate the Odds ratio to confirm the risk of hepatitis on aerobic capacity and the acceleration of aging of the cardiorespiratory and muscular chain”Results Page 7 : Out of the 128 participants assessed, data from 54 participants [26 cases (15 m/11w) and 28 controls (15m/13w)] were retained for the final dataset… Table 1, 2, 3 and 4 : mean change should be mentioned for each group and the change in the measured value should be expressed as a percentage change from the baseline value (mean % change CHB Group and mean % change CG) and in this case the significance of the difference between the percentage change of the parameter for each group should be sought. Then, the comparison between the percentages of change will allow to evaluate the effect of the groups in the statistical analysis\nIn the Discussion : Discussion of methodology should come before discussion of results Why you did not evaluate the physiological cost index of walking (ICP). This index is defined by the difference in heart rate at the end of the 6MWT and that at rest reported to the walking speed during the 6MWT. It is an index that was created and validated by J. MacGregor and which evaluates the cost of cardiac work deployed in walking and which could have interesting correlations with the ECRMC. You justified the use of 6MWW by the fact that it has strong correlations with peak VO2 and this is very interesting in the absence of a technical platform allowing the measurement of peak VO2. However, the strong and significant correlations between DM6 and SpO2 are still known and validated in the literature, thus, the use of the multiplication of 6MWD by the SpO2End is useless in this work especially since you have not shown in this work correlations between this parameter and other measured parameters which could justify its usefulness. The same remarks for the “6MWDxBMI”, “6MWDxmuscle-mass” and “6MWDxbody-fat” especially given the lack of references and scientific validity for these parameters even in your study.\nThe English version of this work leaves something to be desired.\nThe conclusion : The conclusion should be better structured, it should respond to the objectives of the study in a clear and precise manner and not contain references.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No", "responses": [] } ]	1	https://f1000research.com/articles/14-98
https://f1000research.com/articles/14-97/v1	16 Jan 25	{ "type": "Research Article", "title": "Building Trust through ESG: A Study on Consumer Behaviour in Sustainable Fashion", "authors": [ "Neha Rastogi", "Jitendra Singh", "Shagun Tyagi", "Vasim Ahmad", "Rakesh Kumar", "Rajesh Singh", "Ayushi Sharma", "Neeraj Priyadarshi", "Bhekisipho Twala", "Neha Rastogi", "Jitendra Singh", "Shagun Tyagi", "Rajesh Singh", "Ayushi Sharma", "Neeraj Priyadarshi", "Bhekisipho Twala" ], "abstract": "Background This study explores the influence of Environmental, Social, and Governance (ESG) practices on consumer purchasing decisions in the fashion industry. It examines how corporate image and word-of-mouth (WOM) mediate the relationship between ESG practices and consumer trust, impacting purchase intent.\n\nMethods A structured questionnaire was distributed online to 393 participants aware of ESG practices, targeting Generation Z consumers. The survey assessed demographics, ESG awareness, brand image, WOM, and purchasing decisions using a Likert scale across five constructs: ESG Practices, Corporate Image, WOM, Trust, and Purchase Intention. Data were analyzed with Structural Equation Modeling (SEM) in IBM AMOS, following a two-step process: Confirmatory Factor Analysis (CFA) for validation and path analysis for hypothesis testing.\n\nResults The findings indicate that ESG practices significantly enhance corporate image and positive WOM, which, in turn, foster consumer trust. Corporate image has a substantial impact on consumer trust (p < .001), while WOM also contributes to trust (p < .001). Trust was found to be a strong predictor of purchase intention, demonstrating the mediating role of corporate image and WOM between ESG practices and purchasing behavior.\n\nConclusions ESG practices are critical in shaping consumer perceptions and fostering loyalty in the fashion sector. By building a trustworthy corporate image and encouraging positive WOM, fashion brands can effectively influence consumer purchasing decisions. This study highlights the competitive advantage of implementing ESG practices, particularly in appealing to Generation Z consumers who value sustainability and ethical business practices.", "keywords": [ "Sustainability", "ESG", "Consumer Behaviour", "WOM", "Trust", "Corporate Image" ], "content": "1. Introduction\n\nThe growing demand for sustainability and social responsibility highlights the importance of Environmental, Social, and Governance ESG practices worldwide. People’s social responsibility towards the environment, nature, and themselves now influences their decision making while making purchase decisions. It not only influences purchase decisions, but also affects all stakeholders’ decisions regarding whether they are employees of a company or investors. Each stakeholder is now interested in understanding the company’s ESG practices. Based on this, they can make decisions. To achieve sustainability, companies must gain the trust and credibility of their stakeholders. Industries such as the fashion industry have also started incorporating ESG practices in their daily routines. It also helps reduce risk and improve performance. Emphasizing ESG policies attracts and retains customers and uses various communication techniques (Burton et al., 2017). For instance, Puma is a brand that has initiated efforts to encourage universal equality and fair labor practices (Campaign, C. C., 2004). These actions not only improve society but also enhance a company’s positive brand image and offer it a competitive edge in the market (Alam, S. S., & Islam, K. Z., 2021). Therefore, it is imperative to explore ESG practices in the fashion industry and their impact on consumer purchase behavior is absolutely imperative (Koh et al., 2022). In order for companies to lessen environmental footprints and social impacts, they need to abide by ESG practices while also mitigating business risks and building reputations around their brands (Nirino et al., 2021). These include sustainability initiatives, ethical conduct of employees, responsible supply chain management systems, diversity and inclusion policies as well as corporate governance frameworks that ensure compliance with laws (D’amato, A., Henderson, S., & Florence, S., 2009). ESG practices enable organizations to identify environmental or social risks or opportunities that may have financial consequences, subsequently improving the corporate performance of firms and value creation in the long term (Fulton et al., 2012). Levi Strauss & Co. is also a prime example of a sustainability-oriented brand. Levi, the jeans maker, has made a strong commitment to sustainability and implemented several ESG initiatives such as reducing water consumption in denim production and recycling materials in its offerings (Maratos, A., 2022). Furthermore, ESG practices directly influence consumer behaviors while improving their brand reputation and generating positive word-of-mouth. Notably, 90% of consumers trust and remain loyal to businesses that prioritize social and environmental responsibility (Soclworks.com cited by Maratos, A., 2022). This clearly shows how ethical and sustainable business practices are becoming increasingly necessary for customers who see purchasing choices as supporting corporations that share their values. By doing so, they gain increased customer confidence, loyalty to the brand, and market competitiveness (Hejase et al., 2017).\n\nTherefore, this study analyzes the mediating role of corporate image and word-of-mouth between ESG practices and consumer purchase decisions in the fashion industry. This study examines how these practices affect consumer behavior to provide a better understanding of their significance within the context of the fashion business and their possible implications on enterprise outcomes. The literature on ESG has mainly concentrated towards the connection between ESG practices and institutions’ financial performance. However, research on customer perceptions and attitudes towards ESG management and marketing is scarce. A conceptual model, research methodology, recommendations for future studies, implications, and comprehensive discussions are presented in this report (Barić, 2017; Ali et al., 2015; Roloff, 2008; Alsayegh et al., 2020; Tarmuji et al., 2016; Aharoni, 2015; Min and Galle, 2001; Dagher and Itani, 2014; Rezaee, 2017; Shankar et al., 2002; Henisz et al., 2019; Fulton et al., 2012; Lipton, 2020; Matos, 2020; Hoang, 2018; Niinimäki et al., 2020 and Déri, 2013). The manuscript is structured to provide a comprehensive analysis of the research topics of ESG, corporate image, word-of-mouth (WOM), and consumer behavior. It begins with a literature review, identifies gaps, and formulates hypotheses. The conceptual model and research methodology outlined the research design, data collection methods, and analytical techniques. The analysis and results section presents the findings, highlighting the mediating roles of corporate image and WOM in the relationship between ESG practices and consumer behavior. The study’s practical consequences for the fashion industry are examined in the Discussion section, which also offers a path for future research on ESG practices in the industry.\n\nWhile the fashion industry is a significant area for environmental, social, and governance (ESG) considerations, the theoretical literature has predominantly connected ESG activity to financial performance. The fashion industry has a long way to go in terms of understanding the consumer-centric impact of ESG. However, the mediating roles of corporate image and word-of-mouth (WOM) on how ESG practices impact consumer behavior have hardly been investigated. This study seeks to address these gaps by providing a holistic examination of how firm image and WOM mediate the ESG relationship between fashion consumers’ purchase choices. The current study contributes to the literature on ESG investment by proposing and testing a conceptual model, which in turn provides a new understanding of how (mediation) ESG practices affect consumer behavior.\n\nIt would also take into account the varying effects across ESG dimensions, which can provide broader insights into how fashion companies could utilize ESG to enhance their brand image as well as consumers’ loyalty. The paper is divided as follows: a literature review, conceptual model, hypotheses of the research questions proposed, methodology results, and some practical strategies for fashion companies to develop ESG initiatives based on market positioning.\n\nThis study elaborates on how ESG practices influence consumers’ purchasing decisions in fashion companies. This study discusses how the following three specific facets of ESG practices–environmental sustainability, social responsibility, and governance transparency–influence consumer perception and, in turn, their purchase decisions. Additionally, this study examines the role of corporate image as a mediating factor in this relationship and deals with the issue of how a well-managed corporate image can favorably contribute to boosting the positive effect of ESG practices on purchase decisions. Furthermore, it shows how word-of-mouth influences consumer behavioral aspects concerning the impact of ESG practices on consumer-to-consumer communication and brand loyalty. This research provides practical insights into how fashion firms can effectively implement and communicate ESG practices to enhance corporate image, develop positive WOM, and ensure consumer loyalty and sustainable business outcomes.\n\n\n2. Literature review and hypothesis development\n\nThis study focuses on the relationship between various variables such as ESG practices by companies, WOM spread by consumers, their trust, corporate image, and purchase decisions based on ESG practices, corporate image, WOM, and trust, specifically in the fashion industry. ESG practices are one of the important parameters considered by all stakeholders of a company for decision-making, from consumers to employees, and even investors are interested in knowing the ESG score or ESG practices of the company. WOM can improve ESG practices in the digital age by increasing consumers’ confidence. Trust is essential when making decisions, particularly in ethical and environmental sectors. ESG policies and a positive company image result in loyal customer support.\n\nEnvironmental, social, and governance (ESG) refers to a broad range of activities including sustainable development, social impact, ethical standards, green practices, and purpose alignment (Gasperini, 2020; Sandberg et al., 2009; Zumente & Bistrova, 2021). The term ‘perceived ESG’ describes how well a company complies with social and stakeholder duties. Nonetheless, there is still knowledge on how ESG-related activities affect consumer purchasing as well as corporate revenue and profit (La Torre, Leo, & Panetta, 2021). The analysis revealed a significant decrease in the sales of products associated with ESG scandals, indicating that consumers consider ESG issues in their purchasing decisions (Cornell, B., & Damodaran, A., 2020). Reputation signals such as Corporate Social Responsibility (CSR) and sustainability efforts play a crucial role in building corporate brand performance and brand equity (Wang, S. et al., 2021).\n\nMethods\n\nThis study used a descriptive survey research approach to examine the purchase decisions made by Generation Z regarding sustainable fashion and ESG practices. A total of 393 participants were selected through convenience sampling, and the data were collected through an online survey. The survey link was distributed via various social media platforms to ensure wide coverage. The participants were eligible to respond if they were aware of ESG concepts.\n\nData collection\n\nThe questionnaire was structured to capture respondents’ demographics, ESG awareness, brand image, word-of-mouth, and purchase decisions. It included 26 items across five key constructs: ESG Practices, Corporate Image, Word of Mouth (WOM), Trust, and Purchase Intention. Responses were measured on a Likert scale, with participants rating their agreement with each statement.\n\nData cleaning\n\nBefore analysis, responses were cleaned to remove outliers, incomplete data, and any entries that did not meet the inclusion criteria. Only complete responses from eligible participants were analyzed.\n\nStatistical analysis\n\nData were analyzed using Structural Equation Modeling (SEM) with IBM AMOS software, following a two-step approach. In the first step, Confirmatory Factor Analysis (CFA) was conducted to validate the measurement model using key indicators like CFI, GFI, AGFI, NFI, and RMSEA. In the second step, path analysis was performed to test the hypotheses, applying the same fitness criteria. Descriptive statistics were also generated to examine the distribution of demographic data.\n\nReporting guidelines\n\nThis study complies with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist, ensuring adherence to established guidelines for transparency and reproducibility in survey-based research. The full checklist can be accessed on the EQUATOR network website at https://www.equator-network.org/reporting-guidelines/strobe/\n\nESG considerations are crucial for the fashion industry because of their wide-ranging impacts on various stakeholders and the sustainability of the industry (Gadinis, S., & Miazad, A., 2020). Firstly, investors increasingly scrutinize ESG performance, demanding higher returns for firms with robust ESG practices (Reber, B., Gold, A., & Gold, S., 2022). As sustainability becomes a key criterion for consumer purchasing decisions, companies in the fashion industry need to align with ESG standards to maintain investor confidence and market competitiveness (Silvennoinen, M.2022). Employees, a vital component of the fashion workforce, actively seek employers who prioritize ESG issues (Strine Jr, L. E., Smith, K. M., & Steel, R. S., 2020). The industry’s reliance on skilled and creative professionals makes it imperative for fashion businesses to invest in ESG initiatives to attract, retain, and motivate talent (Savitz, A., 2013). Positive workplace practices, aligned with ESG principles, not only enhance the industry’s social responsibility, but also contribute to increased employee productivity and satisfaction (Asrar-ul-Haq et al., 2017).\n\nSuppliers with low ESG ratings face contractual challenges and reduce corporate customer engagement, emphasizing the need for an ESG focus throughout the industry (Odell, J., & Ali, U., 2016). The fashion industry’s environmental and social impacts are significant, making embracing environmental, social, and governance (ESG) practices pivotal in addressing concerns related to resource exploitation, environmental harm, and unsustainable practices. The industry, often criticized for contributing to pollution, waste, and unethical labor practices, can use ESG frameworks to guide responsible business conduct (Singhania & Saini, 2022). The industry’s heavy reliance on natural resources and complex global supply chains underscore the importance of adopting sustainable practices (Cammarano et al., 2022). Implementing ESG considerations provides a structured approach for the industry to address these challenges by fostering transparency, accountability, and responsible resource management (Veenstra & Ellemers, 2020).\n\nFurthermore, the textile and clothing industry is seeing a transfer of consumer attention towards sustainable (and ethically produced) fashion (Lundblad & Davies, 2016). Fashion companies must incorporate ESG practices in their operations to cater better towards consumers with new needs, demands, and expectations, as well as to avoid losing brand reputation (Erhun, F., Kraft, T. & Wijnsma, S. 2021). Failure to do so risks staining your reputation, decreasing consumer trust, and even market share. While consumers and other stakeholders have been driving the push for ESG in fashion, it is not just an obligation from those expectations that need to be met; it is also a strategic imperative. In order to position themselves for a more sustainable future, embracing ESG principles will not only ensure fashion is aligned with global sustainability goals, but also mitigate risks and help strengthen brand reputation in an increasingly aware marketplace (Kandpal et al., 2024).\n\nThe current trend in the literature is to investigate corporate reputation (Almeida, M. D. G. M. C. & Coelho, A. F. M., 2019; Gomez-Trujillo et al., 2020) given that it has become increasingly important and that organizations must identify what determines corporate reputation. Corporate image and reputation are critical signals for companies; however, their impact on product brand equity is often overlooked (Heinberg, M., Ozkaya, H. E., & Taube, M., 2018). The study examines consumer foot traffic in response to negative environmental, social, and governance (ESG) news (Dube, S., Lee, H. S. G., & Wang, D., 2023). The results of previous studies suggest consumers’ willingness to support sustainable and ESG-conscious products, but actual shopping behavior is influenced by factors such as brand loyalty, convenience, and affordability (Swedroe, L. E., & Adams, S. C., 2022; Dube, S., Lee, H. S. G., & Wang, D., 2023). This study suggests that there are no significant changes in consumer foot traffic around negative ESG news events (LI, F. W., & MICHAELY. R., 2023; Noh, S., So, E. C., & Zhu, C., 2023). However, in countries with higher income, education level, democratic political tendencies, and population density, consumer foot traffic decreases for firms with negative ESG news. Consumer loyalty moderates this effect, indicating that loyal consumers are less likely to change their shopping behavior in response to negative ESG news (Huo et al., 2022). This study contributes to the literature by examining consumer reactions to negative ESG news events and shedding light on the nuanced factors that influence shopping behavior (Dai, R., Liang, H., & Ng, L., 2021).\n\nPrior studies have examined the relationship between perceived Environmental, Social, and Governance (ESG), sustainability, word-of-mouth (WOM), and intention (Vo, T. T., Xiao, X., & Ho, S. Y., 2019; Puriwat, W., & Tripopsakul, S., 2022; Bae, G. K., Lee, S. M., & Luan, B. K., 2023). The results show that consumers’ WOM intention is positively affected by eco-friendly service quality in golf resorts and acceptable CSR activities (Bae, G. K et al., 2023). Chae et al. (2015) highlights the significant impact of trust and brand emotion on word-of-mouth promotion and brand loyalty on mobile Social Networking Services (SNS), underscoring the importance of brand trust.\n\nConsumer choices directly impact a firm’s revenues, and in the context of Environmental, Social, and Governance (ESG) performance, consumers may avoid or boycott companies perceived as socially or environmentally irresponsible (Yu, E. P. Y., Van Luu, B., & Chen, C. H., 2020; Choi, J., Roh, T., & Lee, J. H., 2024). Research shows evidence of ESG activities, particularly charitable contributions, being linked to revenue growth, but not all governance-related activities elicit similar consumer responses (Taliento, M., Favino, C., & Netti, A., 2019). Ethical considerations are increasingly being considered in purchasing decisions, with various practices impacting consumer behavior, including environmental responsibility, fair labor practices, social responsibility, and transparency in business practices (Bhaduri, G., & Ha-Brookshire, J. E., 2011). Brand loyalty is a key aspect of customer relationships and is positively influenced by ethical practices such as ethical advertising, pricing, and overall ethical behavior (Román, S., 2003). Trust in a brand plays a crucial role in developing brand loyalty, and sustainable marketing fosters loyalty and repeat business (Filo, K., Funk, D. C., & Alexandris, K., 2008).\n\nGovernment and non-government organizations, along with community groups, play significant roles as stakeholders in corporate reputation (Barrett, M., 2001; Barić, A., 2017). Primary and secondary stakeholders exhibit distinct attributes and levels of involvement within an organization, often influencing the organization’s reputation in different ways (Fassin, Y., 2009). These differences in stakeholder characteristics moderate the association between corporate reputation and its antecedents and consequences, impacting the organization’s image and the effectiveness of its ESG practices (Ali, R., Lynch, R., Melewar, T. C., & Jin, Z., 2015).\n\nThe way stakeholders perceive an organization’s attributes varies significantly across groups, influenced by their experiences and access to information (Rindova, V. P et al., 2005). Groups with greater access, such as market analysts and senior management, often have differing attitudes and behaviors compared to other stakeholder groups (Morsing, M., & Schultz, M., 2006). Corporate reputation is shaped by these varied perceptions of its foundational qualities and expected outcomes, as each group interprets and values these elements differently (Ali, R., Lynch, R., Melewar, T. C., & Jin, Z., 2015). This study underscores the necessity of accurately assessing corporate reputation to support effective management and convey its value within the organization (Van Riel and Fombrun, 2007). Building stakeholder trust requires companies to consistently demonstrate competence, integrity, and accountability—delivering on promises, showcasing expertise, maintaining transparency, and owning up to decisions (Maio, E., 2003).\n\nThis study highlights gaps in the literature regarding the relationship between ESG practices and consumer behavior in the fashion sector. This highlights the need for a dynamic study of ESG initiative changes over time and a micro-level examination of customer reactions. The article also discusses consumer preferences towards sustainable and ethically created clothes, but lacks detail on the role of education in raising awareness. It also discusses cross-cultural differences in brand trust and the interactive impacts of image, word of mouth, and trust on purchasing decisions.\n\nHypothesis developed\n\nESG practices of a company has positive influence on Corporate Image\n\nESG practices of a company has positive influence on Word of Mouth\n\nCorporate image influence trust of consumer\n\nWord of Mouth influence trust of consumer\n\nTrust has positive influence on purchase decision of consumer\n\nSee Figure 1.\n\nThis study examines the relationship between consumer trust; word-of-mouth (WOM); company image; and environmental, social, and governance (ESG) activities in fashion businesses. ESG policies, such as social responsibility and sustainability, improve a company’s reputation. Strong ESG practices generate positive word-of-mouth, which increases the effects of ESG activities. Purchase decisions are strongly influenced by consumer trust, which lowers perceived risks and boosts confidence in encouraging actual purchasing behavior.\n\nMethod\n\nThis study used a descriptive survey research approach to examine the purchase decisions made by Generation Z regarding sustainable fashion and ESG practices (Lamm, A. J., & Lamm, K. W., 2019). A total of 393 people participated online in the convenience sampling process used to select the sample. Data were collected through an online survey, as this link was shared on different social media platforms, so that responses could be collected by covering a large area. There is only one criterion that respondents need to qualify: if they are aware of ESG and concepts related to ESG, they are eligible to fill out the questionnaire. Along with providing detailed insights into customer preferences and impressions, the questionnaire included quantitative questions.\n\nDescriptive statistics were used to analyze the data with a focus on ethics. The study focused on demographic data, awareness, and brand image to better understand customer trust and buying decisions in sustainable fashion. Before analysis, data were removed through a cleaning process in which outliers, data with missing values, and incomplete information were removed. Responses from these respondents were included in the study for analysis purposes that fulfilled the basic criteria and provided complete information.\n\nThe data were analyzed using Structural Equation Modeling (SEM), following a two-step process. First, a Confirmatory Factor Analysis (CFA) was conducted to validate the measurement model. The model’s fitness was evaluated using standard indicators such as CFI, GFI, AGFI, NFI, and RMSEA. In the second step, path analysis was performed to test the hypothesized relationships between variables.\n\nLimitations of the study include convenience sampling, potentially affecting the generalizability of findings to the broader population, and the cross-sectional nature of the study, potentially overlooking changes in attitudes and behaviors over time. Future research should incorporate longitudinal and comparative studies to address these limitations.\n\n\n3. Results\n\nThis study employed a tailor-made questionnaire in alignment with the aims and objectives of the research. This study used a framework with 26 items, including five main variables: ESG Practice, Corporate Image, Word of Mouth, Trust, and Purchase Intention (refer to Table 1 for detailed constructs and items). ESG Practice measures businesses’ application of Environmental, Social, and Governance practices, while Corporate Image measures a company’s reputation by stakeholders, including perceived quality, corporate citizenship, and brand reputation. WOM: Word of Mouth is about how much people speak (positively and negatively) relative to a business, its products, or services. It includes five questions to evaluate how likely people are to say or talk about the business itself or their products. A purchase goal means that a person intends to buy goods or services in the business. It consists of five measures that measure respondents’ propensity to purchase from a firm according to how they view the company’s corporate image, trust, and ESG policies. Comprehensive analysis and interpretation of the study findings are made possible by a structured technique that allows researchers to systematically analyze respondents’ views, attitudes, and behaviors related to ESG practices, business image, word-of-mouth, trust, and purchasing decisions.\n\nThe sample’s demographic distribution shows that the respondents were a diverse group, with the majority being female (60%) and male (39%). With 31% of the sample, the age group of 34 and above constituted the largest portion. “The demographic profile of the respondents is summarized in Table 2, showing that the majority were female (60%) and held graduate-level education qualifications (46%). The age range of 23 to 27 years was second, with 24 percent. The age group of 28–33 years was second, with 23 percent. The youngest age group, 18–22 years, comprised 22% of the total. Of the sample, 46% had a graduate-level education. This was the case for the majority of participants. Of the sample, 35% had a postgraduate education and 22% had less than an undergraduate degree. The data demonstrate the diversity of the sample, with a greater percentage of women, a notable representation of older age groups, and the majority possessing at least graduate-level education.\n\nData were analyzed using Structural Equation Modeling (SEM) techniques, following a two-step approach. The first step involved Confirmatory Factor Analysis (CFA) to validate the measurement model. Model fitness was evaluated using indices like CFI, GFI, AGFI, NFI, and RMSEA. The second step involved path analysis to examine the hypothesized relationships among variables. As indicated in Table 3, calculations were performed to determine the loadings, maximum H reliability, and maximum number of variables extracted to evaluate convergent validity. To assess the dependability of the equation modelling procedure, composite reliability (CR) is crucial. Using AMOS and SPSS, the researchers tested structural equation models and provided descriptive data on the indicators.\n\nFollowing the guidelines from Hair et al. (1998), a Cronbach’s alpha value greater than 0.7 is considered indicative of strong internal consistency. Both convergent and discriminant validity were rigorously assessed. Convergent validity was confirmed through factor loadings and the calculation of Average Variance Extracted (AVE). Each construct displayed factor loadings above 0.6, indicating sufficient convergence among latent variables (Chin et al., 1997). The AVE values ranged from 0.5 upwards, meeting the minimum threshold required for establishing convergent validity. Discriminant validity was verified using the Fornell and Larcker (1981) approach, ensuring that the squared multiple correlations (SMC) for each construct were below the AVE values. Additionally, the AVE values surpassed the minimum benchmark of 0.3, as suggested by Bagozzi and Yi (1988), thereby confirming the robustness of the measurement model’s validity and reliability.\n\nThe results in Table 4 show that the corporate image of a company has a significant and positive relationship with the ESG Practice of a company with a p-value of ***. Similarly, WOM also has a positive and significant relationship with ESG practices. Trust also has a significant relationship with corporate image, revealing that a company’s corporate image helps build trust in their respective consumers. Similarly, positive word of mouth also plays a vital role in building consumers’ trust in making their purchase decisions (Bae et al., 2023; Zumente & Bistrova, 2021; Eccles et al., 2020; Sargentini, 2023; Dube et al., 2023).\n\nTable 5 represents the regression weights; it was found that corporate image is the most influenced by the ESG practices of the company. There is also a strong and positive association between corporate image and consumer trust. This reveals that a more positive image of a company leads to trust in their respective consumers ( Figure 2).\n\n\n4. Discussion\n\nThis study examines how Environmental, Social, and Governance (ESG) practices affect a business’s reputation, customer recommendations, consumer confidence, and buying decisions. Environmental, social, and governance (ESG) practices are business attempts to conduct business in a way that is morally and sustainably acceptable while also improving their standing with stakeholders, competitive advantage, and risk management. They draw clients, set businesses apart from their rivals, and handle social and environmental challenges. Building consumer trust requires both word-of-mouth (WOM) and strong business image. A brand that is well received by customers is enhanced by moral conduct, superior merchandise, and conscientious business methods. Positive evaluations and recommendations spread through word-of-mouth strengthen trust, which in turn affects purchasing decisions by reducing perceived risks and increasing confidence in the company and its products.\n\n\n5. Conclusion\n\nThis study investigates how customer behavior in the fashion business is affected by environmental, social, and governance (ESG) practices. ESG practices are becoming more prevalent in the fashion industry because of the growing demand for sustainability and social responsibility. Brands such as Puma, Levi Strauss, and Levi have introduced’s with the aim of drawing customers, enhancing their brand image, and creating positive word-of-mouth. This study examines how word-of-mouth and corporate image influence consumer purchasing decisions and ESG practices. It offers information on how fashion brands may use ESG to improve their reputations, generate goodwill among customers, and maintain customer loyalty. They conclude that purchasing decisions, company reputation, and image are all positively impacted by ESG metrics. This study highlights the importance of quality control, social responsibility, and sustainability in the fashion industry. This implies that businesses can improve their standing, cultivate clientele, and boost their revenue by embracing sustainability and accountability. The results are applicable to several businesses and pertinent to the current economic environment.\n\n\n6. Limitation and future scope of study\n\nThis study examined the influence of several variables on sustainable fashion consumption. While these variables have been previously identified as important factors in promoting sustainability, there is a need for further research that examines how they interact in the context of sustainable fashion consumption and whether they remain relevant in the current socio-economic and environmental climate. Additionally, there may be other variables that have not yet been fully explored in relation to sustainable fashion consumption, such as the influence of government policies, regulatory frameworks, and the role of social media in promoting sustainable fashion. Therefore, more research is needed to identify these variables and their impacts on sustainable fashion consumption. By exploring these research gaps, future studies can contribute to a more comprehensive understanding of the factors that drive sustainable fashion consumption, and the role of various stakeholders in promoting sustainability in the fashion industry. This research can help to identify new strategies to enhance sustainable fashion practices and create a more sustainable future.\n\nThis study was conducted in accordance with the ethical standards set out in the Declaration of Helsinki for research involving human participants. Ethical approval for this study was granted by the Uttaranchal University Research Ethics Board (REB). The ethics approval number for this study is UU/DRI/EC/2024/008, issued on 30th September 2024. A formal approval letter was issued in a retrospective manner. In July 2024, we obtained verbal permission from the REB to commence our study as written approval was provided only when requested by a journal. The REB reviewed our comprehensive application and confirmed that we met all ethical norms and regulations before granting preliminary verbal consent. Consequently, we initiated our investigation in good faith and fully aligned it with the ethical standards outlined in the preliminary review.\n\nThe Data were submitted to the REB of the university, where board members and the chairperson assessed the viability of the research. After all the members were presented, their research objectives were approved for conducting the study.\n\nAll the study participants provided written informed consent. A self-explanatory written statement was included for the participants and submitted to the university research board.", "appendix": "Data availability\n\nFigshare: Building Trust through ESG, Doi: https://doi.org/10.6084/m9.figshare.27193236.v2 (Ahmad, V. 2024).\n\nThis project contains the following underlying data:\n\n• Building Trust through ESG.xlsx\n\nFidshare: Building Trust through ESG, Doi: https://doi.org/10.6084/m9.figshare.27193236.v2 (Ahmad, V. 2024).\n\nThis project contains the following extended data:\n\n• Questionnaire on ESG-11-14-2024_12_32_AM.pdf\n\nQuestionnaire: The structured questionnaire used for data collection can be accessed via this link: Questionnaire Link. https://docs.google.com/forms/d/e/1FAIpQLSfbAeVuABsjFdPCrXg1l-HD4FenPyhVd7qBvhnQ1GJ5_iOmQA/viewform?usp=sf_link\n\nThis questionnaire includes questions on demographics, ESG awareness, corporate image, word-of-mouth, and purchase decisions, which were all measured on a Likert scale.\n\nConsent Form: There was no separate consent form required. Participants provided their consent directly through the questionnaire.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0).\n\n\nReferences\n\nAbd-El-Salam EM, Shawky AY, El-Nahas T: The impact of corporate image and reputation on service quality, customer satisfaction and customer loyalty: testing the mediating role. Case analysis in an international service company. The Business & Management Review. 2013; 3(2): 177–196.\n\nAharoni Y: The foreign investment decision process. International Business Strategy. Routledge; 2015; pp. 10–20.\n\nAhmad V: Building Trust through ESG (Version 2). figshare. 2024. Publisher Full Text\n\nAlam SS, Islam KZ: Examining the role of environmental corporate social responsibility in building green corporate image and green competitive advantage. Int. J. Corp. Soc. Responsib. 2021; 6(1): 8. 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Publisher Full Text" }	[ { "id": "361566", "date": "27 Jan 2025", "name": "Dr Jagriti Jaiswal", "expertise": [ "Reviewer Expertise Sustainable development", "Issues related to SDGs and sustainability", "behavioral economics", "and agriculture market and policies" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nWhile the paper makes a valuable contribution, there are a few areas where improvements could enhance its clarity, impact, and practical applicability. Key Points for Revision are mentioned below:- 1. Abstract: The abstract is clear but would benefit from Mentioning the practical implications of the study briefly to attract the reader's attention. 2. Introduction: Strengthen the rationale for focusing on the fashion industry by elaborating on its environmental and ethical challenges (e.g., fast fashion's environmental impact). Explain why Generation Z is a critical demographic beyond their interest in sustainability (e.g., their role as trendsetters or their purchasing power). 3. Theoretical Foundations: Add more details on the three components of ESG (Environmental, Social, and Governance) and provide specific examples from the fashion industry. 4. Methodology: While IBM AMOS is an excellent tool, explain why it was chosen and how it ensured robust results for reader’s benefits 5. Results: The results are well-presented. Linking them to actionable insights for fashion brands would improve their usefulness. 6. Discussion: Discuss how corporate image and WOM interact to influence consumer trust and behaviour. 7. Conclusion and Recommendations: The conclusion summarizes the findings well but: It should explicitly outline actionable recommendations for stakeholders in the fashion industry, such as strategies for enhancing ESG transparency or leveraging WOM campaigns. Consider adding a subsection specifically for managerial implications to highlight the study’s practical relevance. 8. Limitations and Future Research: Highlight other unexplored areas like the influence of social media or government policies on ESG practices in fashion. 9. Formatting and Language: There are minor grammatical errors and inconsistencies in formatting that need correction. Overall, This manuscript has significant potential to advance the understanding of ESG practices in the sustainable fashion industry.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] } ]	1	https://f1000research.com/articles/14-97
https://f1000research.com/articles/13-796/v1	15 Jul 24	{ "type": "Systematic Review", "title": "Diagnostic and Prognostic Values of miRNAs in High-Grade Gliomas: A Systematic Review", "authors": [ "Renindra Ananda Aman", "Mohammad Galih Pratama", "Ricky Rusydi Satriawan", "Irfani Ryan Ardiansyah", "I Ketut Agus Suanjaya", "Mohammad Galih Pratama", "Ricky Rusydi Satriawan", "Irfani Ryan Ardiansyah", "I Ketut Agus Suanjaya" ], "abstract": "Abstract*\nBackground Gliomas, particularly glioblastomas, have grim prognoses, necessitating early diagnostic and prognostic indicators. MicroRNAs (miRNAs), influential in cancer research, show potential as glioma biomarkers. This systematic review aimed to examine the efficacy of miRNAs in the diagnosis and prognosis of high-grade glioma.\n\nMethods A comprehensive search was conducted of PubMed, EMBASE, Cochrane Library, and Web of Science for studies published from 2013 to 2023. The eligibility criteria included high-grade glioma, histopathological confirmation, miRNA samples from cerebrospinal fluid or plasma, and relevant outcome data. Studies were excluded if they were experimental or reviews and not in English.\n\nResults Of the 1120 initial results, 8 studies involving 660 subjects met the inclusion criteria. Several studies have assessed miRNA expression and its association with diagnosis and prognosis of high-grade gliomas. Overexpression of miR-221, miR-222, miR-210, miR-21, miR-125b, and miR-223 and under-expression of miR-15b and miR-124-3p showed significant potential in differentiating high-grade glioma patients from controls. Additionally, miRNAs are associated with distinct tumorigenic pathways.\n\nConclusion Elevated or depressed expression levels of specific circulating miRNAs hold significant promise as noninvasive biomarkers for the diagnosis and prognosis of high-grade glioma. These miRNAs offer valuable insights into disease progression and patient outcome. Further validation through extensive clinical trials and in-depth mechanistic studies is essential to realize their full clinical utility.", "keywords": [ "miRNA", "Glioma", "Biomarker", "Prognostic", "Oncogene" ], "content": "1. Introduction\n\nGliomas, a class of tumors originating in the central nervous system, pose a formidable medical challenge given their grim prognosis and complex nature. Glioblastoma is the most prevalent form among adults, with an incidence rate of 6.34 cases per 100,000 individuals.1 This aggressive tumor is characterized by rapid growth, often progressing for weeks or months. Despite the implementation of a multimodal therapeutic approach involving surgery, radiotherapy, and chemotherapy, the average survival for glioblastoma patients is only 15 months.2 Against this backdrop of clinical urgency, the search for early diagnostic and prognostic indicators for gliomas is of paramount importance. Gliomas are the most common and aggressive type of primary brain tumor in adults. It should be noted that, for gliomas, malignancy (e.g., anaplastic astrocytoma and glioblastoma) can arise de novo or progress from the lower grade. Despite all the achievements of modern medicine, the prognosis for patients with high-grade gliomas remains unsatisfactory.3\n\nMicroRNAs (miRNAs) have emerged as a captivating subject of study within the realm of cancer research, owing to their intricate involvement in the disease’s intricate molecular landscape. Comprising a class of small, non-coding RNAs composed of 19 to 22 nucleotides, miRNAs have a powerful influence on gene expression and cellular processes.4 Of note is their role in tumorigenesis, where alterations in miRNA target binding sites and disruptions in the miRNA processing machinery within tumor cells have been identified as significant contributors to cancer development and progression.5\n\nThis burgeoning field of research has delved into the depth of miRNA expression patterns in gliomas, yielding captivating insights into their diagnostic and prognostic potential. A growing body of evidence underscores the intricate correlations between specific miRNAs and the clinical aspects of gliomas, which have shown promise not only as potential biomarkers for early detection but also as indicators of disease progression and therapeutic response.5,6 By elucidating the complex web of miRNA-glioma associations, researchers aim to unlock a treasure trove of information that could ultimately revolutionize the diagnosis, treatment, and management of this relentless disease. This review aims to examine the effectiveness of miRNAs in the diagnosis and prognosis of high-grade gliomas.\n\n\n2. Methods\n\nWe carefully searched the literature using online free accessed software Rayyan (https://new.rayyan.ai/) with literature databases such as PubMed (https://pubmed.ncbi.nlm.nih.gov/), EMBASE (https://www.embase.com/landing?status=grey), Cochrane Library (https://www.cochranelibrary.com/), and Web of Science (https://www.webofscience.com/wos) to identify relevant studies published between 2013 and 2023 using the following strategy:\n\n(((((microrna) OR (mirna)) OR (mirnas) AND (y_5[Filter])) AND (((((high grade glioma) OR (glioblastoma)) OR (anaplastic astrocytoma)) OR (anaplastic oligodendroglioma)) OR (anaplastic oligoastrocytoma) AND (y_5[Filter]))) AND (((diagnostic) OR (diagnosis)) OR (early diagnosis) AND (y_5[Filter]))) AND ((prognostic) OR (survival) AND (y_5[Filter])) Filters: in the last 5 years.\n\nThe selection process for studies to be included in this study adhered to stringent eligibility criteria. Studies were deemed eligible if they satisfied the following criteria: high-grade gliomas, including glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma, as confirmed by histopathological examination. miRNA samples were collected from cerebrospinal fluid or plasma. For prognostic studies, the inclusion criterion required survival curves depicting overall survival (OS), disease-free survival (DFS), cause-specific survival (CSS), or recurrence-free survival (RFS). These survival curves were expected to be accompanied by hazard ratios (HR) and the corresponding 95% confidence intervals (CIs). Conversely, diagnostic studies are required to present data encompassing true positive, true negative, false positive, and false negative outcomes.\n\nStudies were excluded if they were categorized as experimental studies, review articles, or letters. Studies that were not conducted on human subjects and those that were not published in English were excluded. These rigorous inclusion and exclusion criteria were used to ensure the selection of studies that met the stringent standards of scientific rigor and relevance for research.\n\nTwo independent authors collected the study characteristics and original data, including the first author’s name, publication year, study design, study population, population size, age and sex of participants, follow-up duration, sample type, method of measuring miRNA expression, and HRs and their 95% CIs. Studies were included according to the following checklist based on the criteria provided by the MOOSE group: clearly defined study design; clearly described study population (country); sufficiently large sample (N>30); clearly described outcome (OS, CSS, DFS, or RFS); clearly defined miR measurement, including quantitative real-time polymerase chain reaction (qRT-PCR) or in situ hybridization (ISH); clear definition of cut-off values; miR measurement in tumor tissue, plasma, or serum; and sufficiently long follow-up. Studies that did not meet these criteria were excluded. Quality assessment was performed using the Cohcrane’s risk of bias in non-randomized studies of interventions (ROBINS-I) tool. Any discrepancies regarding the risk of bias judgments were resolved by discussion until agreement was reached.\n\nCertainty of evidence refers to the confidence that the observed effects of mRNA expression levels and their implications in glioma accurately reflect their true biological and clinical impact. Using the GRADE framework, factors such as study design, risk of bias, consistency of results, directness of evidence, precision of estimates, and publication bias were assessed meticulously. A high certainty of evidence suggests that further research is unlikely to significantly alter the current understanding, whereas low certainty indicates that new studies could substantially impact the conclusions. This rigorous evaluation ensured that the systematic review provided a reliable foundation for advancing research and informing clinical practices related to mRNA and glioma.\n\n\n3. Results\n\nA Literature search yielded 1120 results, of which 8 studies met the criteria, with a total of 660 subjects. The complete search process is illustrated in Figure 1.\n\nThe quality assessment of each study is shown in Figure 2. The characteristics of the included studies are presented in Table 1. A total of 660 participants were included in this study. The sample size of each study ranged from 39 to 152 patients. The majority of the studies (n = 5) were conducted in China, and the remainder were conducted in, Italy (n = 2), and Russia (n = 1). One study conducted observations and follow-ups after 48, 60, > 60, and > 100 weeks. Most studies have used qRT-PCR to detect and measure the expression levels of miRNAs. In addition to diagnosis, the study assessed prognosis by calculating HRs and 95% Cis. A summary of each miRNA, its potential targets, and pathways is presented in Table 2.\n\nEight studies were assessed5,7–15 and 4 studies had a low risk of bias in the overall domain.7–10 Meanwhile, four studies were concerned with qualitative measure.5,11–12,15 One study has critical judgement13 and the other has serious judgement in the qualitative analysis data.14\n\nFour studies had bias due to the selection of participants because of the variances of the participants’ characteristics.5,11–12,15 One study had bias owing to confounding variables.14 Two studies had some bias due to missing data in some specific miRNA expression.11,12 Four studies have some attrition bias because of many outcomes reported in the studies.11–14 One study had a critical bias due to the heterogeneity of the participants.13 Lastly, one study had a serious risk of bias due to the measurement mechanism of the outcomes.14\n\nA summary of the GRADE assessment for each study is presented in Table 3. Of the eight studies included in this systematic review, six were rated high and two were rated moderate. The true effect from each study was close to the estimate of the effect.\n\n\n4. Discussion\n\nGliomas, the most prevalent and aggressive form of primary brain tumors in adults, continue to present a daunting challenge despite medical advancements. Currently, the treatment approaches for high-grade gliomas rely on surgical procedures, radiation therapy, and chemotherapy. Regrettably, these methods, whether used individually or in combination, struggle to effectively control the disease, resulting in an average life expectancy of just over 12-15 months post-diagnosis.2 Consequently, the importance of timely diagnosis and prognostication remains unclear. The concept of molecular biomarkers has made substantial progress in the past decade, offering insights into glioma pathogenesis, aiding early tumor detection, risk assessment for recurrence, treatment strategy adjustments, and ultimately, improved prognosis.4 Among which, circulating miRNAs have emerged as a prominent focus of research. Although not yet integrated into clinical practice, advancements in this domain suggest that circulating miRNAs may play a pivotal role in high-grade glioma diagnosis and prognosis, potentially replacing the specific elements of contemporary diagnostic procedures.\n\nOur findings revealed that miR-210, miR15b, miR-21, miR-125b, miR 223 could be extracted from glioma tissues. miR-21, miR-221, miR-222, and miR-124-3p can be extracted from blood, indicating their potential as early diagnostic and prognostic tools for gliomas prior to surgery.\n\nDifferent tissues were used as controls in glioma studies. Wu et al,9 Li et al,13 and Stupak et al,10 used adjacent non tumor tissue from the same glioma patient. Lai et al, and Sun et al, used samples of normal brain tissue collected from the internal decompression surgery on patients with cerebral injury and cerebral hemorrhage.7,8 Barbano et al, used RNAs from four healthy individuals consists different brain regions (parietal cortex, frontal cortex, occipital cortex, and striatum).15 In using blood as a source of miRNA, there were also differences between different study. Zhang et al, used venous blood from other non-tumor patient.11 While Olioso et al, used blood from the same patient which were taken repeatedly along the duration of radio- and chemotherapy.14\n\nmiR-221/miR-222\n\nThe expression levels of miR-221 and miR-222 were higher in patients with gliomas than in the controls (P = 0.001). These miRNAs could potentially serve as biomarkers to distinguish glioma patients from controls, with an AUC of 0.83 (95% CI 0.74–0.93) for miR-221 and 0.88 (95% CI 0.79–0.98) for miR-222. The correlation between miR-221/222 expression and glioma prognosis may be partly explained by their role in promoting glioma cell proliferation through the downregulation of p27Kip1 expression. Additionally, miR-221/miR-222 are implicated in glioma cell migration by suppressing PTPμ expression and targeting apoptosis through direct binding to the 3’UTR mRNA region of the PUMA gene.11,13\n\nmiR-210\n\nThe expression levels of miR-210 were significantly elevated in both high-grade (grade III–IV; 6.58 ± 1.42) and low-grade (grade I–II; 4.70 ± 0.93) gliomas compared to normal brain tissues (both p < 0.001). High-grade glioma tissues (III–IV) exhibited a significantly higher expression of miR-210 compared to low-grade tissues (I–II) (p < 0.001). miR-210 regulates glioma cell proliferation by targeting FGFRL 1, and under hypoxic conditions, it establishes a positive feedback loop that enhances HIF-1a stability by suppressing GPD1L, leading to the induction of genes associated with energy metabolism, angiogenesis, cell proliferation, and survival.7\n\nmiR-15b\n\nmiR-15b expression in human glioma tissues was significantly lower than that in the adjacent normal brain tissues (p < 0.01). Moreover, the expression of miR-15b in both grade III and IV glioma tissues was significantly lower than that in grade I–II gliomas (p < 0.01). Overexpression of miR-15b inhibits proliferation by arresting cell cycle progression and inducing apoptosis by directly targeting cyclin D in gliomas. It was reported that miR-15b reduced glioma cell invasion and angiogenesis through NRP and MMP-3.8\n\nmiR-21\n\nmiR-21 expression was significantly (P < 0.001) higher in glioma tissues (20.99 ± 13.04) than in the corresponding non-neoplastic brain tissues (0.73±0.05). miR-21 expression in high-grade (III-IV) gliomas was higher than that observed in low-grade (I-II) gliomas (P < 0.001).9 In the T98G glioma cell line, the level of expression of the PDCD4 gene showed an inverse relationship with the expression of miR-21, and its reduction led to the inhibition of apoptosis. Overexpression of miR-21 in DU145 cells leads to elevated levels of HIF-1a and VEGF, promoting tumor angiogenesis.15 Elevated serum miR-21 levels have been identified as an indicator of a poorer response to trastuzumab. Resistant response to radiotherapy and temozolamide has been demonstrated to be mediated by miR-21.14\n\nmiR-125b\n\nmiR-125b revealed higher expression in glioma patients than controls (P < 0.001) and could potentially serve as a biomarker with an AUC of 0.83 (95% CI 0.74–0.93). miR-125b influences glioma stem cell proliferation by directly targeting E2F2. Additionally, it interacts with the 3′UTR of the apoptosis protein Bcl-2 modifying factor, inhibiting cell apoptosis through p53 and p38MAPK-independent pathways.13\n\nmiR-223\n\nThe expression of miR-223 was significantly higher in grade IV glioma tissues than in adjacent normal tissues (p = 0.014), but no significant differences were observed between the different glioma grades. There is conflicting evidence regarding whether miR-223 acts as a tumor suppressor or oncogene in glioblastoma. Ding et al discovered that the overexpression of miR-223-3p hinder cell proliferation and migration in glioblastomas by controlling inflammation-associated cytokines.10\n\nmiR-124-3p\n\nmiR-124-3p demonstrated lower expression in grade IV glioma patients compared to controls (P = 0.028), with no significant differences between different grades. Functioning as a tumor suppressor, miR-124 regulates the cell cycle at G0/G1 and inhibits CDK6 kinase, thereby suppressing angiogenesis and promoting neuronal differentiation.14\n\nSeveral miRNAs have shown promise as potential prognostic markers for high-grade gliomas, providing valuable insights into disease progression and patient outcome. High-grade gliomas, known for their aggressiveness, require accurate prognostic tools to guide their treatment. In this context, the Hazard Ratio (HR) is a critical statistical measure used to assess the prognostic significance of miRNAs.16 HR represents the ratio of the risk of an event, such as disease progression or mortality, between two groups: one with high miRNA expression and the other with low expression. An HR greater than 1 indicates a higher risk of the event in the high-expression group, suggesting an unfavorable prognosis, while an HR less than 1 signifies a lower risk, implying a potentially better outcome.17 By analyzing the HR associated with specific miRNAs, researchers can identify those that have a substantial impact on high-grade glioma prognosis. These miRNAs not only offer prognostic value but also hold the potential to guide personalized treatment strategies, ultimately improving patient care and outcomes in this challenging condition.\n\nEight miRNAs and their abilities to predict glioma prognosis were investigated in this study. Patients with high levels of miR-221, miR-222, miR-210, miR-21, miR-125b, and miR-223 and low levels of miR-15b and mir-124-3p expression had a significantly higher HR than those with low expression levels. HR represents the ratio of the risk of disease progression or mortality between groups with high and low miRNA expression.\n\nThe use of miRNAs as noninvasive biomarkers for the diagnosis and prognosis of high-grade gliomas offers several advantages. First, miRNAs can be easily detected in various bodily fluids, such as blood or cerebrospinal fluid, eliminating the need for invasive procedures such as brain biopsies.18 This noninvasive approach not only reduces patient discomfort but also lowers the associated risks and costs. Secondly, miRNAs exhibit remarkable specificity, allowing the identification of glioma-specific miRNA signatures. This precision aids in accurate diagnosis and can potentially differentiate high-grade gliomas from other brain conditions, thereby enhancing the diagnostic certainty. Furthermore, miRNAs play critical roles in tumor development and progression, making them valuable indicators of disease aggressiveness and patient prognosis.19 Their ability to reflect dynamic changes in tumor biology over time enables clinicians to tailor treatment strategies for individual patients. In summary, miRNAs serve as noninvasive, specific, and dynamic biomarkers that hold great promise for transforming the diagnosis and prognostication of high-grade glioma and improving patient care and outcomes.\n\nAlthough assessing miRNA expression levels holds promise for predicting glioma prognosis, several challenges must be addressed before using miRNAs in clinical settings. First, cell-free miRNAs can be released from normal human tissues, potentially interfering with results. It is crucial to pinpoint the origin of tumor-specific miRNAs and develop a method capable of effectively distinguishing cancer populations from healthy individuals. Second, there is no standardized procedure for measuring miRNA levels, leading to conflicting findings. Furthermore, a single miRNA can be associated with various tumor types.12 For instance, miR-21’s prognostic significance has been established in breast cancer, pancreatic ductal adenocarcinoma, and gastric cancer patients.12 Therefore, identifying a set of miRNAs specific to glioma holds great promise and could significantly enhance prognostic accuracy.\n\nThe strength of this review article lies in its comprehensive assessment of both the diagnostic and prognostic approaches for miRNAs in the context of various medical conditions. By covering a wide spectrum of applications, this study offers a holistic view of the potential use of miRNAs in medicine. This is validated by country variability, study centers, and various patient characteristics, which suggest broad generalizability. Additionally, the studies included in this review were meticulously evaluated using standardized parameters to ensure the reliability and consistency of the findings. This finding was coupled with the specific types, targets, and mechanisms of each potential miRNA included in the highlighted findings. This rigorous approach enhanced the credibility of the conclusions and recommendations of this study.\n\nThis study had some limitations. One notable limitation was the scarcity of studies that met the eligibility criteria for inclusion. The paucity of relevant research may limit the breadth of the review and ability to draw definitive conclusions regarding certain aspects of the diagnostic and prognostic utility of miRNAs. This scarcity may also introduce potential bias in the interpretation of available data. A quantitative review with a larger sample size is required to verify the statistical significance of the expression of each miRNA. Despite these limitations, this review provides valuable insights into the current state of knowledge on the diagnostic and prognostic potential of miRNAs.\n\n\nEthics and consent\n\nEthical approval and consent were not required.", "appendix": "Data availability\n\nNo data is associated with this article.\n\nFigshare: PRISMA checklist for ‘Diagnostic and prognostic values of miRNAs in high-grade gliomas: A systematic review’. https://doi.org/10.6084/m9.figshare.26140279\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgements\n\nNone.\n\n\nReferences\n\nWang J, Chen J, Sen S: MicroRNA as biomarkers and Diagnostics. J. Cell. Physiol. 2015 Sept 28; 231(1): 25–30. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCondrat CE, Thompson DC, Barbu MG, et al.: MIRNAs as biomarkers in disease: Latest findings regarding their role in diagnosis and prognosis. Cells. 2020 Jan 23; 9(2): 276. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSabarimurugan S, Kumarasamy C, Royam Madhav M, et al.: The significance of mirnas as a prognostic biomarker for survival outcome in T cell – acute lymphoblastic leukemia patients: A systematic review and meta-analysis. Cancer Manag. Res. 2020 Feb; 12: 819–839. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHuang X, Xiong Y, Yang J, et al.: The prognostic significance of mir-21 expression among surgically resected hepatocellular carcinoma patients: Evidence from a meta-analysis and retrospective cohort study. Biomed. Res. Int. 2020 Dec 21; 2020: 1–9. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nZhang Y, Guan D-H, Bi R-X, et al.: Prognostic value of micrornas in gastric cancer: A meta-analysis. Oncotarget. 2017 Jun 21; 8(33): 55489–55510. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nZhang Y, Chen J, Xue Q, et al.: Prognostic significance of micrornas in Glioma: A systematic review and meta-analysis. Biomed. Res. Int. 2019 Mar 26; 2019: 1–14. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMakowska M, Smolarz B, Romanowicz H: MicroRNAs (mirnas) in Glioblastoma Multiforme (gbm)—recent literature review. Int. J. Mol. Sci. 2023 Feb 9; 24(4): 3521. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nJones J, Nguyen H, Drummond K, et al.: Circulating biomarkers for glioma: A Review. Neurosurgery. 2021 Jan 13; 88(3): E221–E230. Publisher Full Text\n\nWu J, Al-Zahrani A, Beylerli O, et al.: Circulating mirnas as Diagnostic and prognostic biomarkers in high-grade gliomas. Front. Oncol. 2022 May 12; 12. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nFisher JP, Adamson DC: Current FDA-approved therapies for high-grade malignant gliomas. Biomedicines. 2021 Mar 22; 9(3): 324. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nOstrom QT, Gittleman H, Stetson L, et al.: Epidemiology of gliomas. Cancer Treat. Res. 2014 Dec 3; 1–14. Publisher Full Text\n\nZhang R, Pang B, Xin T, et al.: Plasma mir-221/222 family as novel descriptive and prognostic biomarkers for Glioma. Mol. Neurobiol. 2015 Jan 31; 53(3): 1452–1460. PubMed Abstract \| Publisher Full Text\n\nWu L, Li G, Feng D, et al.: MicroRNA-21 expression is associated with overall survival in patients with glioma. Diagn. Pathol. 2013 Dec; 8(1). PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSun G, Yan S, Shi L, et al.: Decreased expression of mir-15b in human gliomas is associated with poor prognosis. Cancer Biother. Radiopharm. 2015 May; 30(4): 169–173. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nOlioso D, Caccese M, Santangelo A, et al.: Serum exosomal microrna-21, 222 and 124-3P as noninvasive predictive biomarkers in newly diagnosed high-grade gliomas: A prospective study. Cancers. 2021 Jun 15; 13(12): 3006. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLi X, Zheng J, Chen L, et al.: Predictive and prognostic roles of abnormal expression of tissue mir-125b, mir-221, and mir-222 in Glioma. Mol. Neurobiol. 2014 Dec 11; 53(1): 577–583. PubMed Abstract \| Publisher Full Text\n\nLai N, Dong Q, Ding H, et al.: MicroRNA-210 overexpression predicts poorer prognosis in glioma patients. J. Clin. Neurosci. 2014 May; 21(5): 755–760. PubMed Abstract \| Publisher Full Text\n\nBarbano R, Palumbo O, Pasculli B, et al.: A MIRNA signature for defining aggressive phenotype and prognosis in gliomas. PLoS One. 2014 Oct 3; 9(10): e108950. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nStupak EV, Veryasikina YA, Titov SE, et al.: MicroRNAs in the diagnosis of malignancy of supratentorial brain gliomas and prognosis of disease progression. Cureus. 2023 Mar 8; 15: e35906. PubMed Abstract \| Publisher Full Text \| Free Full Text" }	[ { "id": "340043", "date": "12 Dec 2024", "name": "Dessika Rahmawati", "expertise": [ "Reviewer Expertise In essence", "this review is crucial because it not only advances our understanding of gliomas at a molecular level but also has the potential to translate these findings into tangible benefits for patients. It represents a bridge between cutting-edge research and clinical application", "with the ultimate goal of improving outcomes for individuals affected by this challenging disease." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nFeedback:\nEnsure consistent use of terminology (e.g., \"miRNA\" vs. \"mRNA\" in the context of gliomas). Citations: Verify all citations for accuracy and completeness. For instance, ensure the references like \"1\" and \"2\" directly correspond to listed sources. Methodology: Your methods section is detailed, but consider adding a flowchart or diagram to visually represent the selection and inclusion process. Results and Discussion: If possible, include a brief overview of key findings from the included studies. Highlight any significant miRNA biomarkers identified and their clinical implications.\nOverall, this article provides valuable insights into the role of miRNAs in glioma diagnosis and prognosis. It would be beneficial to ensure that all sections are seamlessly integrated, with a clear connection between the background, methods, results, and conclusions.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Partly\n\nIs the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required.\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes", "responses": [ { "c_id": "13024", "date": "15 Jan 2025", "name": "Renindra Ananda Aman", "role": "Author Response", "response": "1.⁠ ⁠We have make sure that terminology miRNA is the one that we use in our study, not mRNA 2.⁠ ⁠At method section, we add one sentence that explain the flow chart will be displayed at result section. 3.⁠ ⁠From result until discussion section, we have adjust and verify all citations used in our study 4.⁠ ⁠At discussion section, one paragraph has been added explaining brief overview and highlight of significant miRNA" } ] } ]	1	https://f1000research.com/articles/13-796
https://f1000research.com/articles/10-1230/v1	02 Dec 21	{ "type": "Genome Note", "title": "A draft genome sequence of the common, or spectacled caiman Caiman crocodilus", "authors": [ "Kenichi Okamoto", "Nichole Dopkins", "Elias Kinfu", "Nichole Dopkins", "Elias Kinfu" ], "abstract": "The common, or spectacled, caiman Caiman crocodilus is an abundant, widely distributed Neotropical crocodilian exhibiting notable morphological and molecular diversification. The species also accounts by far for the largest share of crocodilian hides on the global market, with the C. crocodilus hide trade alone valued at about US$86.5 million per year. We obtained 239,911,946 paired-end reads comprising approximately 72 G bases using IlluminaTM sequencing of tissue sampled from a single Caiman crocodilus individual. These reads were de-novo assembled and progressively aligned against the genomes of increasingly related crocodilians; liftoff was used to annotate the draft C. crocodilus genome assembly based on an Alligator mississipiensis (a confamilial species) annotation. The draft assembly has been submitted to the National Center for Biotechnology Information and both assembly and annotation are currently available for review at doi.org/10.5281/zenodo.4755063", "keywords": [ "Caiman crocodilus", "spectacled caiman", "genome", "assembly", "next-generation sequencing", "crocodilian", "vertebrate genome" ], "content": "Introduction\n\nThe common, or spectacled, caiman, Caiman crocodilus, is one of the most widely distributed and abundant crocodilian species, ranging continuously from Mexico to Argentina (Busack and Pandya 2001; US Fish and Wildlife Service 2018). A generalist predator, C. crocodilus is remarkably adaptable, occupying a wide range of habitats from urban to seasonal savannahs to tropical rainforests (Medem 1981, 1983), and has recently been introduced to Cuba, Puerto Rico and Florida where it is considered an invasive species (US Fish and Wildlife Service 2018). The broad distribution and diversity of habitats has facilitated considerable intraspecific diversification within C. crocodilus; a recent analysis by Roberto et al. (2020) identified between seven and ten lineages within C. crocodilus across differing biogeographic regions and watersheds throughout Central and South America. Within-species diversity is also morphologically apparent, with skull shape in particular exhibiting systematic patterns of regional differentiation (Medem 1955; Gans 1980; Medem 1981, 1983; Ayarzaguena 1984; Escobedo-Galván et al. 2015). These intraspecific patterns of cranial shape variation within C. crocodilus have been shown to parallel patterns of interspecific cranial diversity found in extant crocodilians (Okamoto et al. 2015).\n\nAdditionally, C. crocodilus is a species of commercial importance, chiefly in the leather industry. While the hides of C. crocodilus contain osteoderms that render the manufacturing process more difficult than for other crocodilians, a majority of the approximately 1.5 million crocodilian skins traded globally come from C. crocodilus (Brazaitis et al. 1998; Caldwell 2015). As with other crocodilians, most legal hides come from commercial farming operations, and the market for caiman hides is estimated to be over US $85 million (Caldwell 2015). Wild populations of C. crocodilus are also hunted for meat and even fishing bait (Da Silveira and Thorbjarnarson 1999; Brum et al. 2015; Pimenta et al. 2018) and provide ecosystem services including nutrient cycling and biological control (Valencia-Aguilar et al. 2013; Marley et al. 2019). Due to its role as an apex predator, C. crocodilus exhibits considerable bioaccumulation, with genotoxic analyses demonstrating molecular signatures of pollution on the C. crocodilus genome (Oliveira et al. 2021).\n\nThus, a draft genome sequence for C. crocodilus can not only assist with improved husbandry, ecotoxicology and wildlife management, but also has the potential to provide insight into evolutionary processes driving intraspecific diversification in continental systems more broadly.\n\n\nMaterials and methods\n\nDNA was extracted from a tissue sample belonging to a single Caiman crocodilus museum specimen (UF-FLMNH 171438) using the DNeasy ™kit from Qiagen (Hilden, Germany). DNA was quantitated using Thermofisher’s (Waltham, MA, USA) Picogreen ™kit (for a final Picogreen concentration of 77.78 ng/μL). Tecan’s (Männedorf, Switzerland) NuGEN Celero ™kit was then used to construct a paired-end library, which was subsequently sequenced on a single Illumina (San Diego, CA, USA) NovaSeq S4 lane. This yielded 239,911,946 paired-end reads of 2 × 150 bp each. Nucleic acid isolation, quantitation, library generation and raw-read sequencing were performed at the University of Minnesota Genomics Center.\n\nThe paired-end reads (as of October 2021, accessible at doi.org/10.5281/zenodo.5598241) were assembled de novo using the Iterative de Bruijn Graph Assembler (IDBA-UD; Peng et al. 2012). To assess the reliability of our pipeline from sequencing to de novo assembly using IDBA-UD, we repeated the sequencing and assembly using a museum-derived tissue sample from a single Alligator mississippiensis individual (UF-FLMNH 175565). This resulted in 249,325,204 paired-end reads of 2 × 150 bp each. As was the case for the C. crocodilus individual, the reads were then de novo assembled using IDBA-UD, and we used QUAST (Gurevich et al. 2013) to determine that the IDBA assembly of A. missippiensis captured approximately 94.2% of a recently published A. missippiensis assembly (GCA_000281125.4; Rice et al. 2017), with an NG50 of 21172 based on de novo assembled contigs alone.\n\nWe scaffolded the resulting draft C. crocodilus contigs using a two-step procedure. First, we scaffolded the caiman’s contigs against a Crocodylus porosus assembly (GCF_001723895.1; Ghosh et al. 2020) using ragtag (Alonge et al. 2019). We then re-scaffolded the resulting contigs/scaffolds against the confamilial Alligator mississipiensis assembly (GCA_000281125.4), again using ragtag. The draft assembly was then submitted to the National Center for Biotechnology Information (NCBI).\n\nContaminants, mitochondrial DNA, vectors, adapters, and sequences shorter than 200 bp identified by NCBI were manually removed using seqkit (Shen et al. 2016) and custom scripts (available at http://github.com/kewok/ncbi_scrubber). As of July 2021, this draft assembly can be accessed at doi.org/10.5281/zenodo.4755063.\n\nThe resulting scaffold (10.5281/zenodo.4755063) was then masked using RepeatMasker (Smit et al. 2015) relying on the HMMER database (Finn et al. 2011) and with “alligator” specified as species. Finally, liftoff (Shumate and Salzberg 2020) was used to generate a draft annotation based on the masked assembly using the annotations associated with A. mississipiensis (GCA_000281125.4; Rice et al. 2017) as a reference.\n\ntable 2asn_gff (National Center for Biotecnology Information 2020) was used to generate a Sequin file (National Center for Biotechnology Information (US) 2014), and features flagged as errors were manually removed using custom scripts (available at https://github.com/kewok/ncbi_scrubber); as of July 2021 the draft annotation is available at 10.5281/zenodo.4755063).\n\n\nResults and conclusions\n\nOur assembly yielded a draft assembly of length 2,341,057,913 bp with 465,471 scaffolds and contigs, and an N50 of 70,464,410 bp (Proch::N50 - Telatin 2018). A total of 297,374 gene features were predicted.\n\nHere we have described the first draft assembly and annotation of the C. crocodilus genome. We feel these data can assist natural resource management, ecotoxicology, agriculture, as well as research into broader questions about the interplay between microevolutionary and macroevolutionary processes across broad biogeographic scales.\n\n\nCompeting interests\n\nThe authors declare no competing interests.\n\n\nData availability\n\nThe draft assembly has been submitted to the National Center for Biotechnology Information and both assembly and annotation are currently available for review at (doi.org/10.5281/zenodo.4755063).", "appendix": "Acknowledgments\n\nWe are especially indebted to Dr. P. S. Soltis, T. A. Lott and the Genetic Resources Repository at the University of Florida - Florida Natural History Museum (UF-FLNHM) for generously providing us with tissue samples. We would like to thank the University of Minnesota Genomics Center (Minneapolis, MN, USA) for their guidance and for isolating DNA from museum samples, and for performing library preparation and raw sequencing. We wish to thank the Minnesota Supercomputing Institute (MSI) at the University of Minnesota and the Department of Chemistry at the University of St. Thomas for providing critical computational resources that contributed to the research results reported within this paper. Finally, we are very grateful to Dr. S. Pirro and Dr. M. Kieras at Iridian Genomes (Bethesda, MD, USA) for valuable insight on scaffolding the draft assemblies.\n\n\nReferences\n\nAlonge M, Soyk S, Ramakrishnan S, et al.: RaGOO: Fast and accurate reference-guided scaffolding of draft genomes. Genome Biol. 2019; 20: 1–17. Publisher Full Text\n\nAyarzagüena J: Variaciones en la dieta de Caiman sclerops. La relación entre morfología bucal y dieta. Memoria De La Sociedad De Ciencias Naturales La Salle. 1984; 44: 123–140.\n\nBrazaitis P, Watanabe ME, Amato G: The Caiman Trade. Sci. Am. 1998; 278: 70–76. Publisher Full Text\n\nBrum SM, da Silva VM , Rossoni F, et al.: Use of dolphins and caimans as bait for Calophysus macropterus (Lichtenstein, 1819) (Siluriforme: Pimelodidae) in the Amazon. J. Appl. Ichthyol. 2015; 31: 675–680. Publisher Full Text\n\nBusack SD, Pandya S: Geographic variation in Caiman crocodilus and Caiman yacare (Crocodylia: Alligatoridae): Systematic and legal implications. Herpetologica. 2001; 57: 294–312.\n\nCaldwell J: World Trade in Crocodilian Skins 2013-2015. Technical report. UN Environment Programme World Conservation Monitoring Centre; 2015.\n\nda Silveira R, Thorbjarnarson JB: Conservation implications of commercial hunting of black and spectacled caiman in the Mamirauá Sustainable Development Reserve, Brazil. Biol. Conserv. 1999; 88: 103–109. Publisher Full Text\n\nEscobedo-Galván AH, Velasco JA, González-Maya JF, et al.: Morphometric analysis of the Rio Apaporis Caiman (Reptilia, Crocodylia, Alligatoridae). Zootaxa. 2015; 4059: 541–554. PubMed Abstract \| Publisher Full Text\n\nFinn RD, Clements J, Eddy SR: HMMER web server: Interactive sequence similarity searching. Nucleic Acids Res. 2011; 39: W29–W37. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nGans C: Allometric Changes in the Skull and Brain of Caiman crocodilus. J. Herpetol. 1980; 14: 297–301. Publisher Full Text\n\nGhosh A, Johnson MG, Osmanski AB, et al.: A High-Quality Reference Genome Assembly of the Saltwater Crocodile, Crocodylus porosus, Reveals Patterns of Selection in Crocodylidae. Genome Biol. Evol. 2020; 12: 3635–3646. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nGurevich A, Saveliev V, Vyahhi N, et al.: QUAST: Quality assessment tool for genome assemblies. Bioinformatics. 2013; 29: 1072–1075. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMarley G, Lawrence AJ, Phillip DA, et al.: Mangrove and mudflat food webs are segregated across four trophic levels, yet connected by highly mobile top predators. Mar. Ecol. Prog. Ser. 2019; 632: 13–25. Publisher Full Text\n\nMedem F: A new subspecies of Caiman sclerops from Colombia. Fieldiana: Zoology. 1955; 37: 339–343. Publisher Full Text\n\nMedem F: Los Crocodylia de Sur America Volumen I. Bogotá, Colombia: Ministerio de Educación Nacional; 1981.\n\nMedem F: Los Crocodylia de Sur America Volumen II. Bogotá, Colombia: Ministerio de Educación Nacional; 1983.\n\nNational Center for Biotechnology Information (US): Submitting Sequences using Specific NCBI Submission Tools. The GenBank Submissions Handbook. Bethesda, MD: National Center for Biotechnology Information (US); 2014; p. NBK566995\n\nNational Center for Biotecnology Information: table 2asn_gff.2020.\n\nOkamoto KW, Langerhans RB, Rashid R, et al.: Microevolutionary patterns in the common caiman predict macroevolutionary trends across extant crocodilians. Biol. J. Linn. Soc. 2015; 116: 834–846. Publisher Full Text\n\nOliveira VCS, Viana PF, Gross MC, et al.: Looking for genetic effects of polluted anthropized environments on Caiman crocodilus crocodilus (Reptilia, Crocodylia): A comparative genotoxic and chromosomal analysis. Ecotoxicol. Environ. Saf. 2021; 209: 111835. PubMed Abstract \| Publisher Full Text\n\nPeng Y, Leung HC, Yiu SM, et al.: IDBA-UD: A de novo assembler for single-cell and metagenomic sequencing data with highly uneven depth. Bioinformatics. 2012; 28: 1420–1428. PubMed Abstract \| Publisher Full Text\n\nPimenta NC, Barnett AA, Botero-Arias R, et al.: When predators become prey: Community-based monitoring of caiman and dolphin hunting for the catfish fishery and the broader implications on Amazonian human-natural systems. Biol. Conserv. 2018; 222: 154–163. Publisher Full Text\n\nRice ES, Kohno S, St John J, et al.: Improved genome assembly of American alligator genome reveals conserved architecture of estrogen signaling. Genome Res. 2017; 27: 686–696. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nRoberto IJ, Bittencourt PS, Muniz FL, et al.: Unexpected but unsurprising lineage diversity within the most widespread Neotropical crocodilian genus Caiman (Crocodylia, Alligatoridae). Syst. Biodivers. 2020; 18: 377–395. Publisher Full Text\n\nShen W, Le S, Li Y, et al.: SeqKit: A cross-platform and ultrafast toolkit for FASTA/Q file manipulation. PLoS ONE. 2016; 11: e0163962. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nShumate A, Salzberg SL: Liftoff: accurate mapping of gene annotations. Bioinformatics. 2020. In press.\n\nSmit A, Hubley R, Grenn PRepeatMasker Open-4.0.2015.\n\nTelatin A: Proch::N50.2018.\n\nUS Fish and Wildlife Service: Common Caiman (Caiman crocodilus) Ecological Risk Screening Summary. Technical report. US Fish and Wildlife Service; 2018.\n\nValencia-Aguilar A, Cortés-Gómez AM, Ruiz-Agudelo CA: Ecosystem services provided by amphibians and reptiles in Neotropical ecosystems. Int. J. Biodivers. Sci. Ecosyst. Serv. Manag. 2013; 9: 257–272. Publisher Full Text" }	[ { "id": "101899", "date": "24 Dec 2021", "name": "Steven Salzberg", "expertise": [ "Reviewer Expertise genomics", "bioinformatics" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper describes the assembly and annotation of a crocodile genome. It’s a very brief note that provides some useful background about the species, Caiman crocodilus, but it needs some additional work before it would be acceptable for indexing. All of the following requests should be quite easy to satisfy, but they are all essential.\nFirst, the data are available on a Zenodo website, but that is unacceptable. All genomic data must be deposited in GenBank, EMBL, or DDBJ, and made available for any scientific publication. This practice has been near-universal for the past 25 years. The authors seem to know this, because they state that the assembly has been submitted to NCBI (the home of GenBank). However, the paper fails to provide GenBank accession numbers or a BioProject identifier. The authors need to get these identifiers and put them in the manuscript before the paper can be accepted. NCBI routinely provides such identifiers prior to publication.\nSecond, the raw reads are also at their Zenodo site, which again is not adequate. They need to deposit them either in SRA or ENA, and provide the accession numbers for those as well.\nThird, because the paper does not provide anything other than a brief description of the methods used for assembly and annotation, it needs at least a cursory effort at quality evaluation. For the assembly, the authors could run Merqury to get an overall base-level quality value. That’s a really minimal step. A more thorough step would be to run QUAST to estimate the number of mis-assemblies. This is especially important with an assembly based only upon short Illumina reads.\nThe other missing part is at least a short discussion of the annotation results. They mapped over the annotation from an alligator genome, which is fine, but they don’t report any numbers other than the total number of “features,” which is nearly 300,000. How many protein-coding genes did they annotate? How many non-coding RNAs? How many total protein-coding transcripts, and total transcripts of all types? These numbers are very easy to extract and the authors should at least comment on them.\nMany of the references are garbled or nonsensical:\nFor example, this is supposedly a reference about the term N50:\nTelatin A: Proch::N50.2018.\nI don’t know what this means.\n\nAnother example is this reference to the RepeatMasker software:\nSmit A, Hubley R, Grenn PRepeatMasker Open-4.0.2015.\nI can't figure out what that is, but the RepeatMasker program is well known and they should reference it properly.\n\nThis reference refers to a piece of unpublished software from NCBI, apparently, and note that it misspells “Biotechnology” in the NCBI name:\nNational Center for Biotecnology Information: table 2asn_gff.2020.\n\nThe reference to Shumate and Salzberg (2020) says \"in press' but that paper was published in June 2021: https://academic.oup.com/bioinformatics/article-abstract/37/12/1639/6035128.\n\nAre the rationale for sequencing the genome and the species significance clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Partly\n\nAre sufficient details of the sequencing and extraction, software used, and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a usable and accessible format, and the assembly and annotation available in an appropriate subject-specific repository? No", "responses": [ { "c_id": "12996", "date": "15 Jan 2025", "name": "Kenichi Okamoto", "role": "Author Response", "response": "Comment: This paper describes the assembly and annotation of a crocodile genome. It’s a very brief note that provides some useful background about the species, Caiman crocodilus, but it needs some additional work before it would be acceptable for indexing. All of the following requests should be quite easy to satisfy, but they are all essential. First, the data are available on a Zenodo website, but that is unacceptable. All genomic data must be deposited in GenBank, EMBL, or DDBJ, and made available for any scientific publication. This practice has been near-universal for the past 25 years. The authors seem to know this, because they state that the assembly has been submitted to NCBI (the home of GenBank). However, the paper fails to provide GenBank accession numbers or a BioProject identifier. The authors need to get these identifiers and put them in the manuscript before the paper can be accepted. NCBI routinely provides such identifiers prior to publication. Second, the raw reads are also at their Zenodo site, which again is not adequate. They need to deposit them either in SRA or ENA, and provide the accession numbers for those as well. Response: We thank the reviewer for highlighting these points. We had planned to update the NCBI identifiers upon acceptance, but now realize the Zenodo references were insufficient substitutes for the NCBI identifiers at the review stage as well. The manuscript has now been updated to include the BioProject Identifier (PRJNA716363) and the Sequence Read Archives (SRR22317059). Comment: Third, because the paper does not provide anything other than a brief description of the methods used for assembly and annotation, it needs at least a cursory effort at quality evaluation. For the assembly, the authors could run Merqury to get an overall base-level quality value. That’s a really minimal step. A more thorough step would be to run QUAST to estimate the number of mis-assemblies. This is especially important with an assembly based only upon short Illumina reads. Response: We had initially hoped to reassure readers about the reliability of our approach by testing it on a de novo Alligator mississippiensis assembly and comparing the resulting genome to the published reference genome for this species. However, we agree with the reviewer that descriptions of comparable assessments on the final Caiman crocodilus assembly itself are needed. We now characterize the misassemblies identified by QUAST and, as we describe in our response to Reviewer #2 as well, our revised manuscript also describes the results from running a BUSCO analysis on the genome assembly. Comment: The other missing part is at least a short discussion of the annotation results. They mapped over the annotation from an alligator genome, which is fine, but they don’t report any numbers other than the total number of “features,” which is nearly 300,000. How many protein-coding genes did they annotate? How many non-coding RNAs? How many total protein-coding transcripts, and total transcripts of all types? These numbers are very easy to extract and the authors should at least comment on them. Response: Reviewer #2 also thought the annotation needed to be better characterized, and we appreciate both reviewers’ constructive suggestions on the relevant summary statistics to include. Our revised manuscript now reports the values requested by the Reviewers, and we comment on them in the context of two other existing crocodilian annotations. Briefly, in response to Reviewer #1's questions, after removing isoforms our annotation contains 18836 functional transcripts, 20020 mRNAs and 15981 coding sequences. The annotation includes 115941 exons and 99960 introns in the coding sequences. Comment: Many of the references are garbled or nonsensical: For example, this is supposedly a reference about the term N50: Telatin A: Proch::N50.2018. I don’t know what this means. Another example is this reference to the RepeatMasker software: Smit A, Hubley R, Grenn PRepeatMasker Open-4.0.2015. I can't figure out what that is, but the RepeatMasker program is well known and they should reference it properly. This reference refers to a piece of unpublished software from NCBI, apparently, and note that it misspells “Biotechnology” in the NCBI name: National Center for Biotecnology Information: table 2asn_gff.2020. The reference to Shumate and Salzberg (2020) says \"in press' but that paper was published in June 2021: https://academic.oup.com/bioinformatics/article-abstract/37/12/1639/6035128. Response: We thank the reviewer for noticing these and have corrected all these references in our revised manuscript." } ] }, { "id": "128753", "date": "28 Apr 2022", "name": "Marc Tollis", "expertise": [ "Reviewer Expertise Comparative genomics", "phylogenetics", "vertebrates" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nA spectacled caiman genome is a welcome contribution to the field, however I believe some additional steps need to be taken before this manuscript can be acceptable for indexing. Fortunately, these steps are standard for most genome reports so the authors should have little problem addressing these issues.\nThe authors give a convincing rationale for sequencing the spectacled caiman genome - it is economically and ecologically important - but I believe they left out a key point. This is the first publicly available caiman genome, and the third member of the Alligatoridae (American and Chinese alligator genomes are available). There are relatively few other crocodilian genomes available (a crocodile and a gharial), so this assembly helps with the lack of crocodilian genomes and fills in an important taxonomical gap for vertebrate comparative genomics. I think the authors can make this point rather easily.\nThe sequencing and assembly steps are well described, as well as the annotation process, however the results of these methods are not well described and thus it is difficult to place the importance of this resource in further proper context. How does the contiguity in terms of N50 compare to other crocodilian (or reptile) genomes? A BUSCO analysis would help provide an estimate of the gene completeness of the genome, and is part of the standard battery of tests for new genome assemblies, but has not been done.\nThe authors report almost 300,000 gene features, but it is not elaborated upon what these features are. How many contain coding sequences? How many contain a Pfam domain? How many contain a reciprocal blast hit with another crocodilian genome? What is the average length of exons and introns, average number of exons per gene? Answers to these questions and a comparison to annotations from other genomes would be essential for understanding the usefulness of this annotation.\nFinally, the authors need to provide the accession numbers or BioProject number that indicates the submissions to NCBI. If the assembly has been submitted as stated in the manuscript, this should be relatively straightforward as the BioProject already exists or the accession number has been issued. The same goes for the raw reads, they should be deposited in the NCBI Short Read Archive and accession numbers should be reported. Zenodo is a good place to keep the assembly that was used for the analyses, but NCBI submission is standard for the field.\n\nAre the rationale for sequencing the genome and the species significance clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Partly\n\nAre sufficient details of the sequencing and extraction, software used, and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a usable and accessible format, and the assembly and annotation available in an appropriate subject-specific repository? Partly", "responses": [ { "c_id": "12997", "date": "15 Jan 2025", "name": "Kenichi Okamoto", "role": "Author Response", "response": "Comment: A spectacled caiman genome is a welcome contribution to the field, however I believe some additional steps need to be taken before this manuscript can be acceptable for indexing. Fortunately, these steps are standard for most genome reports so the authors should have little problem addressing these issues. The authors give a convincing rationale for sequencing the spectacled caiman genome - it is economically and ecologically important - but I believe they left out a key point. This is the first publicly available caiman genome, and the third member of the Alligatoridae (American and Chinese alligator genomes are available). There are relatively few other crocodilian genomes available (a crocodile and a gharial), so this assembly helps with the lack of crocodilian genomes and fills in an important taxonomical gap for vertebrate comparative genomics. I think the authors can make this point rather easily. Response: We thank the reviewer for sharing this evaluation with us. Their point that our assembly can also contribute to vertebrate comparative genomics more broadly had not occurred to us and is well taken. We now raise this point explicitly throughout our revised submission. Comment: The sequencing and assembly steps are well described, as well as the annotation process, however the results of these methods are not well described and thus it is difficult to place the importance of this resource in further proper context. How does the contiguity in terms of N50 compare to other crocodilian (or reptile) genomes? A BUSCO analysis would help provide an estimate of the gene completeness of the genome, and is part of the standard battery of tests for new genome assemblies, but has not been done. Response: Although our initial hope was that assessing our assembly strategy using genomic DNA extracted from an American alligator specimen could help reassure readers, we agree with the reviewer that more thoroughly describing the characteristics of our caiman genome sequence, even if we don’t have another assembly to compare to, was warranted. We therefore appreciate the reviewer identifying which metrics on our results would be of value to readers. We thus revised the manuscript to include further characterizations, including the BUSCO analysis as the reviewer recommended. Briefly, 7480 BUSCO groups were searched, of which 96% were identified as single-copy complete BUSCOs. Furthermore, in response to the reviewer’s comment on comparing contiguity, we now report the results of the QUAST analysis for our common caiman genome, as was suggested by Reviewer #1. Per Reviewer #2’s recommendation, in the revised manuscript, this value is now placed in the context of other crocodilian and selected reptile genomes. Comment: The authors report almost 300,000 gene features, but it is not elaborated upon what these features are. How many contain coding sequences? How many contain a Pfam domain? How many contain a reciprocal blast hit with another crocodilian genome? What is the average length of exons and introns, average number of exons per gene? Answers to these questions and a comparison to annotations from other genomes would be essential for understanding the usefulness of this annotation. Response: We thank the reviewer taking the time to identify the relevant statistics that would better describe our annotation to readers. As we note in our response to Reviewer #1, who had a made a very similar observation, we have revised our manuscript to more thoroughly characterize our annotation along the lines requested by the Reviewers. Briefly, in response to the comment, the annotation includes 15981 coding sequences (excluding isoforms), 9983 pFam domain hits (at E<10^-5), and average length of 562 bps and 4334 bps for exons and introns, respectively and 7.3 exons per coding sequence on average. We have revised our manuscript to report all these values. Finally, we strongly agreed with the Reviewer’s suggestion that placing the annotation in the context of those of other crocodilians could be informative to readers. Thus, in addition to the basic summary statistics about the annotation, we also include in our revision the results of comparing our annotation to other crocodilian genomes. We note that because we based our annotation off an existing American alligator annotation, we evaluated reciprocal blast hits with the Crocodylus porosus (saltwater crocodile) annotation and add in the revision how we found 7894 hits. Comment: Finally, the authors need to provide the accession numbers or BioProject number that indicates the submissions to NCBI. If the assembly has been submitted as stated in the manuscript, this should be relatively straightforward as the BioProject already exists or the accession number has been issued. The same goes for the raw reads, they should be deposited in the NCBI Short Read Archive and accession numbers should be reported. Zenodo is a good place to keep the assembly that was used for the analyses, but NCBI submission is standard for the field. Response: Reviewer #1 also made a very similar point. As we discuss in our response to their comment as well, we have now been issued accession numbers for the assembly and sequence read archive (SRA) and the assembly. We appreciate both reviewers highlighting the need to include these numbers, and the manuscript has now been updated to include the BioProject Identifier (PRJNA716363) and the Sequence Read Archives (SRR22317059)." } ] } ]	1	https://f1000research.com/articles/10-1230
https://f1000research.com/articles/11-346/v1	22 Mar 22	{ "type": "Systematic Review", "title": "CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis", "authors": [ "Yusra Pintaningrum", "Vitriyaturrida .", "Ivana Purnama Dewi", "Hendy Bhaskara Perdana Putra", "Idar Mappangara", "Muzakkir Amir", "Irawan Yusuf", "Agussalim Bukhari", "Vitriyaturrida .", "Ivana Purnama Dewi", "Hendy Bhaskara Perdana Putra", "Idar Mappangara", "Muzakkir Amir", "Irawan Yusuf", "Agussalim Bukhari" ], "abstract": "Background: In-stent restenosis (ISR) remains a major drawback in coronary stenting. The association between the CYP2C19 loss of function (LOF) gene and the prevalence of ISR after coronary stenting remains controversial. Previous studies have produced conflicting results and have been limited by their small population sizes. We conducted this systematic review and meta-analysis to determine the association between the presence of the CYP2C19 LOF gene and the prevalence of ISR. Methods: A systematic online database search was performed until April 2021. The primary outcome was ISR and assessed using OR with 95% CI. Publication bias was assessed using the Newcastle Ottawa Scale. I2 was applied to examine heterogeneities among the studies. Results: A total of 284 patients (four non-randomized controlled trial studies) were included in this study. Two hundred and six patients had wild-type genotypes, while 78 patients had the LOF genotype. Among the 78 patients with the LOF gene, 40 patients had an ISR. Meanwhile, of the 206 patients with a wild-type gene, 69 patients had an ISR. The LOF gene was associated with a higher risk of ISR (OR 95% CI = 2.84 [1.54–5.24], p = 0.0008). A major limitation in our study was the small number of previous studies and small sample sizes. Conclusions: Patients with LOF genes, regardless of the allele variation, treated with clopidogrel, had a higher risk of developing ISR after coronary stenting.", "keywords": [ "CYP2C19", "polymorphism", "coronary in-stent restenosis", "systematic review", "clopidogrel" ], "content": "Introduction\n\nDespite the fact that the prevalence of in-stent restenosis (ISR) has decreased gradually, consistent with stent evolution, ISR remains a major drawback in coronary stenting.1 ISR is defined as stenosis with a diameter > 50% at the stent segment or its edges. In the stent era, ISR is primarily a result of neointimal hyperplasia. Stent implantation causes injury to endothelial cells and induces several complex biological responses, including the activation, proliferation, and migration of smooth muscle cells (SMC) into the endovascular lumen. Vascular smooth muscle cells (VSMCs) play a crucial role in the pathogenesis of vascular diseases, including vascular inflammation and restenosis following angioplasty.2 Stent implantation also stimulates the release of thrombogenic and vasoactive cytokines.3\n\nAn animal study conducted by Niu et al. revealed that expression of the P2Y12 receptor in the vessel wall promoted atherogenesis and VSMC migration from media to intima. Direct activation of P2Y12 also mediates VSMC proliferation.4 Furthermore, thrombin-induced P2Y12 is known to enhance mitogenesis in human SMC.5 Clopidogrel has long been used as a P2Y12 inhibitor.\n\nClopidogrel is converted to an active metabolite by the enzyme CYP2C19. The genes encoding the CYP enzyme are polymorphic, and several variants have been related to increased or decreased activity of the drug. Based on the genetic polymorphism of CYP2C19, wild-type homozygote CYP2C1911 is a powerful metabolizer. However, carriers of CYP2C19 LOF alleles (2, 3, 4, 5) are poorer metabolizers.6 Several studies have been conducted to assess the association between ISR events and CYP2C19 polymorphism.7–10 However, the results are conflicting. Therefore, this study aims to conduct a meta-analysis regarding the association between CYP2C19 LOF genes and ISR events.\n\n\nMethods\n\nThis study was conducted following Cochrane’s methodology and PRISMA guidelines.11 It is registered in the PROSPERO database, registration number: 293424.\n\nWe performed a systematic search of several online databases (Scopus, PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Science Direct, and Research Gate) for all studies on CYP2C19 polymorphism and in-stent restenosis. We used the terms “coronary restenosis” AND “in-stent restenosis” AND “gene polymorphism” AND “CYP2C19” AND “genotype”.\n\nThe criteria included were observational studies or randomized controlled trials (RCTs), which examined the association between gene polymorphism and coronary restenosis after stent implantation. Exclusion criteria included case reports, case series, studies in languages other than English, and non-human studies. Two reviewers (V. and HBPP) independently screened the search results according to the inclusion and exclusion criteria. Any discrepancies were settled through discussion with a third investigator (YP) until a consensus was reached.\n\nThe RCTs were evaluated based on Cochrane methodological criteria. However, the quality of observational studies was evaluated using the Newcastle – Ottawa Scale.12\n\nThe primary endpoint was in-stent restenosis after stent implantation regardless of the type of previous stent.\n\nStatistical analysis was carried out using RevMan 5.4 software (RRID:SCR_003581). All outcomes were assessed as an odds ratio (OR) with a 95% confidence interval (CI). A P-value equal to or less than 0.05 was considered statistically significant. I2 assessed heterogeneity. I2 values less than 25% were defined as low heterogeneity; I2 values between 25% and 50% were defined as moderate heterogeneity, and I2 values greater than 50% were defined as high heterogeneity. A fixed-effects model was used in cases of low or moderate heterogeneity. However, a random-effects model was used when heterogeneity was high.\n\n\nResults\n\nThe initial search identified a total of 43 studies. Of these 43 studies, one article did not contain full text, and 13 studies were duplicates, leaving 29 studies. Of the remaining studies, 20 were excluded due to irrelevant titles or abstracts. Furthermore, five full-text articles were categorized as case reports, reviews, letters to the editor, or did not provide data for calculation. Finally, four observational studies were included in the qualitative synthesis (Figure 1). A total of 284 patients were included in the study. Two hundred and six patients had wild-type genotypes, while 78 patients had a LOF genotype. The quality of the four observational studies is shown in Table 1.\n\nThe patients included in the studies had similar characteristics; they were predominantly male (62%–72%) (Table 2), with a mean age range of 60–66 years, except for the study by Da Costa et al., which did not report their patients’ characteristics.7 The patients in the Wirth et al. study had the highest proportion of diabetes and hypertension compared to the other studies.9\n\nIn most of the studies examined, the wild gene (11) was dominant (in 65%–89% of patients) (Table 2). Only in the study by Da Costa et al. was the wild gene the minority (in only 25% of patients).7 The four selected studies examined different LOF genes. The study by Nozari et al. showed the heterozygote 12 LOF gene.10 In contrast, the study by Da Costa et al. examined LOF heterozygote 12 and homozygote 22 genes without clearly specifying the percentage.7 The study by Zhang et al. only mentioned that the LOF gene has a 2 or 3 allele.8 The study by Wirth et al. stated that the LOF gene has a 2 allele.9\n\nDa Costa et al. did not state clearly the stent type used in their study.7 However, Zhang et al. only used drug-eluting stents (DES).8 Meanwhile, Wirth et al. and Nozari et al. used bare-metal stents (BMS) and DES in their studies without clearly stating the percentages (Table 2).9,10\n\nFrom all of the studies, the only incidence of ISR can be calculated quantitatively. However, regardless of the time of presentation from the stent implantation to ISR detection, it is known that there were forty incidents of ISR in the 78 patients with LOF genes and 69 incidents of ISR in the 206 patients with a wild gene. Furthermore, our analysis found an increased risk of ISR was observed in patients with a LOF gene (OR 95% CI = 2.84 [1.54–5.24], P = 0.0008) (Figure 2).\n\n\nDiscussion\n\nThe response to clopidogrel differs from person to person. Many investigations have been conducted to determine the biological components involved in this variance. Polymorphisms in the liver cytochrome isozyme P450 (CYP2C19, CYP3A4, and CYP3A5), as well as the P2Y12 receptor itself, seem to be the major cause of variation.13,14 The ability of the LOF gene to reduce the clopidogrel response in platelets was the first to be revealed, as seen by enhanced platelet aggregation in terms of CYP2C19 polymorphisms.13\n\nNumerous studies have found that CYP2C19 polymorphisms vary greatly among ethnic groups. In comparison to the white population (25%–35%) and the black population (35%–45%), the Asian population (55–70%) exhibited a greater prevalence rate of the LOF CYP2C19 allele variation (CYP2C19 2 and 3). In comparison to the white population (18%), the Asian population (4%) exhibited a lower frequency of the CYP2C19 GOF variant allele (CYP2C19 17).14\n\nA study by Mega et al. involving 1,477 acute coronary syndrome patients, with primary outcomes characterized by death from nonfatal myocardial infarct (MI), nonfatal stroke, and other cardiovascular causes, showed a significantly higher rate of LOF polymorphism (12.1% versus 8%; P = 0.01) than wild-type CYP2C19.15 For 450 days after clopidogrel therapy, similar results were reported for the rate of stent thrombosis (2.6% versus 0.8%; P = 0.02). Another study of 259 patients using clopidogrel medication for one month after their first MI found that individuals with CYP2C19 polymorphisms had considerably poorer five-year survival (HR = 3.69; 95% CI = 1.69–8.5; P = 0.0005), which was linked to considerably poorer clinical outcomes following coronary stenting.16 In another study, 552 individuals were revealed to have the wild-type CYP2C19 allele, and 245 had at least one of two alleles. Patients who were homozygous for the wild-type gene had considerably lower platelet aggregation levels than those with two alleles (11% versus 23%; P < 0.0001).17\n\nThe present study showed a significant association between ISR risk and the LOF gene. The odds of ISR were 2.8% higher in the LOF gene compared to the wild gene. The wild gene can metabolize clopidogrel more effectively than the LOF gene. Zhang et al. and Nozari et al. stated that they used clopidogrel 75mg in their study.8,10 Moreover, Zhang et al. also had a third group of patients with the LOF gene who were administered a double dose of clopidogrel (150 mg). There were no significant differences in this group compared to patients with the wild gene who were given a normal dose of clopidogrel (75 mg).8\n\nThe first choice for a clopidogrel resistance management strategy is to increase the dose of clopidogrel, with the current loading dose for clopidogrel being 300 mg. A larger loading dosage of 600 mg was compared to a lower loading dosage of 300 mg in two studies. Cuisset et al. randomly selected 292 patients undergoing stenting for non-ST elevation myocardial infarction (STEMI) to receive a loading dose of either 300 mg or 600 mg 12 hours before percutaneous coronary intervention (PCI). One month after the intervention, all patients were administered aspirin 160 mg and clopidogrel 75 mg daily. The 600 mg loading dosage group demonstrated reduced adenosine diphosphate (ADP) induced platelet aggregation and P-selection expression compared to the 300 mg loading dosage group.\n\nFurthermore, there were fewer cardiovascular incidents in the 600 mg loading dosage group after one month (7 vs 18 events; P = 0.02).18 One hundred and forty-eight patients undergoing elective PCI were randomly assigned to three groups in a study conducted by L’Allier et al. Group A patients were administered 75 mg clopidogrel on the morning of the procedure and 300 mg clopidogrel a day (≥15 hours) before the procedure. Group B patients were administered 600 mg clopidogrel in the morning (≥2 hours) of the procedure. Meanwhile, group C patients were administered 600 mg clopidogrel on the morning of the procedure and 600 mg clopidogrel a day before the procedure. Group C revealed substantially higher relative inhibition of peak and final ADP-stimulated platelet aggregation than groups A and B. Thus, it appears that a successive 600 mg/dose of clopidogrel bolus resulted in more substantial platelet inhibition than a single loading dosage.19\n\nThe effectiveness of a daily maintenance dosage of clopidogrel 150 mg in patients undergoing elective PCI was examined in a study by Angiolillo et al. Both groups of patients continued medication for 30 days before returning to the regular dose. ADP-induced platelet aggregation (20 μM) was higher in 75 mg clopidogrel/day patients than in 150 mg clopidogrel/day individuals (64% versus 52.1%; P < 0.001).20 The VerifyNow test evaluated relative platelet aggregation in response to 5 μM ADP (45.1% vs 65.3%; P < 0.001), and platelet function inhibition (60 versus 117; P = 0.004) was substantially improved in patients who received clopidogrel 150 mg compared to those given 75 mg.20\n\nA larger trial of 153 individuals with a low clopidogrel response (platelet reactivity index 69%) to 75 mg/day or 150 mg/day (n = 95 or n = 58) clopidogrel found similar results. After two weeks of therapy, clopidogrel 150 mg/day was linked with a considerably lower platelet reactivity index than 75 mg/day (43.9% versus 58.6%; P < 0.001). After switching to clopidogrel 150 mg/day for two weeks, 20 out of 31 patients in the 75 mg/day group were responsive (platelet reactivity was 69%).21 Overall, the outcomes of this study point to the possibility of employing higher clopidogrel bolus and maintenance dosages.\n\nOther alternative drugs include prasugrel, ticagrelor and cilostazol. Although there is limited evidence to suggest that using prasugrel interacts with proton pump inhibitors (PPIs) via cytochrome P450, a study of TRITON-TIMI 38 and PRINCIPLES 44 showed that PPIs did not affect the efficacy of prasugrel. Thus, the use of PPIs with prasugrel is preferable. Ticagrelor is a new platelet aggregation inhibitor. Ticagrelor, like clopidogrel, binds to P2Y12, which acts as an antagonist to the ADP receptor on platelets, preventing platelet aggregation.\n\nUnlike clopidogrel, ticagrelor reversibly binds to P2Y12 and does not displace ADP from the receptor, allowing it to target 2-MeS-ADP-induced signalling. Furthermore, because ticagrelor does not need hepatic enzymatic activation, it is more consistent in reducing platelet aggregation. It has a lower risk of medication interactions and is not affected by CYP polymorphisms.22\n\nCilostazol suppresses cAMP degradation in platelets by inhibiting platelet aggregation via phosphodiesterase-3-blockers. As a result, cilostazol may be an option for people who are resistant to clopidogrel. In patients receiving contemporary stent-based percutaneous procedures, using cilostazol in combination with clopidogrel and aspirin may minimize restenosis cerebral and cardiac side effects.23 As a result, cilostazol is more beneficial than clopidogrel at high maintenance dosages. However, cilostazol was terminated more often in this trial due to the adverse effects.\n\nShim et al. randomly categorized 400 patients who underwent successful PCI with DES into triple antiplatelet therapy (clopidogrel, cilostazol, and aspirin) and dual antiplatelet therapy (clopidogrel and aspirin) groups. They reported a significant decrease in clopidogrel resistance in the triple antiplatelet group (19.7% versus 40%, P < 0.001). As a result, the rate of clopidogrel resistance in patients undergoing PCI with DES can be reduced.24 Several trials compared the effectiveness and safety of using cilostazol with aspirin and clopidogrel in dual antiplatelet therapy (DAPT). Cilostazol combination therapy has significant advantages in major cardiac side effects, death from any cause, cardiac death, target lesion revascularization, and in-segment restenosis. Benefits are reported in patients with clopidogrel resistance.23\n\nSeveral limitations were evident in the present study. First, regarding the association between the LOF gene and ISR, there were limited studies with small sample sizes, which may have limited statistical power. Second, none of the studies included were RCTs. Third, varying types of LOF genes were included in the studies, and some studies did not state clearly whether they were examining homozygote LOF genes or heterozygote LOF genes. Fourth, the studies utilized different stent types and did not clearly state the percentage of BMS and DES used in their studies, as we know that BMS have a higher tendency to form ISR. Fifth, none of the studies used intracoronary imaging. Furthermore, individual patient-level data were not available.\n\n\nConclusions\n\nIn conclusion, the present study supports the theory that, in patients who have undergone coronary stenting and been treated with clopidogrel, the presence of the LOF gene increases their risk of ISR. Furthermore, larger-scale studies are required to examine appropriate strategies in patients with the LOF gene who have undergone coronary stenting.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nFigshare: PRISMA checklist for ‘CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis’. https://doi.org/10.6084/m9.figshare.19312115.11\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0)", "appendix": "References\n\nShlofmitz E, Iantorno M, Waksman R: Restenosis of Drug-Eluting Stents: A New Classification System Based on Disease Mechanism to Guide Treatment and State-of-the-Art Review. Circ. Cardiovasc. Interv. 2019; 12: e007023. PubMed Abstract \| Publisher Full Text\n\nMansour A, Bachelot-Loza C, Nesseler N, et al.: P2Y12 Inhibition beyond Thrombosis: Effects on Inflammation. Int. J. Mol. Sci. 2020; 21: 1391. PubMed Abstract \| Publisher Full Text\n\nKern MJ, Sorajja P, Lim MJ, et al.: The Interventional Cardiac Catheterization Handbook. 4th ed.Elsevier; 2018.\n\nNiu X, Pi SL, Baral S, et al.: P2Y12 Promotes Migration of Vascular Smooth Muscle Cells Through Cofilin Dephosphorylation During Atherogenesis. Arterioscler. Thromb. Vasc. Biol. 2017; 37: 515–524. PubMed Abstract \| Publisher Full Text\n\nRauch BH, Rosenkranz AC, Ermler S, et al.: Regulation of functionally active P2Y12 ADP receptors by thrombin in human smooth muscle cells and the presence of P2Y12 in carotid artery lesions. Arterioscler. Thromb. Vasc. Biol. 2010; 30: 2434–2442. PubMed Abstract \| Publisher Full Text\n\nBergheanu S, Pons D, Karalis I, et al.: Genetic determinants of adverse outcome (restenosis, malapposition and thrombosis) after stent implantation. Interv. Cardiol. 2020; 2: 147–157. Publisher Full Text\n\nda Costa IR , Borges KF, dos Santos TR , et al.: CYP2C192 polymorphism influenced response to clopidogrel treatment but was not related to restenosis in atherosclerotic smokers. Genet. Mol. Res. 2020; 19. Publisher Full Text\n\nZhang M, Wang J, Zhang Y, et al.: Impacts of CYP2C19 Polymorphism and Clopidogrel Dosing on in-Stent Restenosis: A Retrospective Cohort Study in Chinese Patients. Drug Des. Devel. Ther. 2020; Volume 14: 669–676. PubMed Abstract \| Publisher Full Text\n\nWirth F, Zahra G, Xuereb RG, et al.: CYP2C192 Allele Carrier Status and Coronary In-stent Restenosis: Is There an Association?. J. Explor. Res. Pharmacol. 2018; 3: 55–60. Publisher Full Text\n\nNozari Y, Vosooghi S, Boroumand M, et al.: The impact of cytochrome P450 2C19 polymorphism on the occurrence of one-year in-stent restenosis in patients who underwent percutaneous coronary intervention: A case-match study. Anatol. J. Cardiol. 2015; 15: 348–353. PubMed Abstract \| Publisher Full Text\n\nPintaningrum Y, Vitriyaturrida, Dewi IP, et al.: CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis. Figshare. Dataset. 2022. Publisher Full Text\n\nWells G, Shea B, O’Connell D, et al.: The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.2013. Reference Source\n\nUchiyama S: Clopidogrel Resistance: Identifying and Overcoming a Barrier to Effective Antiplatelet Treatment. Cardiovasc. Ther. 2011; 29: e100–e111. PubMed Abstract \| Publisher Full Text\n\nAkkaif MA, Daud NAA, Sha’aban A, et al.: The Role of Genetic Polymorphism and Other Factors on Clopidogrel Resistance (C.R.) in an Asian Population with Coronary Heart Disease (CHD). Molecules. 2021; 26: 1987. PubMed Abstract \| Publisher Full Text\n\nMega JL, Close SL, Wiviott SD, et al.: Cytochrome P-450 polymorphisms and response to clopidogrel. N. Engl. J. Med. 2009; 360: 354–362. Publisher Full Text\n\nCollet JP, Hulot JS, Pena A, et al.: Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: A cohort study. Lancet. 2009; 373: 309–317. PubMed Abstract \| Publisher Full Text\n\nTrenk D, Hochholzer W, Fromm MF, et al.: Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J. Am. Coll. Cardiol. 2008; 51: 1925–1934. Publisher Full Text\n\nCuisset T, Frere C, Quilici J, et al.: High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J. Thromb. Haemost. 2006; 4: 542–549. PubMed Abstract \| Publisher Full Text\n\nL’Allier PL, Ducrocq G, Pranno N, et al.: Clopidogrel 600-mg double loading dose achieves stronger platelet inhibition than conventional regimens: Results from the PREPAIR randomized study. J. Am. Coll. Cardiol. 2008; 51: 1066–1072. PubMed Abstract \| Publisher Full Text\n\nAngiolillo DJ, Capranzano P, Goto S, et al.: A randomized study assessing the impact of Cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: Results of the OPTIMUS-2 study. Eur. Heart J. 2008; 29: 2202–2211. PubMed Abstract \| Publisher Full Text\n\nAleil B, Jacquemin L, De Poli F, et al.: Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: Results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study. JACC Cardiovasc. Interv. 2008; 1: 631–638. PubMed Abstract \| Publisher Full Text\n\nStorey RF, Melissa Thornton S, Lawrance R, et al.: Ticagrelor yields consistent dose-dependent inhibition of ADP-induced platelet aggregation in patients with atherosclerotic disease regardless of genotypic variations in P2RY12, P2RY1, and ITGB3. Platelets. 2009; 20: 341–348. PubMed Abstract \| Publisher Full Text\n\nTamhane U, Meier P, Chetcuti S, et al.: Efficacy of Cilostazol in reducing restenosis in patients undergoing contemporary stent based PCI: A meta-analysis of randomized controlled trials. EuroIntervention. 2009; 5: 384–393. PubMed Abstract \| Publisher Full Text\n\nShim CY, Yoon SJ, Park S, et al.: The clopidogrel resistance can be attenuated with triple antiplatelet therapy in patients undergoing drug-eluting stents implantation. Intl. Jour. Cardiol. 2009; 134: 351–355. PubMed Abstract \| Publisher Full Text" }	[ { "id": "128371", "date": "04 Apr 2022", "name": "Dyana Sarvasti", "expertise": [ "Reviewer Expertise Cardiovascular Prevention and Rehabilitation" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis meta-analysis study is interesting and useful, although it only involves four non-randomized controlled trials. It can be used as additional knowledge about the management of antiplatelet therapy use in patients undergoing PCI who are suspected of having the presence of the CYP2C19 LOF gene. Unfortunately, the research objectives related to the use of antiplatelets are not fully described in the abstract, even though in the discussion and conclusions there are many mentions of the relationship between LOF genes, ISR, and various types of antiplatelets, especially clopidogrel. If possible, the association of the CYP2C19 LOF gene with antiplatelet use (clopidogrel) should also be addressed in the research objectives in the abstract.\nIn addition, there are some mistypes that need to be corrected. Here are some points related to this:\nIn table 2, it appears that “Cross sectional” is missing a hyphen. Consider adding the hyphen(s). In abbreviations in table 2, It appears that “bare metal” is missing a hyphen. Consider adding the hyphen(s). In abbreviations in table 2, It appears that “drug eluting” is missing a hyphen. Consider adding the hyphen(s). There is an inconsistency in writing the title of the bibliography in the reference list. Sometimes it is written in lower case, sometimes in upper case. Consider making corrections.\nThank you for your kind attention.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Partly\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes", "responses": [ { "c_id": "8332", "date": "07 Jun 2022", "name": "Ivana Purnama Dewi", "role": "Author Response", "response": "Dear Dyana Sarvasti, M.D Thank you for your kind review We will make some corrections regarding your suggestions Best regards, Yusra Pintaningrum, M.D" } ] } ]	1	https://f1000research.com/articles/11-346
https://f1000research.com/articles/8-1727/v1	08 Oct 19	{ "type": "Brief Report", "title": "Neuronal subset-specific Pten-deficient mice do not exhibit deficits in sensorimotor gating processes", "authors": [ "Matthew S. Binder", "Suzanne O. Nolan", "Joaquin N. Lugo", "Matthew S. Binder", "Suzanne O. Nolan" ], "abstract": "Background: Deficits in sensorimotor gating have been reported in individuals with autism spectrum disorder (ASD), as well as in ASD murine models. However, this behavior has been rarely examined in the neuronal subset-specific (NS)-Pten knockout (KO) model of ASD. NS-Pten KO mice exhibit hyperactivity of the PI3K/AKT/mTOR signaling pathway which is implicated in the onset of autistic deficits. This study investigates the potential relationship between PI3K/AKT/mTOR signaling and deficits in sensorimotor gating.\n\nMethods: To assess sensorimotor gating in NS-Pten KO mice we utilized a three-day paradigm. On day 1 (habituation) the mice were administered 80 repetitions of a 120-dB startle stimulus. On day 2, prepulse inhibition was measured with 90 trials of the startle stimulus that was paired with a smaller (70, 75, or 80 dB) prepulse stimulus. Day 3 was assessed one week later, consisting of randomized startle trials and trials with no stimulus and was used to determine the startle threshold. Results: No significant difference between NS-Pten KO or wildtype (WT) mice was found for habituation (p > 0.05). No significant differences were found between groups when assessing the percentage of prepulse inhibition at 70, 75, and 80 dB (p > 0.05). There was also no difference in startle threshold between groups (p > 0.05). Conclusion: Our study found that the NS-Pten KO model does not display significant deficits in sensorimotor gating processes. The present findings help to elucidate the relationship between PI3K/AKT/mTOR hyperactivation and sensory reactivity.", "keywords": [ "autism", "pten", "macrocephaly", "ASD", "sensorimotor" ], "content": "Introduction\n\nSensorimotor gating is the ability of a sensory stimulus to suppress a motor response1. It can be measured by assessing prepulse inhibition (PPI), wherein a weak auditory stimulus inhibits a startle response that is induced by the following presentation of a loud sound2. Deficits in PPI have been widely reported in various neurological conditions, including autism spectrum disorder (ASD)3–5. Similar to humans, impairments in PPI have been reported in ASD models such as Fmr1 and Cntnap2-knockout (KO) mice; however, the underlying mechanism is unknown6,7. Pten mutant mice are another model of autism and can be used to investigate the connection between a cell signaling pathway commonly implicated in ASD, the PI3K/AKT/mTOR pathway, and specific autistic-like deficits8. In the present study, we use neuronal subset-specific (NS)-Pten KO mice that exhibit hyperactivation of the PI3K/AKT/mTOR pathway in the cortex, hippocampus, and cerebellum, and assess PPI in order to further elucidate the potential relationship between PI3K/AKT/mTOR signaling and deficits in sensorimotor gating9.\n\n\nMethods\n\nMale and female mice on a FVB based mixed background were obtained from Baylor College of Medicine and have been bred for more than 10 generations at Baylor University. Heterozygous NS-Pten males (n=6) and females (n=12) were used to breed NS-Pten wildtype (WT) and KO pups (RRID: MGI:3714016). The housing for the breeders consisted of two females housed with one male. Genotype was determined from toe clippings taken on postnatal day (PD) 10 (performed by Mouse Genotype, Escondido, CA, USA). On PD 21, animals were weaned and housed with mixed genotype littermates in groups of n=3–5 in cages (Allentown Caging PC7115HT, Allentown, PA, USA) filled with sani-chip bedding (7090 Teklad, Envigo, Somerset, NJ, USA) kept in a room on a 12-hr light/dark diurnal cycle held at 22°C. Mice had ad libitum access to food and water. All animals were tested at 9–10 weeks of age between the hours of 10:00 and 11:30 a.m. A total of 29 male mice were assessed, 17 NS-Pten KO and 12 WT mice. The target sample size was determined by, and is in accordance with, the PPI literature10–12. The final sample sizes were as follows: day 1: n=12 WT, n=17 KO, day 2: n=12 WT, n=13 KO, day 3: n=9 WT, n=9 KO. All test procedures were carried out in compliance with the NIH Guidelines for the Care and Use of Laboratory Animals and were approved by Baylor University’s Institutional Animal Care and Use Committee. Once the experiment concluded, mice were placed into a CO2 chamber and euthanized.\n\nSensorimotor gating was assessed via the SR-LAB system, which consists of a 15 × 14 × 18 inch isolation cabinet, a plexiglass cylinder (3.2-cm diameter) mounted on a sensor platform, a standard speaker used to generate white noise, and a high-frequency speaker used to generate stimuli (San Diego Instruments, San Diego, CA, USA). The paradigm consisted of three separate testing days: habituation, prepulse inhibition, and startle response, and was conducted as previously described6.Each test day is further detailed in the Figure 1 legend. To eliminate potential confounds during testing, background sound levels were maintained at 68 dB and the experimenter was not present.\n\n(a) On the first day of testing, the animal was acclimated to the room for 30 minutes then was placed inside the cylinder for a 5-minute habituation period, which was followed by 80 startle stimuli delivered at a fixed interval of 15 seconds. The startle stimulus was a 40-ms, 120-dB noise burst, with a rise/fall time of less than 1 ms. We found that there was no significant difference in habituation between KO and WT mice (p > 0.05). (b) Day 2 of testing occurred 24 hours after day 1 and tested prepulse inhibition. Once the mice were in the apparatus, there was a 5-minute habituation phase that was followed by 20 presentations of a 40-ms, 120-dB noise burst that had a fall time of less than 1 ms. In the prepulse phase, mice were presented with 90 trials consisting of three prepulse intensities, 70, 75, and 80 dB. Each prepulse was 20 ms in duration with a rise/fall time of less than 1 ms and were spaced 15 seconds apart. We found no difference in the percentage of prepulse inhibition between groups following prepulses of 70, 75, or 80 dB (p > 0.05). (c) One week after the prepulse session, the startle threshold was assessed. Following the 5-minute habituation period, the mice were presented with 99 trials of 11 trial types. These include a no stimulus trial and 10 startle stimuli trials ranging from 75–120 dB at 5 dB intervals. The startle stimuli are 40 ms noise bursts with a rise/fall of less than 1 ms. The 11 trial types were pseudorandomized, with each trial type being presented once in a block of the 11 trials. We observed no difference in startle threshold between NS-Pten KO and WT mice (p > 0.05). Data are presented as the mean ± standard error of the mean (SEM).\n\nGraphPad Prism 7 software (La Jolla, CA) or SPSS 21.0 (IBM, USA) were used to analyze the data. Repeated-measure ANOVAs were run for habituation, prepulse inhibition, and startle threshold. No post-hoc tests were performed. A total of n=4 KO mice were excluded from the day 2 analysis and n=11 mice (3 WT and 8 KO) were excluded from the day 3 analysis due to protocol malfunction or death as a result of the severity of the knockout. A value of p < 0.05 was considered significant for each statistical test.\n\n\nResults\n\nWhen assessing the sensorimotor gating paradigm, no main effects were found for habituation (F[1,27] = 0.17, p >0.05), prepulse inhibition (F[1,23] = 2.65, p >0.05) or startle threshold (F[1,16] = 2.33, p >0.05). There were also no interactions for habituation (F[7,189] = 0.91, p >0.05), prepulse inhibition (F[2,46] = 0.71, p >0.05), or startle threshold (F[10,160] = 1.94, p >0.05) (Figure 1a–c). Raw results for each procedure on each day for every animal are available as Underlying data13.\n\n\nDiscussion\n\nThe NS-Pten KO mice did not exhibit significantly different sensorimotor gating from WT mice. A previous study by Kwon et al. (2006) assessed neuron-specific enolase (Nse)-Pten KO mice in a variation of the PPI protocol and reported a decrease in percent inhibition at 4 dB but no differences at 8 or 16 dB10. Our study assessed percent inhibition at 70, 75, and 80 dB, per established protocol, and found no differences at these intensity6. Therefore, this indicates that there may only be changes in percent inhibition in Pten mutant mice when the prepulse is comparatively quiet, as no impairments are reported for dB levels higher than 4 dB. Additionally, in accordance with our study, no differences in prepulse inhibition have been reported in the BTBR and Shank1 mouse models of autism14,15. This indicates that alterations in sensory reactivity may be a less sensitive measure of an autistic-like phenotype and may also only be present in particular ASD models.\n\nOverall, the current study found that hyperactivity of the PI3K/AKT/mTOR pathway does not result in sensorimotor gating deficits in NS-Pten KO mice, suggesting that the pathway may not directly affect prepulse inhibition. This conclusion is supported by a prior study that assessed PPI in a transgenic mouse model of tuberous sclerosis complex, another model of ASD and mTOR hyperactivation, which similarly reported no deficits in prepulse inhibition between WT and KO mice16. Taken together, these studies indicate that despite mTOR’s contribution to an autistic-like phenotype, it does not significantly contribute to the onset of sensorimotor gating deficits in several different ASD models. Ultimately, our study is in support of the literature and helps to further elucidate the relationship between hyperactivation of the PI3K/AKT/mTOR pathway and deficits in sensory reactivity.\n\n\nData availability\n\nFigshare: Neuronal subset-specific Pten-deficient mice do not exhibit deficits in sensorimotor gating processes. https://doi.org/10.6084/m9.figshare.9885401.v113.\n\nThis project contains the following underlying data:\n\nPPI Day1 Pten Raw Data 9-6.xlsx (raw data from all experiments performed for all animals; day 1).\n\nPPI Day 2 Pten Raw Data 9-6.xlsx (raw data from all experiments performed for all animals; day 2).\n\nPPI day 3 Pten Raw Data 9-6.xlsx (raw data from all experiments performed for all animals; day 3).\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).", "appendix": "Acknowledgements\n\nWe would like to thank Samantha Hodges and Paige Womble for their critical review of the paper. The authors do not have any conflicts of interest to declare.\n\n\nReferences\n\nPowell SB, Weber M, Geyer MA: Genetic models of sensorimotor gating: relevance to neuropsychiatric disorders. Curr Top Behav Neurosci. 2012; 12: 251–318. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHiroi N, Nishi A: Chapter 17 - Dimensional Deconstruction and Reconstruction of CNV-Associated Neuropsychiatric Disorders. In: M.V. Pletnikov, J.L. Waddington (Eds.), Handbook of Behavioral Neuroscience, Elsevier. 2016; 23: 285–302. Publisher Full Text\n\nMadsen GF, Bilenberg N, Cantio C, et al.: Increased prepulse inhibition and sensitization of the startle reflex in autistic children. Autism Res. 2014; 7(1): 94–103. PubMed Abstract \| Publisher Full Text\n\nMena A, Ruiz-Salas JC, Puentes A, et al.: Reduced Prepulse Inhibition as a Biomarker of Schizophrenia. Front Behav Neurosci. 2016; 10: 202. 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PubMed Abstract \| Publisher Full Text\n\nLugo JN, Smith GD, Arbuckle EP, et al.: Deletion of PTEN produces autism-like behavioral deficits and alterations in synaptic proteins. Front Mol Neurosci. 2014; 7: 27. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKwon CH, Luikart BW, Powell CM, et al.: Pten regulates neuronal arborization and social interaction in mice. Neuron. 2006; 50(3): 377–388. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKokash J, Alderson EM, Reinhard SM, et al.: Genetic reduction of MMP-9 in the Fmr1 KO mouse partially rescues prepulse inhibition of acoustic startle response. Brain Res. 2019; 1719: 24–29. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBrody SA, Dulawa SC, Conquet F, et al.: Assessment of a prepulse inhibition deficit in a mutant mouse lacking mGlu5 receptors. Mol Psychiatry. 2004; 9(1): 35–41. PubMed Abstract \| Publisher Full Text\n\nLugo J, Binder M, Nolan S: Neuronal subset-specific Pten-deficient mice do not exhibit deficits in sensorimotor gating processes. figshare. Dataset. 2019. http://www.doi.org/10.6084/m9.figshare.9885401.v1\n\nSilverman JL, Yang M, Turner SM, et al.: Low stress reactivity and neuroendocrine factors in the BTBR T+tf/J mouse model of autism. Neuroscience. 2010; 171(4): 1197–1208. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSilverman JL, Turner SM, Barkan CL, et al.: Sociability and motor functions in Shank1 mutant mice. Brain Res. 2011; 1380: 120–137. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nChévere-Torres I, Maki JM, Santini E, et al.: Impaired social interactions and motor learning skills in tuberous sclerosis complex model mice expressing a dominant/negative form of tuberin. Neurobiol Dis. 2012; 45(1): 156–164. PubMed Abstract \| Publisher Full Text \| Free Full Text" }	[ { "id": "55104", "date": "16 Oct 2019", "name": "Benjamin K. Yee", "expertise": [ "Reviewer Expertise Prepulse inhibition", "Behavioural phenotyping of mutant mice", "animal models of schizophrenia" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nWhether sensorimotor gating, as evaluated by the prepulse inhibition (PPI) of the acoustic startle reflex paradigm, is attenuated or exaggerated in ASD is still controversial. The present study attempted to investigate this using a mutant mouse model. Specifically, neuronal deletion of Pten in the mouse is expected to result in P13K/AKT/mTOR hyperactivity implicated in ASD onset. The study may potentially clarify whether this genetic manipulation would be sufficient to modify PPI expression. No difference between mutants and wild type (WT) mice was reported. Indeed, the magnitude, habituation and threshold of the startle response as such were reported to be highly comparable between genotypes. The null results led the authors to conclude that the contribution of the mTOR pathway to ASD-related PPI deficits is limited. Closer examination of the methods and data reveal significant concerns that undermine confidence in the reliability and robustness of the reported findings.\n\nNo attempt was made to examine sex difference, while it is highly relevant to ASD.\n\nMethodology details were not sufficient. Essential test parameters such as ITI and SOA in prepulse-pulse trials were not reported. Wide of response window was not reported, although it could be discerned from the raw data file.\n\nApparently, 8 (out of 17) mutant mice died from Experiment 1 to Experiment 3. This led one to suspect that the mutant mice had serious and widespread physiological defects, which could undermine any meaningful comparison. One would like to see body weights reported at least. Were the mutants significantly lighter?\n\nStatistical results are poorly reported. Only “main effects” (supposedly the genotype effects) were considered. Statistics towards ascertaining the presence of startle habituation (e.g., Trials or blocks of 10 trials effects), and prepulse inhibition (the effect of prepulse intensities) etc. are not provided. To report that “no main effects were found for habituation F(1,27)=…” is inappropriate, because the comparison of habituation between genotypes could only be meaningfully evaluated by reference to the Genotype x Blocks of 10 trials interaction. Reporting the main effect of Genotype does not allow an effective assessment of the habituation profile, merely the overall magnitude of startles.\n\nThe plot shown in Figure 1a cannot be reproduced from the raw data provided.\n\nIt is also observed that the first trial of Day 1 data were all very low (in all mice). This is highly unusual and may indicate a protocol failure, or misalignment of data.\n\nExamination of Day 2 data for PPI assessment also reveals another anomaly. At least 4 mice (ID: 2081, 2084, 2085, 2072) exhibited very weak startle values (well under 100) in all “120startle” trials – substantially lower than the startle magnitude obtained on the previous startle habituation test. The change is massive and inexplicable. The problem may be more extensive and include other mice. The authors should exercise due diligence in examining their data before analysis.\n\nIn their discussion of Kwon et al.’s (2006) reported findings of a PPI deficit (Nse)-Pten KO mice, the authors mistook the prepulses at 4dBm 8dB and 16dB as the actual magnitude of the prespulses used by Kwon et al. In fact, these refer to prepulse of intensity at 4, 6 and 18 decibels units above background. The use of 70, 75 and 80dB prepulses here were presented against a background noise level of 68dB, and thus effectively be +2, +7 and +12 decibel units above background. Hence, it is incorrect to conclude (by comparison between the present study and Kwon et al.) that “there may only be changes in percent inhibition in Pten mutant mice when the prepulse in comparatively quiet”. If anything, the +2 (or 70 dB) condition here was even lower than the weakest prepulse used by Kwon et al.\n\nThe authors evaluated the startle reactivity curve as a function of increasing pulse intensity – as a means to examine the “startle threshold”. Yet no attempt was made to measure individual startle threshold for comparison between genotypes. Otherwise, it is misleading to conclude that threshold did not differ when only the group’s average profile was presented.\n\nHence, although the available data tend to support the overall lack of an effect of the gene KO on PPI, the methods, presentation, data analysis are clearly inadequate.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Partly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "5195", "date": "11 Feb 2020", "name": "Joaquin Lugo", "role": "Author Response", "response": "Reviewer comments are first followed by a bullet point of our response. No attempt was made to examine sex difference, while it is highly relevant to ASD. Thank you for your comment. Previous studies investigating the adult phenotype in the NS-Pten model only assessed males (see citations 9 and 10 in the document). Moreover, a similar study that assessed PPI using the Nse-Pten mouse also only investigated males (citation 11). In order to best align our study with other pertinent studies, and to provide similar points of comparison, we also only assessed male mice, acting in accordance with the literature. Methodology details were not sufficient. Essential test parameters such as ITI and SOA in prepulse-pulse trials were not reported. Wide of response window was not reported, although it could be discerned from the raw data file. The methods section has been modified to state that the SOA was 100 ms and to clarify that the ITI in the PPI procedure was an average of 15 seconds with individual trials ranging from 7-23 seconds. Apparently, 8 (out of 17) mutant mice died from Experiment 1 to Experiment 3. This led one to suspect that the mutant mice had serious and widespread physiological defects, which could undermine any meaningful comparison. One would like to see body weights reported at least. Were the mutants significantly lighter? Per your suggestion, the weight data for WT and KO mice across each testing timepoint were analyzed. No differences in weight were found between WT and KO mice at any test point. NS-Pten KO mice do present with spontaneous seizures that can result in death, however, the KO mice that did not die prematurely did not display a significantly different weight from the controls, indicating that their constitution was sufficient to reliably assess the effects of PPI. Furthermore, our timepoints of testing are in accordance with the literature, making our comparison with other studies valid. Lastly, a graph of the weight data comparing WT to control mice per each testing timepoint has been created and has been uploaded. Statistical results are poorly reported. Only “main effects” (supposedly the genotype effects) were considered. Statistics towards ascertaining the presence of startle habituation (e.g., Trials or blocks of 10 trials effects), and prepulse inhibition (the effect of prepulse intensities) etc. are not provided. To report that “no main effects were found for habituation F(1,27)=…” is inappropriate, because the comparison of habituation between genotypes could only be meaningfully evaluated by reference to the Genotype x Blocks of 10 trials interaction. Reporting the main effect of Genotype does not allow an effective assessment of the habituation profile, merely the overall magnitude of startles. Thank you for your input, the results section has been updated to better specify the statistical tests run and the corresponding results. Additionally, the overall statistical design of the study has been added to the statistical analysis section in the methods. Regarding the statistical measure used, we agree with you that a main effect by itself is not sufficient to best assess the data, that is why we also included the statistics for the interactions of each test. For habituation, no interactions were found, indicating that the stated results are an effective assessment of the habituation profile and that our statistics were not improper. In light of your comment, the results section has been reworded in order to better highlight this and to clarify any ambiguity. The plot shown in Figure 1a cannot be reproduced from the raw data provided. The plot shown in figure 1 a was created by taking the data in the T-AB columns in the excel document for the habituation day then pasting them into a grouped data file in Graphpad. The x axis for the grouped file was the trials 1-10, 11-20, etc and group A was the WT whereas group B was the KO. All data analyzed and graphed came from the corresponding excel documents. It is also observed that the first trial of Day 1 data were all very low (in all mice). This is highly unusual and may indicate a protocol failure, or misalignment of data. We do not understand this comment. The first trial in day 1 shows the largest startle response. Please clarify your comment. Examination of Day 2 data for PPI assessment also reveals another anomaly. At least 4 mice (ID: 2081, 2084, 2085, 2072) exhibited very weak startle values (well under 100) in all “120startle” trials – substantially lower than the startle magnitude obtained on the previous startle habituation test. The change is massive and inexplicable. The problem may be more extensive and include other mice. The authors should exercise due diligence in examining their data before analysis. We ran additional analysis to examine this, specifically, the mice in question were removed from analysis and the analysis was rerun excluding them, no difference between genotype was found (F(1,20) = .17, p = .69). Therefore, the results and conclusions in the paper remain consistent. Additionally, the protocol run for those mice was in compliance with all of the other trials and no oddities were documented, indicating that the lower values may be an artifact of the mouse that was being run. Due to this, and to avoid undue manipulation within the groups, all of the mice were included. In their discussion of Kwon et al.’s (2006) reported findings of a PPI deficit (Nse)-Pten KO mice, the authors mistook the prepulses at 4dBm 8dB and 16dB as the actual magnitude of the prespulses used by Kwon et al. In fact, these refer to prepulse of intensity at 4, 6 and 18 decibels units above background. The use of 70, 75 and 80dB prepulses here were presented against a background noise level of 68dB, and thus effectively be +2, +7 and +12 decibel units above background. Hence, it is incorrect to conclude (by comparison between the present study and Kwon et al.) that “there may only be changes in percent inhibition in Pten mutant mice when the prepulse in comparatively quiet”. If anything, the +2 (or 70 dB) condition here was even lower than the weakest prepulse used by Kwon et al. Thank you for pointing this out. The discussion has been amended with a more specific interpretation of Kwon et al’s (2006) findings. Furthermore, additional explanations have been made to explain any differences in results. The authors evaluated the startle reactivity curve as a function of increasing pulse intensity – as a means to examine the “startle threshold”. Yet no attempt was made to measure individual startle threshold for comparison between genotypes. Otherwise, it is misleading to conclude that threshold did not differ when only the group’s average profile was presented. We believe that the repeated measures ANOVA with genotype as the between-subjects factor and stimulus intensity as the within subjects factor is sufficient to adequately, and thoroughly, assess the data. Specific details further explaining our statistics have been added to the paper to help clarify any confusion." } ] }, { "id": "54867", "date": "08 Nov 2019", "name": "Maarten van den Buuse", "expertise": [ "Reviewer Expertise Prepulse inhibition", "animal models of psychiatric disease." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis Brief Report shows that a specific Pten-deficient mouse model shows no change in prepulse inhibition compared to wildtype controls. This is discussed in the context of literature about changes in PPI in humans with autism and in autism animal models. Albeit negative, this report could then be of value as an additional component of this literature. Unfortunately there are some problems with the study and the way it is presented.\n\nAbstract, background:\n\"has been rarely examined” - does this mean it has been examined once before? What was the result?\n\nIntroduction:\nIt would be helpful if the neuronal subset-specific Pten KO mouse was described in more detail. What do we know about behavioural changes in this mouse model. Importantly, were there deficits in social behaviour? If this has not been published yet, it would be good to add some of those additional behavioural tests here.\n\nMethods, subjects:\nWhy were only males included in the study?\n\nMethods, sensorimotor gating:\nAs far as I know, the SR-LAB system has only one speaker and there is no “high-frequency” speaker (what is that anyway) to produce the stimuli.\n\nMethods, sensorimotor gating:\nIt would be more clear if the prepulses were described as level over background, i.e. PP2, PP7 and PP12.\n\nMethods, sensorimotor gating:\nWhat was the interval between the onset of the prepulse and the onset of the startle pulse (SOA)? What was the interval between various trials in the PPI protocol (ITI)? Is it, like the figure legend suggests, always 15 seconds? This would be unusual because the ITI is variable in most of the PPI literature.\n\nResults:\nDetails of the statistical analysis are missing. In the Statistical Analysis section in the Methods, or in the Results section, it has to be explained what the between-group and within-group factors are and main effects and importantly interactions between those factors have to be detailed. For example, for PPI, was there a prepulse intensity x genotype interaction?\n\nDiscussion:\nAgain, it would be more clear if the prepulses were described as level over background, i.e. PP2, PP7 and PP12. This would allow better comparison with previous studies.\n\nFigure 1:\nAlong the horizontal axis do not use labels at an angle.\n\nFigure 1, legend:\nA lot of technical detail here should be included in the Methods section, not in a figure legend. There is also no need to constantly repeat rise-fall times. This can be mentioned once in the Methods as a feature of all stimuli.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate? No\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "5196", "date": "11 Feb 2020", "name": "Joaquin Lugo", "role": "Author Response", "response": "Reviewer 2. The original comments are first followed by a bullet point with our response.Abstract, background:\"has been rarely examined” - does this mean it has been examined once before? What was the result? Thank you for your comment. The sentence has been modified to clarify that no other study has assessed prepulse inhibition in neuronal subset specific KO mice. Introduction: It would be helpful if the neuronal subset-specific Pten KO mouse was described in more detail. What do we know about behavioural changes in this mouse model. Importantly, were there deficits in social behaviour? If this has not been published yet, it would be good to add some of those additional behavioural tests here. Per your insight, a sentence has been added into the introduction that details the established behavioral phenotype of NS-Pten KO mice, clarifying that this model presents with deficits in repetitive behavior, sociability, and communication. Methods, subjects: Why were only males included in the study? Previous studies investigating the adult phenotype in the NS-Pten model only assessed males (see citations 9 and 10 in the document). Moreover, a similar study that assessed PPI using the Nse-Pten mouse also only investigated males (citation 11). In order to best align our study with other pertinent studies, and to provide similar points of comparison, we also only assessed male mice, acting in accordance with the literature. Methods, sensorimotor gating:As far as I know, the SR-LAB system has only one speaker and there is no “high-frequency” speaker (what is that anyway) to produce the stimuli. It has been clarified in the methods that 1 speaker was used to generate the white noise and startle stimuli. Methods, sensorimotor gating:It would be more clear if the prepulses were described as level over background, i.e. PP2, PP7 and PP12. Thank you for your suggestion, the methods have been changed to discuss the prepulses used as being relative to the background noise. Methods, sensorimotor gating:What was the interval between the onset of the prepulse and the onset of the startle pulse (SOA)? What was the interval between various trials in the PPI protocol (ITI)? Is it, like the figure legend suggests, always 15 seconds? This would be unusual because the ITI is variable in most of the PPI literature. The methods section has been modified to state that the SOA was 100 ms and to clarify that the ITI in the PPI procedure was an average of 15 seconds with individual trials ranging from 7-23 seconds. Results:Details of the statistical analysis are missing. In the Statistical Analysis section in the Methods, or in the Results section, it has to be explained what the between-group and within-group factors are and main effects and importantly interactions between those factors have to be detailed. For example, for PPI, was there a prepulse intensity x genotype interaction? Per your insight, the statistical analysis section now clarifies what the between subjects and within subjects’ factors are for each test day. Additionally, the results section has been amended to make it clearer that there were no main effects or interactions present for any test day. Discussion:Again, it would be more clear if the prepulses were described as level over background, i.e. PP2, PP7 and PP12. This would allow better comparison with previous studies. The discussion section now refers to the prepulses in terms of their increase over the background level (ppi 2,7, and 12 dB) in order to make clearer comparisons to other studies. Figure 1:Along the horizontal axis do not use labels at an angle. The labels on the x axis for all figures are now horizontal. Figure 1, legend:A lot of technical detail here should be included in the Methods section, not in a figure legend. There is also no need to constantly repeat rise-fall times. This can be mentioned once in the Methods as a feature of all stimuli. The detail concerning each testing day has been moved to the methods section. Also, the rise fall times are now only mentioned once." } ] } ]	1	https://f1000research.com/articles/8-1727
https://f1000research.com/articles/13-778/v1	09 Jul 24	{ "type": "Research Article", "title": "Alternative dispute resolution: Mediation as a model", "authors": [ "Naser Sherman", "Bashar Talal Momani" ], "abstract": "Background The topic of Alternative Dispute Resolution (ADR) in civil and commercial contexts presents a contemporary legal challenge aimed at fostering equitable solutions. Among ADR methods, mediation stands out for its ability to reduce time, costs, and litigation duration. This study explores the conceptual framework, essential conditions, and procedural aspects of mediation. It evaluates the sufficiency, regulation, and effectiveness of mediation principles in conflict resolution and risk mitigation.\n\nMethods This study is conducted through a comprehensive review of current literature on Alternative Dispute Resolution methods, with a particular focus on mediation as an alternative to dispute settlement. The study utilizes qualitative analysis techniques to examine the effectiveness of mediation principles and their application in resolving civil and commercial disputes. Comparative analyses are also conducted to extract useful insights from various legal systems and authorities.\n\nResults The study provides an analysis that illustrates the effectiveness of mediation in resolving disputes, emphasizing its potential benefits in terms of time and cost savings, as well as its srole in facilitating amicable resolutions. The results of this study shall contribute to the current body of knowledge on mediation and provide practical recommendations for its application in diverse legal contexts.\n\nConclusion In conclusion, the study proposes strategies to enhance mediation practices, promote a culture of its adoption, and integrate it more closely into the judicial system. Additionally, it anticipates the future effectiveness of mediation in jurisdictions lacking comprehensive legislation, drawing from successful Western experiences to guide potential developments in Arab legal frameworks.", "keywords": [ "Mediation", "Mediator", "Civil and Commercial Disputes", "Arab Legal systems" ], "content": "1. Introduction\n\nMediation is a general idea that has existed in societies since its inception. However, it did not gain momentum as a legal idea except in contemporary civil and commercial laws. It appeared due to the slowness and complexity of the judiciary in judicial procedures as disputes may take a long time and more expenses, including experts, lawyers, and court fees inter alia. We may add to that the state of hatred between litigants when the court ruling is issued because the judgment in judicial disputes may not be satisfactory to both parties, but it is rather in favor of one over the other. This may be justified for logical and legal reasons. The judiciary seeks to reach the judicial truth which may be in agreement or disagreement with the realistic truth. Mediation was primarily introduced for the purpose of solving these problems. By virtue of this mediation, a third party takes over the study of the dispute and elaborates a solution and a settlement that satisfies the two parties to the dispute. It is an advanced method of resolving disputes between the parties by their agreement. The parties appoint a person called the mediator, whose task is to limit the dispute through the continuity of communication between the parties individually and jointly with the aim of bridging the gap between them so as to meet and agree eventually on a mutual compromise. Mediation then, is a voluntary process in nature, and the mediator may not make a decision that has become the basis of the dispute. Rather, her/his role is limited to trying to conciliate the opposing views of the parties and to proposing alternative solutions before them without imposing any of these on them.\n\nThe research problem revolves around the fact that most of the legislations have not codified legal mediation in an independent law that regulates it as an alternative to resolving disputes and that its provisions are distributed or spread in many laws. Therefore, this paper tries to answer the following questions:\n\n• Can mediation resolve commercial and civil disputes?\n\n• Is mediations considered an alternative to the judiciary in resolving these disputes?\n\n• What are the requirements of a mediator?\n\n\n2. Literature review\n\nMediation is one of the most preoccupying topics for many scholars and researchers given its vital role in resolving civil and commercial disputes. It is also efficient as it saves time (Shi’an and Ahmed, 2017; Hamdan and Frederick, 2014), the topic has been the subject of numerous case studies (Al-Naqash, 2009; Badawi, 2003), unlike ours, have addressed the procedural and confidential methods of resolving disputes (Abdel Reza, 2015; Aqeelah, 2011) and emphasize its role as an alternative method (Dheeb, 2009; Al-Qurtubi, 1985; Ben Belkacem, 2009; Odilqoriev, 2022; Fuad Abd Al-Baqi et al., n.d.; Al-Ahmad, 2008, n.d.; Al-Salibi, 2010, n.d.; Mubarak, 2002; Sadiq, 1982; Al-Nasser and Al-Ghanem, 2003; She’an and Ahmed, 2014, n.d.; Zaki, 1993; Al-Qudah, 2004; Mustafa, 1952; Sloma, 2023; Al-Khafaji and Al-Khafagi, 2021; Cachard, 2008; Jean Louis Lascoux, 2009).‏Valentyna Sloma’s study, entitled “Mediation as a Method of Resolving Civil Legal Disputes” (Sloma, 2023), focuses on defining.\n\nValentyna Sloma’s study, entitled “Mediation as a Method of Resolving Civil Legal Disputes”, focuses on defining mediation and its characteristics as an extrajudicial, voluntary, and confidential method. The study highlights mediation’s effectiveness in property law disputes and emphasizes its role as an alternative method for resolving civil legal disputes.\n\nFrank E.A. Sander’s “Alternative Methods of Dispute Resolution: An Overview” underscores the importance of continuous research and experimentation in developing a conceptual framework for alternative dispute resolution. It aims to raise awareness about the benefits of alternative methods of resolving disputes.\n\nFaras Karim Shi’an and Hind Faiz Ahmed’s study, “Mediation in Electronic Disputes,” examines mediation in electronic disputes under Iraqi laws and international agreements. The study discusses the absence of mediation in Iraqi legislation and its effectiveness in settling disputes.\n\nMohamed Nabil Naqash’s study, “Banking and Insurance Mediation in Tunisian Law,” analyzes mediation and conciliation in banking operations in Tunisian law. It highlights the prevalence of mediation in commercial disputes and advocates its use before resorting to courts.\n\nMounir Mahmoud Badawy’s study, “Mediation and Third-party Role in Dispute Resolution,” explores the mediator’s role in conducting mediation procedures and facilitating settlement solutions. The study emphasizes mediation as a successful means for resolving disputes and conflicts.\n\nMohammed Ali Abdel Reza’s study, “Mediation in the Peaceful Resolution of Disputes in Iraqi Legislation: A Comparative Study,” investigates mediation as a means of amicable dispute resolution in Iraqi legislation. It addresses various issues related to mediation and emphasizes the mediator’s role in achieving speedy resolutions.\n\nNahla Yassin Hamdan and Frederick Pearson’s study examines disputes within companies and advocates extrajudicial settlement as the optimal approach. The study identifies governance issues leading to disputes and emphasizes the need for non-judicial resolution methods.\n\nForqan Ali Hussein Al-Khafaji and Hussein Al-Khafagi’s study addresses mediation as an alternative means of resolving disputes and the necessity of Iraqi legislation to regulate it. The study highlights the importance of legislative regulation of mediation and other alternative dispute resolution methods in Iraq.\n\nWhat distinguishes our study from previous ones is its particular focus on the procedural aspects of the mediation process so as to achieve a resolution in civil and commercial disputes. While previous studies primarily highlighted the benefits of mediation and analyzed its role in resolving conflicts, our study goes beyond that to provide a comprehensive view of the mediation process, including its procedural aspects.\n\nWe shall provide detailed guidance on how to apply mediation as a method for resolving disputes, starting from the inception of the process to reaching a final settlement. We shall outline the necessary steps to initiate mediation, such as selecting the appropriate mediator, establishing confidentiality procedures, and collaborating with involved parties. Additionally, we shall analyze the factors that may impact the success of the mediation process and how to address them.\n\nAs such, our study stands out as a practical reference for researchers and stakeholders interested in the mediation process, offering specific and detailed guidance on organizing and executing mediation in an effective and fruitful manner.\n\nThis study is in line with the Mediation and Conciliation in Civil and Commercial Disputes Law, enacted by the United Arab Emirates in 2023. This law aims to enhance justice and facilitate the resolution of disputes through non-judicial means. It comes within the UAE’s continuous efforts to foster a favorable business environment and promote a culture of settlement and mediation.\n\nThis law represents a significant step towards enhancing mediation as a primary method for resolving disputes, providing the necessary legal framework to regulate and facilitate mediation and conciliation processes. The law includes provisions that specify the conditions and procedures necessary for conducting mediation, such as appointing qualified mediators, ensuring confidentiality of information, and defining procedures for reaching final settlements.\n\nFurthermore, the law provides legal protection for parties participating in mediation processes, encouraging active engagement and fostering confidence in the outcomes. Additionally, the law works to promote a culture of conciliation and peaceful dispute resolution, in order to contribute to improving the business climate and attracting investors to the country.\n\nOverall, the Mediation and Conciliation in Civil and Commercial Disputes Law for the year 2023 in the United Arab Emirates represents a significant step towards enhancing justice and stability in the legal environment and achieving fair resolution of disputes.\n\n\n3. Methods\n\nThe methodology developed in this study adopts the descriptive analytical approach to the different principles of arbitration. The research will seek to provide an in-depth analysis to critically assess the importance of mediation as one of the effective and equitable methods of arbitration. This study draws upon basic resources, including but not limited to literary publications, scholarly periodicals, and online articles.\n\nThrough the methodology adopted in this study, which relies on the analytical approach, researchers from various countries can directly benefit from this research. They can utilize the theoretical and methodological framework elucidated here to conduct similar studies focusing on the importance and effectiveness of mediation as an equitable and effective method in arbitration. Furthermore, researchers can draw from the primary sources used, including literary publications, scholarly journals, and online articles, to support their analyses and academic discussions.\n\nIn this way, your study becomes a valuable contribution that the global academic community can benefit from in deepening their understanding of the importance of mediation as an effective tool in arbitration. It also encourages them to conduct further research to advance this field in their own countries and local communities.\n\n\n4. Concept and origins\n\nMediation is based on the provision of some kind of dialogue to the conflicting parties to meet and converge views through an impartial person who assumes this task in order to reach an amicable solution that satisfies all the conflicting parties (Sloma, 2023).\n\nArticle 8 of UAE Law No. 40 of 2023 concerning Mediation and Reconciliation in Civil and Commercial Disputes states: Article (8):\n\nMediation is permissible for all civil and commercial disputes that are amenable to resolution, provided it does not contravene applicable laws, public order, or morals within the state, taking into account the provisions of Article (28) of this law, and without affecting the provisions of local laws governing mediation. Mediation may encompass the entirety of a dispute or a portion thereof. The provisions of mediation outlined in this chapter shall apply under the following circumstances:\n\na. if mediation procedures are conducted within the state;\n\nb. if mediation involves an international commercial dispute outside the state, and the parties agree to abide by the provisions of this law;\n\nIn the 1960s, the American Civil Court introduced the “American Rule”. This rule means that the parties to the dispute are obliged to pay lawyers, regardless of the success or loss of their case (Odilqoriev, X.T., 2022). In doing so, the application of this rule has resulted in substantial costs and exorbitant amounts for the parties. The United States is one of the countries that relies on mediation in the resolving of the civil disputes.\n\nIn USA, mediation plays a key role in the resolution of extrajudicial disputes due to the complexities of the judicial system, and the high costs of litigation, especially lawyers’ fees because lawyers receive their fees in a manner consistent with their working hours to reach the judicial judgment in the dispute. Mediation in American laws initially emerged in relation to the resolution of labor disputes, especially with the enactment of the Addiction Act in 1898 (Sloma, 2023),while, after the enactment of the Railway Labor Law in 1926, the commissions of mediation and reconciliation were formed to deal with labor issues. Mediation was not only limited to labor disputes. It was used as an effective means of resolving family disputes in the United States, where the Judges’ Association and Family Courts were established, with the aim of promoting reconciliation in family cases, as an alternative to litigation. These institutions were subsequently established across various regions of the USA, including the Family Mediation Association and the Family Mediation Academy (JeanRobert, 1993; Elias Nassif, 2012; Musaada, Ayman, 2004). After that, mediation has become a mandatory procedure in USA family affairs, particularly for the issues related to marriage and divorce (Agnéstavel & Lascoux, Jean Louis, 2009).\n\nIn the Latin legal system, mediation has been used since the end of the nineteenth century. Napoleon Bonaparte enacted a mediation law in 1803. The American mediation model prevailed in Germany, while it was less applied in France. There, the mediation system, from the outset, has been directly integrated within the justice courts (Odilqoriev, X.T., 2022). Article (48) of the French Code of Civil Procedure of 1806 stipulates that the initiation of any lawsuit regarding a judicial dispute is inadmissible unless it is preceded by an attempt at preliminary reconciliation before the Magistrate’s Court. By introducing this article, it appears that the French legislator has given the litigants an opportunity to seek alternative means of resolving their disputes before levelling it before the court.\n\nMediation, from a formal standpoint, is an alternative litigation mechanism that aims to resolve the dispute, through the intervention of a neutral person, called a mediator, who works to help the parties to the conflict negotiate, in order to reach a settlement to resolve the dispute. The third paragraph of Article 1 of the UNCITRAL Model Law of the Year (2002) for international commercial conciliation defines mediation as “any process, whether referred to as conciliation or mediation, or by another term of similar meaning, in which the two parties request another person or persons (conciliator or conciliators) to assist them in their endeavors to reach an amicable settlement of their dispute arising out of a contractual or other legal relationship.”\n\nIn light of the foregoing, mediation can be defined as a voluntary process based on the will of the parties to the conflict to resort to it, and in which they work with a third person, called a mediator, who enjoys the capacity of integrity and impartiality and who can find a mutually acceptable solution that ends the dispute (Mustil arbitration, 1980).\n\nMediation has become a prominent tool in legal and economic thought. At the global level, it is an urgent matter to meet the requirements of modern business due to the rapid and continuous expansion and development of trade patterns (Al-Khafaji & Al-Khafagi, 2021) on the one hand. On the other hand, mediation has characteristics that distinguish it from traditional means of resolving disputes. These advantages have become acceptable for resolving disputes, reducing the burden on the judiciary and speeding up disputes solving with flexibility.\n\nThere is no doubt that slow justice is a denial of justice. So, we argue that the mediation process largely serves this purpose, namely, the rapid pace of settling disputes. This is shown by the legislator’s determination of the period in which mediation is accomplished. The Jordanian legislator goes further, as it sets the period for which the parties restrict the provision of the mediator with documents related to the dispute starting from the date of referring the dispute to mediation. The purpose is to ensure the resolution of disputes at a rapid pace as mediation avoids complicated formalities. Several requirements must be followed on pain of nullity, imposing restrictions on the parties involved in the litigation. In mediation, there is no procedure resulting in nullity, so on the contrary, mediation aims to follow any procedure that could lead to a satisfactory solution to the parties to the dispute. Moreover, resorting to mediation is not mandatory. It is the right of any of the parties to refuse mediation and resort to the judiciary to proceed with the case in accordance with what is legally prescribed for it. The parties to the conflict derive this right from the constitution.\n\nHowever, it must be noted that mediation differs from arbitration, as this is a means of settling disputes in which the arbitrator’s ruling on the subject matter of the dispute replaces the judicial ruling. Accordingly, there are those who see that the position of the arbitrator is identical to that of the judge, even if their sources differ (David (René), 1982; Abdul Al-Qadir, Nariman, 1996). The parties agree to select the members of the arbitration tribunal to decide on the issue in dispute. The arbitrator shall have the role of a judge in resolving the dispute subject to the arbitration agreement, by an arbitration award that is binding on them, and stems from the will of the arbitrators and not the will of the parties to the dispute. Arbitration is binding. As for mediation, it is not. Also, the judgment issued by the arbitration tribunal, or the arbitrator shall be considered an executive document whenever the order for its implementation is issued by the public judiciary in the state, and it is challenged by the legally prescribed appeal methods. Just as mediation differs from a legal point of view from reconciliation, as this latter according to the provisions of the civil law, is a contract by which the two parties actually resolve a conflict that has arisen between them, or prevent a potential conflict. This results from each party’s voluntary relinquishment of some of its demands (Camara Fatou kiné, 2009). As for mediation, it is the endeavors undertaken by the two parties with the mediator to help the conflicting parties, to reach an agreement on a solution that ends the dispute amicably, instead of initiating legal procedures. So, mediation is a means; as for reconciliation, it is not a means, but rather an end in nature. And this is done by reaching an agreement on reconciliation (Kanakria, Walid, 2020).\n\nFrom a legal point of view, a mediator is the person who undertakes the implementation of the mediation process, s/he must have a set of characteristics, and s/he must seek to bring the disputants to a settlement that they are satisfied with (Lord Mustill & Stewart C Body, 2001). In fact, Article 6 of UAE Law No. 40 of 2023 concerning Mediation and Reconciliation prohibits both the mediator and the reconciler from acting as an arbitrator or expert in the dispute, or accepting delegation in a dispute against any of the parties regarding the subject of the mediation or reconciliation, or any related matter, even after the conclusion of the mediation or reconciliation proceedings, unless the parties agree otherwise regarding the mediation. Also, it prohibits giving testimony against any party to the dispute concerning the subject of the mediation or reconciliation, or any related matter, even after the conclusion of the mediation or reconciliation proceedings, unless authorized by the concerned party or agreed upon by the parties to the contrary, except in cases involving a crime. It prohibits as well acting as a mediator or reconciler in a dispute where one of the parties is a spouse or relative up to the fourth degree by blood or marriage.\n\nThe qualities that must be present in the mediator can be limited to the following:\n\n• Legal capacity\n\nThe mediator must be fully qualified, and the eligibility condition is a fundamental issue required in all jobs and tasks. On the obstacles and difficulties encountered, the mediation process requires, during all its stages, a mediator with sophistication, acumen, and personal skills that qualify him to manage negotiations (Jalloul, Dalila, 2012). Article (31) of UAE Law No. 40 of 2023 concerning Mediation and Reconciliation stipulates the conditions for occupying the position of mediator. It states that: the conditions for appointing reconcilers and mediators and their qualification shall be determined by a decision of the council or the head of the local judicial authority, as deemed appropriate. It shall include the following conditions: not to have lost eligibility or been convicted of a crime involving honor or trustworthiness, even if her/his status has been restored. Another condition is to be known for honesty, neutrality, and experience. A further one is to successfully complete specific courses and examinations, determined by a decision of the council or the head of the local judicial authority, as deemed appropriate.\n\n• Neutrality and impartiality\n\nNeutrality means liberating the mind from all fanaticism and preparing it with all that is acceptable to the law, and the impression of justice. Neutrality represents the first characteristic of the mediation process, as it takes multiple implications, and is defined in a variety of ways. One side should not be favored over the other (David (René), 1982).\n\nExperience and competence have special importance in settling disputes through mediation because an experienced and competent mediator gains more confidence in her/himself first and in the mediation process second. Experience and competence provide the mediator with the trust of the parties in her/his person and her/his ability to settle the dispute and ultimately they get satisfaction with her/his judgment and agree to implement it. The mediator must also be legally qualified in both academic and practical terms, in a manner that enables her/him to conduct the mediation process and achieve the desired goal in it with high efficiency and capacity. (Ibid, at 266-67) This can only be achieved through training and legal preparation in accordance with intensive theoretical and practical programs in the field of mediation and dispute settlement, as well as the knowledge of legislation which should foster the ability of the mediator in settling disputes (Peter S. Caldwell, 1992).\n\nMediation is inherently a voluntary process in which the mediator is not permitted to make decisions on the core issues of the dispute (Cachard, 2008). Rather, her/his role is limited to trying to bring the two parties’ points of view closer without being bound by the procedures stipulated in the Civil Procedures Law. However, this does not mean that there are no restrictions or procedural rules that the mediator adheres to. The mediator must carry out her/his work according to specific principles that help her/him deliver the litigants to a solution satisfactory to both parties. Mediation is based on supportive negotiation that leads to resolving the conflict in the shortest time, with an agreement the strength of which lies in the self-determination, as the mediator seeks to bridge the views between the opponents who disclose to the mediator their basic interests, and their anxiety factors, in order to enable her/him to find solutions that are satisfactory to all parties (Aflouk, Muhammad Ali Abd Al-Redha & Al-Zubaidi, Yasser Ataiwi, 2015). The procedures can be divided into two types: rules related to starting and conducting mediation and others related to its termination.\n\nArticle (18) of the UAE Mediation and Reconciliation Law for the year 2023 outlines the mediation procedures as follows:\n\nThe mediator must inform the disputing parties of the mediation sessions and officially announce their date, time, and location through any of the legally prescribed means of communication, including electronic methods.\n\nThe disputing parties are required to attend the mediation sessions personally or through a legal representative, with proper authorization. If one of the parties is a legal entity, their legal representative or authorized agent must attend. Parties may also engage advisors to accompany them during the sessions. The mediator has the discretion to determine the number of individuals accompanying each party based on what is deemed suitable for facilitating the settlement process considering the circumstances and nature of the dispute. Attendance of non-parties in the dispute requires the consent of all parties involved.\n\nEach party must submit to the mediator, before the first scheduled session, a concise memorandum summarizing their claims or defenses, along with the documents and evidence supporting them. These memoranda and documents are not to be exchanged between the parties.\n\nArticle (18) of the UAE Mediation and Reconciliation Law for the year 2023.\n\n• Procedures for initiating & conducting mediation\n\nThe first session is an introduction session in which the mediator introduces her/himself and the litigantsto introduce themselves. S/he explains to them her/his role as a mediator, and affirms her/his neutrality and the confidentiality of procedures. The trust of the parties in the mediator is more important than their trust in each other (Sander, 1985).\n\nThe mediator must keep the secrets that s/he finds, because these secrets have reached her/his own person by virtue of her/his work as a mediator. If it were not the case, s/he would not obtain them. So, the secrets that s/he must keep include the information and documents that s/he has access to for her/his capacity as a mediator (Al-Tahiwi, Mahmoud Al-Sayed 2006). As a personal trait, the more competent and capable the mediator is, the more likely s/he can reach an agreement that satisfies the conflicting parties (Okechukwu Dominic, 2012). There are several methods that the mediator follows to reach this agreement, the most important of which are:\n\n• Clarifying ideas and providing the necessary facilities:\n\nThis method is based on clarifying to the parties’ ideas and demands, and placing them within their correct frameworks. The mediator shall make the necessary facilities and provide assistance to the parties in communication and negotiation (Odega, Bensalem, 2009) between them within the framework of a strategy. This strategy is designed to take the parties’ hand to identify the topics and issues related to the conflict (Ibid 83-89) and a correct understanding of their needs and their true interests.\n\n• Evaluating facts and expressing an opinion:\n\nThis method is represented by the mediator meeting with each of the parties to the dispute separately to assess her/his legal status and express her/his expected opinion regarding her/his case, by reviewing the legal texts and judicial jurisprudence in this regard. Here lies the importance of the mediator having scientific and practical experience that enables her/him to evaluate issues in a convincing manner that maintains confidence and impartiality. This requires, in addition to scientific and practical experience, familiarity with the training skills and technical methods used, in dealing with parties (Civil Litigation & Alternative Dispute Resolution, without date).\n\nThe mediator must have the moral characteristics required of a respectable person in order not to be subjected to question or suspicion, and the parties would not question whether they are in front of a mediator or an arbitrator. Only then, they can have the confidence that drives them to put all their affairs in the hands of this person, whom they know, trust and believe in her/his ability to provide them with assistance to get out of the impasse (Al-Ahmad, at 118, n.d.). In addition to that, the mediator’s status and prestige binds the parties morally and socially to accept the solution that s/he offers them (Sloma, 2023).\n\nThe role of the mediator is to correct the situation by asking questions about the claims and the answers that s/he has received. This may lead her/him to obtain facts that the parties neglected to mention which may help resolve the dispute (Al-Khafaji & Al-Khafaji, 2021), and which may not occur otherwise. This is done by facilitating the means and methods of discussion between the parties to the conflict by converging viewpoints and opinions between them. It also happens by strengthening the parties’ sense of legal responsibility towards the issue and enhancing the importance of resolving the disputed issue via a set of legal alternatives, suitable for resolving the dispute. It is also crucial to preserve the independence of each of the parties to the conflict.\n\nIf the mediator reaches a settlement of the dispute, s/he submits a report to the case management judge or the magistrate judge and attaches the settlement agreement signed by the parties to the dispute to ratify it to be considered as a final judgment that is not subject to any method of appeal (Badawi, Mounir Mahmoud, 2003). If the judge approves an agreement, mediation then comes to the implementation phase. The implementation of this agreement is voluntary in principle, because the parties have agreed on it (Henry, M., 1993). Thus, they are considered to be more able to understand and abide by it.\n\nMany of the laws that regulate mediation set a specific period for the mediator to reach a solution to the dispute, including what was stipulated in the Jordanian Mediation Law No. 37 of 2003. Provided that the mediation sessions take place in the presence of the litigant parties and their legal representatives, the mediator shall, within a period not exceeding three months from the date of referring the dispute to her/him, do the following: set a session, inform the parties to the dispute and their agents, deliberate according to the rules, meet with the parties to the dispute and their representatives, negotiate with them the subject of the dispute and take whatever s/he deems fit for bridging views for the purpose of reaching an amicable solution to the conflict. The Tunisian legislator also stipulates that the mediator in the field of banking must undertake the complaints submitted to her/him within a maximum deadline of eight days from the date of receiving the mediation request and proposes appropriate compromise solutions within a maximum deadline of two months from the date of the undertaking (Kiné, Camara 2004).\n\n• Termination of the Mediation\n\nMediation ends either by agreeing to resolve the dispute, or by not agreeing to resolve it. If the parties agree to end the dispute, this is considered a success for the mediator in her/his work. The mediator subsequently submits a report called the mediation agreement signed by the mediator and the parties to the dispute. Yet, this agreement may be wholly conducive to a complete solution to the dispute (Cachard, 2008). It may be partial leading to the resolution of some issues, and others remain without agreement. Also, if the agreement is complete, the report is referred, after it is signed to the court for approval by the judge. If it is partial, it is written in the minutes that have been agreed upon and signed by the mediator and the parties. The file is referred to the judge, and the parties are bound by the signed agreement. The parts that have not been agreed upon are referred by the judge to the competent court for a final judgment (Al-Salibi, Bashir, at 60, n.d.).\n\nWhen the judge ratifies the mediation agreement, s/he does not ratify it as carrying out her/his function as the judicial authority (Moneim, 1999). Rather, s/he ratifies it as the custodian of the state authority. Mediation ends in accordance with the provisions of the UNCITRAL Model Law on International Commercial Conciliation of 2002 in one of the following cases:\n\nThe first case: the mediator fails to reach an amicable settlement of the dispute between the litigants. In this case, there are numerous reasons, any of which may lead to the termination of the mediation process. Examples of these reasons are stated in Article (11) of the UNCITRAL Model Law on Commercial Conciliation. They are as follows:\n\n1- After consulting with the parties to the conflict, a declaration is issued stating that there is no justification for undertaking further efforts at reconciliation on the date of the declaration.\n\n2- A party to the dispute issues a declaration addressed to the other party, or other parties, and to the conciliator in the event that s/he is appointed, indicating that the conciliation procedures have ended on the date of the announcement.\n\nThe second case: when the mediator reaches an amicable settlement of the dispute between the litigants, and the settlement agreement is approved by the parties to the dispute, the mediation process ends at the moment of ratification of the settlement agreement.\n\nThe third case: the expiration of the period specified for the settlement of the dispute, as stipulated in the first paragraph of Article Seven of the Jordanian Mediation Law, which obliges the mediator to complete the mediation work within a period not exceeding three months from the date of referring the dispute to her/him.\n\nThe fourth case: the parties to the dispute have not attended the mediation sessions without a legitimate excuse, as stipulated in Article (5) Paragraph (B) of the Jordanian Mediation Law.\n\n\n4. Mediation discrimination from arbitration\n\nMediation is an analytical and optional process where disputing parties choose a mediator to assist in resolving conflicts. The mediator facilitates communication and information exchange between the parties, offering guidance and support to reach mutually satisfactory solutions (Jean Louis Lascoux, 2009). It is noteworthy that the mediator’s role is limited to providing a safe and neutral environment for parties to discuss the issue and reach a settlement without imposing decisions on them. Additionally, the mediator must be well-trained in techniques for successful conflict resolution and creative solutions (Sloma, 2023).\n\nThe forms of mediation vary according to the nature and circumstances of the dispute. This includes simple mediation, which involves informal sessions with the mediator to facilitate dialogue and reach a settlement. There’s also formal mediation, which includes court procedures and the appointment of a panel chaired by the mediator to resolve disputes. There is consultation mediation as well which involves parties seeking advice from a lawyer or expert in the field before resorting to mediation to resolve the dispute (Sloma, 2023).\n\nOne of the distinctive aspects of mediation is its flexibility in the dialogue and exchange of ideas, striving to ensure that each party is heard and their needs and interests are fairly addressed. It also works to promote understanding and build trust between the parties, making the solutions reached more sustainable and acceptable to all.\n\nIn contrast, arbitration is characterized by its formal and binding nature, where arbitrators decide disputes based on evidence presented and applicable laws, without the need for parties’ consent to the final decision. Arbitration is characterized by confidentiality and efficiency in issuing decisions, making it a common choice for disputes requiring a quick and binding resolution (Al-Khafaji & Al-Khafagi, 2021).\n\nIn conclusion, while mediation seeks to achieve balance and cooperation between the parties, arbitration aims to issue final decisions that effectively and bindingly resolve disputes.\n\n\n4. Conclusion\n\nThis research has made it clear that mediation and other alternative methods have become acceptable to litigants and appropriate for many disputes especially in civil and commercial disputes. No one can overlook their importance in international disputes, given the requirements of these types of disputes including flexibility and speed. They are also important in disputes arising from the use of modern means of communication, such as the internet, ecommerce, and disputes related to intellectual property, among others. The right of mediation is considered as an alternative to the judiciary to resolve these disputes. It should not be granted to every person or institution, but rather a mediator must have the qualifications to carry out the mediation process and the ability to provide solutions to the disputants without relying on legal texts, provided that they do not violate public order and public morals.\n\nTherefore, we believe that it has become necessary to work on spreading and consolidating the culture of resorting to mediation. It has accordingly a positive role in reducing the burden on the judiciary. Thus, specialized courses and seminars should be held to qualify people who are able to conduct mediation. We also believe that the judicial mediation system must be activated within the judicial authority because the survival of mediation outside Legislation framework weakens its effectiveness in settling civil and commercial disputes. However, there rise the necessity to issue legislations regulating the mediation process as an alternative solution to settling civil and commercial disputes. It is also primordial to work to establish an independent special body or bodies that have special provisions and procedures that differ from what the judicial authority is subject to in supervising and controlling mediation between disputants.", "appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReferences\n\nAbdel Reza MA: Mediation in Peaceful Resolution of Disputes in Iraqi Legislation: A Comparative Study. The Journal of Al-Haq Mission. 2015; 7: 2.\n\nAbdul Al-Qadir N: Arbitration Agreement in Civil and Commercial Matters No. (27) of 1994. 1st ed.Cairo: Dar Al-Nahda Al-Arabiya; 1996; 12.\n\nAflouk MAAA-R, Al-Zubaidi YAA: Mediation in Peaceful Conflict Resolution in Iraqi Legislation: A Comparative Study. 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Cairo: Cairo University Press; 1993; 825." }	[ { "id": "311826", "date": "22 Aug 2024", "name": "Enas Mohammed Al-Qodsi", "expertise": [ "Reviewer Expertise Civil LawCivil LiabilityArtificial IntelligenceContractsSustainable Development" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe research paper focuses on Alternative Dispute Resolution (ADR), with a specific emphasis on mediation as a model. It explores the benefits of mediation compared to traditional litigation, highlighting advantages such as cost-effectiveness, time efficiency, and the preservation of relationships between disputing parties. The paper also discusses the principles, processes, and challenges of mediation, emphasizing its flexibility, voluntary nature, and confidentiality, which allow it to adapt to the needs of the parties involved. Evaluation of Key Points: 1. Clarity of Concepts: Strengths: The research clearly defines and explains the concept of mediation and its role within the broader context of ADR. Suggestions: The clarity of the concepts can be further enhanced by providing more practical examples that distinguish mediation from other forms of ADR, such as arbitration. 2. Research Methodology: Strengths: The paper utilizes a critical and comparative analysis to evaluate mediation against other dispute resolution methods. Suggestions: The methodology could be detailed further, particularly regarding how data was collected and analyzed, and how case studies (if any) were selected. A clear explanation of the research process will enhance the reliability of the findings. 3. Case Studies or Practical Examples: Strengths: The paper effectively discusses the theoretical benefits of mediation. Suggestions: It would be beneficial to include case studies or practical examples that support the theoretical claims. This addition would strengthen the paper by providing concrete evidence of mediations' effectiveness. 4. Discussion of Challenges: Strengths: The research strongly focuses on the advantages of mediation. Suggestions: A more balanced discussion is recommended, including potential challenges associated with mediation, such as power imbalances between parties and situations where mediation may not be appropriate. Addressing how these challenges can be mitigated would provide a more comprehensive analysis. Key Points to be Addressed: To ensure the research is scientifically sound, the following aspects should be clearly addressed: Strengthening Theoretical Foundation: The paper should establish a solid theoretical foundation by clearly defining key concepts and explaining their relevance to the topic of mediation. Enhancing Methodological Rigor: The authors should ensure that the methodology is transparent, systematic, and reproducible. This includes explaining how data was collected and analyzed and acknowledging any limitations or biases. Providing Empirical Support: The research should be backed by empirical evidence, such as case studies or data analysis, to substantiate theoretical claims. Balanced Perspective: The paper should offer a balanced discussion that not only highlights the benefits of mediation but also addresses potential challenges and how they can be overcome.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "12279", "date": "14 Jan 2025", "name": "Naser Sherman", "role": "Author Response", "response": "Dear Reviewer, Thank you very much for your thorough and detailed review of the research. Your comments are extremely valuable and will undoubtedly contribute to improving the quality of the work. I would like to address each of the points you raised: 1. Clarity of Concepts: - Response: I appreciate your recognition of the clarity in defining mediation and its role within Alternative Dispute Resolution (ADR). It is important to clarify that mediation is a method of amicable dispute resolution, and distinguishing it from other ADR methods, such as arbitration, is crucial. This will certainly help in enhancing the clarity of the concepts. 2. Research Methodology: - Response: Thank you for acknowledging the use of critical and comparative analysis. I agree with you, and I have provided a brief explanation of the research methodology. The criteria for selecting case studies focused mainly on the most recent studies. 3. Case Studies or Practical Examples**: - Response: Case studies or practical examples have been briefly included in the paper to support the theoretical benefits of mediation. 4. Discussion of Challenges: - Response: Your recommendation to provide a more balanced discussion that includes the potential challenges of mediation is appreciated. Regarding overcoming these challenges, they can be addressed by enacting modern legislation that accurately regulates mediation. Once implemented, these laws will reveal challenges that can then be addressed with appropriate proposals. 5. General Feedback: - Response: The theoretical foundation has been strengthened, methodological rigor ensured, and empirical support along with practical examples provided. Regarding the statistical analysis, since this paper primarily focuses on qualitative analysis, there was no need for detailed statistical interpretation. Thank you once again for your constructive feedback. I am committed to addressing these points and improving the quality of the paper." } ] }, { "id": "307497", "date": "10 Oct 2024", "name": "Eka An Aqimuddin", "expertise": [ "Reviewer Expertise International law", "International Settlement of Dispute" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article only represents the mediation in United Arab Emirates. If the author would like a broader audience, it should be compared to the mediation in another country.\nPerhaps the author can make a comparison with ADR in Europe or another continent.\nThis article also did not give a new insight of mediation. The conclusion of mediation as ADR is common in another part of the world. As a reader, I did not get fresh knowledge from this article.\nIn sum, there is no problem question you would like resolved.\nIn my review, the article has no research questions or legal issues. Consequently, it does not enhance the discourse in public, especially the academic community.\nThe discourse in the article is very confined. It requires expansion through comparisons with practices in other nations. By employing this approach will elucidate differences and similarities, providing the reader with a novel viewpoint.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] } ]	1	https://f1000research.com/articles/13-778
https://f1000research.com/articles/13-5/v1	03 Jan 24	{ "type": "Research Article", "title": "Conditioning factors for the scientific productivity of undergraduate students of health sciences at a private Peruvian University: A cross-sectional analytical study", "authors": [ "César Antonio Bonilla-Asalde", "Isabel Cristina Rivera-Lozada", "Oriana Rivera-Lozada", "Isabel Cristina Rivera-Lozada" ], "abstract": "Background The objective of this study was to determine the conditioning factors for scientific research productivity in university students of health sciences.\n\nMethods A cross-sectional analytical observational study was conducted. The study population was 4104 students enrolled during the 2021-I semester in the Faculty of Health Sciences of a private Peruvian university. A sample size of 400 students was determined and a stratified probability sampling was used. The variables were measured through surveys. The dependent variable was scientific research productivity, and the independent variables were institutional culture, knowledge management and technological capital. Summary measures are reported according to the type of variable. The chi-square test with a significance level of p<0.05 was applied to assess the association between the variables of interest. A multiple logistic regression analysis was performed using the Stepwise method. Prevalence ratios (PR) with their respective 95% confidence intervals (95%CI) were calculated.\n\nResults From the total of 400 students, 74.5% were male, 57.25% were aged between 18 and 27 years, 17% belonged to the school of human medicine and 72% were in their sixth year of studies. Scientific research productivity was associated with management commitment (PR=1.493; 95%CI: 1.077–2.068, p=0.015), sense of personal growth (PR=1.632; 95%CI: 1.041–2.558; p=0.024), recognition by the university (PR=1.385; 95%CI: 1.012–1.896; p=0.043), strategic alliances (PR=1.422; 95%CI: 1.032–1.959; p=0. 03), having research proposals (PR=1.522; 95%CI: 1.114–2.08; p=0.009), dissemination of results obtained (PR=1.542; 95%CI: 1.12–2.122; p=0.01), availability of human resources (PR=1.591; 95%CI: 1.165–2.173; p=0.004), access to equipment and software (PR=1.482; 95%CI: 1.061–2.069; p=0.018) and to laboratories (PR=1.438; 95%CI: 1.047–1.974; p=0.024).\n\nConclusion It is concluded that the research productivity of undergraduate students of health sciences is low. It is necessary to strengthen research promotion measures in universities for the control and monitoring of students’ scientific participation.", "keywords": [ "Higher education", "scientific research", "student research", "research universities" ], "content": "Introduction\n\nNowadays, the academic development of universities is oriented primarily to the training of human talent, research and technological progress, a situation that is reflected in the research indicators used to determine the level of competitiveness, academic quality and resource allocation. In the face of this reality, university directives increase the demands on teachers, students and researchers in order to raise academic standards as well as the position in the various rankings that serve as a comparative benchmark in the educational system (Sirvent et al., 2016).\n\nIt is interesting to mention that, unlike countries in Europe, Asia and Oceania, in Latin America three quarters of research is concentrated in universities and mainly in public ones, tipping the balance towards conducting applied research rather than basic research, which is oriented towards the development of science and technology (Alarco, Changllio-Calle and Cahuana-Salazar, 2017).\n\nResearch published in journals of importance in the region of the Americas exceeds 100,000 titles in the period 1996–2003; however, very few correspond to production by university students, 75% belong to Brazil, Argentina, Chile and Mexico, placing Peru in 8th place with 3% in that concept (Osada, Loyola-Sosa and Berrocal, 2014).\n\nIn Peru, research in university campuses is limited by a myriad of factors, including state investment, the lowest in this hemisphere -0.1% of GDP, below Brazil, Mexico, Colombia and Chile. This information allows us to understand why in the period prior to the enactment of the 2014 University Law, only three universities, one national and two private, concentrated 64% of the scientific production (Perdomo et al., 2020).\n\nMoquillaza (2019) draws attention to the scarcity of information in indexed journals related to the scientific production of students in higher education institutions and the small number of journals that accept research conducted by students. Another aspect to point out in the Peruvian case has to do with the limited number of journals corresponding to university publishers that do not exceed 10% of these publications.\n\nWhile as from 2018 there is evidence of greater research in Peru, it remains globally low; among the possible causes is the lack of indexed journals for research authored by students. Frequencies of reports are found in Colombia 11%, Chile 10% and similar in Peru. Student perception of the causes, besides the above, are related to the lack of research experience of the teaching staff and that the contents provided in research methodology courses are insufficient, in addition to not teaching or giving guidelines on writing an article and how to submit it to a journal for its publication (Santibáñez, 2017; Castro-Rodríguez, 2019).\n\nCastro-Rodríguez et al. (2018), explain that only 4.5% of papers published in Scielo Peru had a contribution from at least one student from a Peruvian university, reflecting the pitfalls faced by university students when publishing an academic paper, as well as the lack of opportunities to be incorporated into research groups, a deficit in incentives and the underestimation of student capacities to develop quality research. Therefore, the objective of this research was to determine the conditioning factors for the scientific research productivity of undergraduate students of health sciences at a private university in Peru.\n\n\nMethods\n\nAn analytical cross-sectional observational study was conducted. The study population consisted of 4104 undergraduate students. The study included students of both genders enrolled in the 2020-I semester at the Faculty of Health Sciences of the Norbert Wiener Private University and who had taken research subjects. Students who did not wish to participate in the study and those who did not complete the requested information properly were excluded.\n\nA sample size of 400 students was calculated and a stratified probability sample was made by proportional allocation among the students who met the selection criteria of the study.\n\nThe independent variables included institutional culture, knowledge management and technological capital measured on a nominal scale. The dependent variable was scientific research productivity.\n\nThe information from the participants was gathered through four questionnaires (Bonilla-Asalde et al., 2023b) based on the model of Rueda-Barrios and Rodenes-Adam (2016). All questions were posed according to a dichotomous qualitative scale (1=Yes, 2=No). Three questionnaires were applied for the independent variables. The first was composed of 24 questions on institutional culture and included participatory culture, motivational culture and teamwork culture as dimensions. The second questionnaire was composed of 13 questions on knowledge management and included the dimensions of socialization, externalization and internalization. The third questionnaire was composed of 15 questions on technological capital and included the dimensions R&D investment, technological endowment and technological tools. For the dependent variable, a seven-question questionnaire was applied with the dimensions of publications and visibility of the researcher. Data gathering was conducted via email during the period of March–August 2021.\n\nThe data gathering instruments were developed by the research team and validated by Aiken’s V coefficient, and the binomial test with the participation of ten methodological and thematic experts in university education who assessed the clarity, objectivity, updating, organization, sufficiency, adequacy, coherence, methodology and relevance of the content of the instruments. Reliability was assessed through a pilot test that included 30 students from the Faculty of Health Sciences of the Norbert Wiener Private University. The four instruments were subject to the Kuder Richardson test (KR-20) and a KR coefficient equal to 0.80 was obtained for the questionnaire on institutional culture; 0.82 for knowledge management; 0.79 for technological capital and 0.86 for scientific research productivity.\n\nThe data obtained (Bonilla-Asalde et al., 2023a) were gathered in the Microsoft Excel 2010 software and were analyzed with the SPSS software version 25.0. Tables with absolute and relative frequencies were reported for categorical variables, while measures of central tendency and dispersion were calculated for quantitative variables.\n\nTo evaluate the relationship between each independent variable with the dependent variable, a bivariate analysis was performed using Pearson’s chi-square test with their respective p-values; values of p<0.05 were considered statistically significant. The prevalence ratio (PR) and its respective 95% confidence interval were calculated for each relationship.\n\nLikewise, to evaluate the relationship between the independent variables and performance in scientific research, a multiple logistic regression analysis was applied, using the Stepwise method where the indicators that showed a value of p<0.05 in the previous bivariate analysis were added.\n\nThis study was carried out following the guidelines of the 1964 Helsinki Declaration and its subsequent amendments. This study was evaluated and approved by the Institutional Research Ethics Committee of the Norbert Wiener University on February 5, 2021, expedient 521-2021. All the participants in the study signed the informed consent form before their participation and their identity was anonymized for the elaboration of the database, so their integrity was not violated.\n\n\nResults\n\nA total of 400 students from the Faculty of Health Sciences of the Norbert Wiener Private University were analyzed, of which 74.5% (n=298) were male and 57.25% (n=229) were between 18 and 27 years of age. Also, 17% (n=68) were studying in the School of Human Medicine, while 5% (n=20) in the School of Human Nutrition. Besides, 78% (n=288) were in their sixth year of studies, while 0.5% (n=2) were in their eleventh year (Table 1).\n\nThe indicators of institutional culture were evaluated in the sample studied. 70.75% (n=283) stated that there are no agreements for the dissemination of research. 76% (n=304) expressed the opinion that there is a concern for the personal growth of students, 65.5% (n=262) expressed interest in research and 60.25% (n=241) considered that there is no recognition of students who practice research by the university.\n\nWhen evaluating the knowledge management indicators, it was found that 69.25% (n=277) consider that access to information is adequate. 77% (n=308) consider that there is adequate advice from teachers on research, while 72.5% (n=290) reported that there are no mechanisms for the dissemination of results. On the other hand, 62.75% (n=251) stated that they are not part of any scientific network and 82.75% (n=331) do not have access to indexed scientific journals. In addition, 60.25% (n=241) considered that the university does not use the results of research conducted by students.\n\nTechnological capital indicators were evaluated. It was found that 66% (n=264) consider that they do not have supporting human resources for research. 62.25% (n=249) stated that they had sufficient databases to conduct research, while 80% (n=320) considered that they did not have collaborative tools for research (Table 2).\n\nTable 3 shows the descriptive analysis of the dependent variable. It was found that 72.25% (n=289) have not published any article in indexed journals or congresses and 98.5% (n=394) do not have any research project approved for execution. Furthermore, none of the students in the study sample has an H index and only 2.5% (n=10) have at least one publication in Open Access (Table 3).\n\nIn the bivariate analysis, a statistically significant association was found between scientific research productivity and management commitment (CPR=1.493; 95%CI: 1.077–2.068; p=0.015), personal growth (PR=1.632; 95%CI: 1.041–2.558; p=0.024), receiving recognition for practicing research (PR=1.385; 95%CI: 1.012–1.896; p=0.043) and strategic alliances (CPR=1.422; 95%CI: 1.032–1.959; p=0.03). Regarding knowledge management, research proposals (CPR=1.522; 95%CI: 1.114–2.080; p=0.009), shared results (CPR=1.542; 95%CI: 1.120–2.122; p=0.01) and use of research results (CPR=1.436; 95%CI: 1.049–1.965; p=0.024) were significantly associated with scientific research productivity. In the technological capital dimension, the availability of human resources support (CPR=1.591; 95%CI: 1.165–2.173; p=0. 004), visibility of investment in research (CPR=1.481; 95%CI: 1.08–2.029; p=0.014), having equipment and software (CPR=1.482; 95%CI: 1.061–2.069; p=0.018) and laboratories (CPR=1.438; 95%CI: 1.047–1.974; p=0.024) (Table 4).\n\n* Crude prevalence ratio.\n\nThe multiple logistic regression model found association between scientific research performance with management commitment (APR=1.392; 95%CI: 1.001–1.935; p=0.049) and availability of human resources to support research (APR=1.471; 95%CI: 1.063–2.063; p=0.02) (Table 5).\n\n* Adjusted prevalence ratio.\n\n+ p-value estimated by multiple logistic regression using the Stepwise method, with significance level of p<0.05.\n\n\nDiscussion\n\nDetermining the conditioning factors of scientific research productivity of undergraduate students of health sciences in order to provide relevant information that allows to know and understand the scientific behavior of this group of interest contributes to identify the university institutional responsibility as knowledge generating organizations (Daher, Panuncio and Hernandez, 2018) as well as to account for the level of implementation of the scientific method by the student body and the research practices that manage to permeate teachers (Chachaima-Mar, Fernández-Guzmán and Atamari-Anahui, 2019).\n\nIn contemporary society, universities, through the fulfillment of their mission of education, research and social interaction, play a transcendental role in the production and management of knowledge, innovation and technological development, for which they need to have clear, timely and relevant information regarding the factors that limit or promote scientific activity in students (Santibáñez, 2017; López, 2019).\n\nThis study found that only 27.75% of the students included in the population have publications in indexed journals and/or congresses, and only 1.6% have approved research projects. Besides, none of the students in the sample has a registered H-index. These results evidence the low participation of students in research, as previously reported by Castro-Rodríguez (2019) with a student scientific production of 10%, different from the previous study by Castro-Rodríguez et al. (2018) who reported 3.5% of students with at least one publication. This low student participation in research can be explained because 72% of the sample was in the sixth cycle of studies and research courses are oriented in the last cycles of the degree.\n\nHowever, we found that 76% consider it important to do research as part of their personal growth; also, 65.5% of the sample has interest in participating in research, which is far from what was reported by Rojas and Méndez (2016) who analyzed the barriers in the process of teaching research in undergraduate, showing that there is less and less interest in engaging in research, but this situation is a consequence of a decreasing trend in the attitude towards research at a higher university level and the teaching responsibility to awaken and encourage a different attitude towards research processes (Alarco, Changllio-Calle and Cahuana-Salazar, 2017). This discordance between the high percentage of students interested in research and the low level of participation could be explained, according to our results, that for many, the university does not comply with some important aspects, such as offering agreements that promote student research, or the little recognition of the research interest of some students, besides, the academic community does not recognize the effort made by the university to advance in this aspect (Mirón-Chacón et al., 2020; Castro-Rodríguez, 2019).\n\nThe results indicate that providing recognition to students for their research activity is associated with performance rather than academic productivity, as previously reported in the study by Rueda-Barrios and Rodenes-Adam (2016) who found a statistically significant relationship between both variables. Universities need to promote the dissemination of research in the student body as well as to make visible the institutional effort to position the university in the research field both internally and externally, through various means that include national and international scientific journals, congresses and incentives to promote research, but that go unnoticed at the student level, as indicated by Oyarzún Maldonado et al. (2020). This aspect is relevant since the evidence suggests that recognition is a good practice that promotes and facilitates research management, such as the case of the universities best placed in world rankings that include incentive policies for research and those who do it (Tomàs-Folch, Ruíz and Labao, 2015).\n\nThere are uniform criteria to study scientific research productivity, but there are gaps in the application of these principles, caused, among other aspects, by the weak dissemination of internal policies on scientific publication among students. Many times, this effort is only reflected in the fulfillment of an indicator. It is also necessary the participation of the professor who teaches research, the advisor or mentor, to accompany the deep understanding of the implications of the scientific method transmitted by these policies (Vera and Vera, 2015).\n\nAnother important factor found in this study was related to knowledge management, a relevant aspect according to some authors since it is one of the key indicators that allows measuring the quality of universities (Calderón, 2017). We found a concern by students since they report that there is no proper dissemination and use of the results of the research in which they participate as part of the recognition and dissemination of their activities; likewise, most do not participate in scientific networks or groups, nor do they have access to scientific journals that facilitate the publication process. This is of great importance, since according to Rueda-Barrios and Rodenes-Adam (2016) these aspects are related to scientific productivity. However, in this study, we only found a statistically significant association with the dissemination of results. This difference is probably due to the characteristics of the sample, since the authors included professionals who did research.\n\nEven though the results state that students recognize the qualification of the professors who teach research, this result is contradictory to those identified in the externalization dimension, where they express low participation in scientific networks and the perception of scarce dissemination of research results in indexed journals. In this regard, it should be emphasized that a network of knowledge and scientific research expresses the collective multidisciplinarity of the community and institutions when establishing strategic alliances for research purposes or to develop research projects based on quality practices, strengthening scientific cooperation and efficiency in the management of human, logistic and financial resources. This is an aspect to improve in Peruvian universities if they wish to actively improve scientific knowledge management and its assumption as a new institutional challenge (Bedoya et al., 2018).\n\nKnowledge management by researchers, whether teachers or students, demands financial, institutional, logistical resources, among others, that researchers cannot assume and that necessarily require institutional support that the university management can solve through research policies and competitive fund strategies that encourage student researchers to walk the path of research (Ramirez, 2015; Daher, Panuncio and Hernandez, 2018). In spite of the above, there are gaps related to the development of mechanisms that influence the level of student interest and effort to publish. This raises the need to develop a research culture that contributes to consolidate and establish relationships between students, teachers and administrators, within the framework of knowledge communities, research networks and incentives for students to participate in research processes, so that the results also benefit the university (Mendoza et al., 2020).\n\nThis research finds evidence of the need to empower students as agents of change by channeling the research potential through strategies that incorporate research incentive structures for the participation and dissemination of new knowledge produced in response to a society that claims innovative solutions to the different problems that afflict the contemporary world. In this sense, the university is called to lead these research processes through an inter- and transdisciplinary approach that makes it possible to address the main scientific weaknesses of students, the ongoing training of teachers and the continuous promotion of relevant and participatory research activity of students that will result in better student scientific research productivity (Morán-Mariños, Montesinos-Segura and Taype-Rondan, 2019).\n\nThe research had limitations in terms of the population included which, being composed of students from the Norbert Wiener University, may not be representative of the whole country in consideration of the socioeconomic characteristics. Likewise, the research recognizes the complexity involved in evaluating scientific production that goes beyond the classification of the journal in which it is published, the H index, the number of publications in indexed journals, language, inter-institutional or international collaboration, among others. However, the relevance of this study lies in the fact that it is one of the first at national level to evaluate the association of student scientific research productivity with variables such as institutional culture, knowledge management and technological aspects with their respective dimensions.\n\n\nConclusions\n\nStudent performance in scientific research was associated with management commitment, the feeling of personal growth through research, the recognition provided by the university, the existence of strategic alliances, the existence of research proposals, the dissemination and use of the results obtained by the students, and the availability of technological capital. These findings are consistent with what is described in the literature, they also provide relevant information to better understand the current situation of research in university faculties. There is little student participation in research, and this is an indicator that is not properly addressed in universities to promote a scientific attitude in their students, which may have medium-term consequences in terms of academic quality and university social impact. This suggests the need to reinforce university programs or systems for the control and follow-up of student scientific activity. Finally, there is a need to conduct studies of greater scope that delve more deeply into the conditioning factors of student performance in scientific research and the future panorama at national and international level.", "appendix": "Data availability\n\nZenodo: Conditioning factors for the scientific productivity of undergraduate students of health sciences at a private Peruvian University. https://doi.org/10.5281/zenodo.8378295 (Bonilla-Asalde et al., 2023a).\n\nThis project contains the following underlying data:\n\n- Conditioning factors for the scientific productivity of undergraduate students of health sciences at a private Peruvian University.xlsx (dataset)\n\nZenodo: Conditioning factors for the scientific productivity of undergraduate students of health sciences at a private Peruvian University: A cross-sectional analytical study (SURVEY). https://doi.org/10.5281/zenodo.10162604 (Bonilla-Asalde et al., 2023b).\n\nThis project contains the following extended data:\n\n- Survey (a copy of the questionnaire)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAlarco JJ, Changllio-Calle G, Cahuana-Salazar M: Undergraduate research: Interest by sex and academic cycle. 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Education in the Knowledge Society (EKS). 2015; 16(1): 103–118. Ediciones Universidad de Salamanca. Publisher Full Text\n\nRojas Betancur M, Méndez Villamizar R: SOFIA-SOPHIA Processos de formação em investigação na Universidade: O que resta para os estudantes?2016.\n\nRueda-Barrios G, Rodenes-Adam M: Determining factors in Colombian research groups’ scholarly output. Revista Española de Documentación Científica [Spanish Journal of Scientific Documentation]. 2016; 39(1): e118–e118. Spanish Research Council. Publisher Full Text\n\nSantibáñez GG: Cinco tesis sobre investigación científica en la Universidad Politécnica de Nicaragua. Five theses on scientific research at the Polytechnic University of Nicaragua. 2017.\n\nSirvent M, et al.: Algunas reflexiones acerca del proceso de formación en investigación de estudiantes de grado y posgrado. [Some reflections on the research training process of undergraduate and graduate students], in academic memory (ed.) V Encuentro Latinoamericano de Metodología de las Ciencias Sociales [V Latin American Meeting on Social Science Methodology. Buenos Aires]. Buenos Aires. 2016. (Accessed: September 12, 2022). Reference Source\n\nTomàs-Folch M, Ruíz JMR, Labao TM: Good practices applied to research management at top ranking universities. Education Policy Analysis Archives/Archivos Analíticos de Políticas Educativas. 2015; 23: 1–23. Arizona State University. Publisher Full Text\n\nVera L, Vera A: Performance of the Tutor in the Accompaniment Process for Scientific Production. Revista de Estudios Interdisciplinarios en Ciencias Sociales. 2015; 17(1): 58–74. (Accessed: September 11, 2022). Reference Source" }	[ { "id": "282097", "date": "04 Jul 2024", "name": "Mario Valladares-Garrido", "expertise": [ "Reviewer Expertise Medical Education" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbstract The abstract is well-structured and provides a comprehensive overview of the study. However, a few improvements could enhance clarity and comprehensiveness:\nBackground Context: Briefly explain the significance of scientific research productivity in health sciences education. Operational Definitions: Clarify how key variables (e.g., scientific research productivity) were defined and measured. Elaborate on Conclusion: Offer specific recommendations for universities on how to strengthen research promotion measures based on the study's findings.\nMethods The methods section is comprehensive and well-structured, with clear and appropriate methodological choices. However, a few improvements could enhance the clarity and comprehensiveness:\nIt is crucial to know the exact number of students who were excluded based on the established exclusion criteria (i.e., those who did not wish to participate in the study and those who did not properly complete the requested information). It is necessary to know the parameters used to estimate the sample size of 400 students: the proportion, precision (margin of error), and confidence level. This information is essential for understanding the sample size calculation. Operational Definitions: Provide more detail on how key constructs (e.g., institutional culture, knowledge management) are operationalized within the study. Enhance Operational Details: Include specific examples or definitions of how independent and dependent variables were measured.\nResults\nThe section mentions a multiple logistic regression analysis to determine associations with scientific research productivity. However, since the study design is cross-sectional and you have reported adjusted prevalence ratios (PRa), not odds ratios (OR), it would be more appropriate to refer to the analysis as a multiple regression model for estimating prevalence ratios (PR).\nDiscussion The discussion effectively addresses key findings and their implications but could be enhanced with more actionable insights and specific examples from other contexts to provide a clearer path forward for improving student scientific research productivity.\nData on Student Research Participation: The discussion highlights low research participation, but it would be useful to provide comparative context. For example, how does this participation compare with other universities or regions? This can help in understanding the relative position of the studied population. Role of University Support: While the discussion mentions university support and recognition as crucial, more specifics on what kind of support (e.g., financial, mentorship, infrastructure) would be beneficial. Recognition of Faculty Involvement: The role of faculty in promoting research is noted, but the discussion could expand on how faculty involvement can be enhanced. For example, how can universities incentivize faculty to mentor students in research? Institutional Gaps: Identifying institutional gaps is crucial, but the discussion could be more actionable by recommending concrete steps universities can take to address these gaps, such as creating more research opportunities, providing access to scientific journals, and fostering a culture of research from early undergraduate years. It would be beneficial to add a section on the implications of the findings for medical education. This section could discuss how the study's results could influence curriculum design and educational practices in health sciences faculties. Specific recommendations could focus on enhancing student engagement in scientific research, integrating research practices early in the curriculum, and strengthening institutional support and research culture to foster a scientific mindset among students. The conclusions drawn are consistent with the findings, but it would be stronger with more emphasis on practical implications. How can universities implement the study’s findings? What are the next steps for research in this area?\nLimitations:\nPotential Information Bias: The study should acknowledge the possibility of information bias due to unmeasured variables that could act as confounders. Selection Bias: The study's focus on students from Norbert Wiener University raises concerns about selection bias. The lack of representativeness of the broader student population may limit the generalizability of the findings. It's essential to explicitly state how this bias might have influenced the results and the extent to which the findings can be applied to other universities or contexts. Participation Bias: The potential for participation bias should be addressed, particularly if students who participated in the study differ systematically from those who did not.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [] }, { "id": "299561", "date": "26 Jul 2024", "name": "Valia Luz Venegas Mejia", "expertise": [], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe results provide specific information to improve the quality of the research process in universities, since the association that is revealed would allow its implementation focused on the best use of the budget, recognition and other criteria linked to the research process of the mechanisms of quality assurance of universities at the national and international level.\nMain points The sources are relevant and current, they allow the research to be supported. The methodological design is solid, requiring statistical techniques consistent with the findings. Meets the journal's publication criteria. The interpretations of the statistical figures and tables present the most notable data, which are supported by the discussion of the results. Tables can be easily viewed to expand information and understanding.\n\nMinor points Although the conclusions are supported by the arguments, it would be advisable to accompany it with more relevant statistical results of the findings when the findings are described and supported.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] } ]	1	https://f1000research.com/articles/13-5
https://f1000research.com/articles/13-1022/v1	09 Sep 24	{ "type": "Research Article", "title": "Influence of auditory-based cognitive training on auditory resolution, executive function, and working memory skills in individuals with mild cognitive impairment – a pilot randomized controlled study", "authors": [ "Priya G", "Kishan MM", "VaniLakshmi R", "Gopee Krishnan", "Priya G", "Kishan MM", "VaniLakshmi R" ], "abstract": "Background Age-related central auditory processing disorder and mild cognitive impairment (MCI) can be concomitant in older adults, making it difficult to communicate, especially in challenging listening conditions. This preliminary study investigated the efficacy of auditory-based cognitive training on the auditory processing abilities and cognitive functions of older adults with MCI.\n\nMethods In this randomized controlled trial twenty-two older adults with mild cognitive impairment (MCI) were randomly assigned to either an experimental (n=11) or a control group (n=11). The experimental group received 15 cognitive training sessions through tasks involving the auditory domain. The outcome measures of this study included auditory resolution (Temporal gap detection, frequency discrimination, and modulation detection) and cognitive measures (Trail making tests and digit recall), which were administered at three-time points (before training, post-training, and follow-up). The linear mixed model computed the effects of training on the outcome measures.\n\nResults A significant improvement was observed in the modulation detection threshold between baseline and follow-up and between post-training and follow-up sessions. However, GDT and FD thresholds did not reveal any statistically significant difference. In the trail making test, Part B showed consistent significance across the time points, whereas Part A and the delayed recall task showed no significant difference.\n\nConclusion Auditory-based cognitive training may improve auditory processing and executive function in older adults with mild cognitive impairment (MCI).\n\nTrial registration\nCTRI/2019/01/017073, registered on 14.01.2019", "keywords": [ "Mild cognitive impairment", "Auditory processing", "Cognitive training", "older adults", "memory." ], "content": "Introduction\n\nAging is a natural process that affects people, causing a decline in cognitive and sensory abilities.1 Aging leads to degenerative changes in the auditory structures and functions in older adults above 65 years, resulting in Presbycusis or Age-Related Hearing Loss (ARHL). Around 65% of adults above 60 experience this hearing loss, with the prevalence rate increasing from 15.4% among older adults above 60 to 58.2% among older adults above 90.2 ARHL is caused by the loss of sensory cells and degenerative changes in the central auditory nervous system.3 Another common condition that affects older adults is mild cognitive impairment (MCI). MCI is characterized by a decline in memory, attention, and cognitive function,4 and it is a precursor of dementia, especially if it is an amnestic type.5 ARHL makes it difficult to perceive speech, particularly in noisy environments, and can lead to a decline in cognitive function.6,7 MCI can exacerbate speech perception problems.8,9 Therapeutic management or training addressing sensory, cognitive, and learning issues may slow down or lessen the impact of aging.\n\nAuditory and cognitive training are important components of rehabilitation for both healthy and aging populations, including those with disorders. Auditory training actively involves the trainees distinguishing the sounds presented systematically.10 Although auditory training was initially used to enhance sensory refinement of speech sounds (bottom-up), literature shows it can also be beneficial for top-down processes, which are important for listening, especially in challenging conditions.11,12 Cognitive training involves using standardized tasks that are cognitively challenging to improve an individual’s cognitive functions.13 Studies have shown that cognitive interventions effectively enhance the cognitive function of older adults with Mild Cognitive Impairment (MCI).14–16 They also improve auditory and cognitive functions, enhancing speech perception in various situations.17,18\n\nMany people have shown interest in exploring this type of training to alleviate cognitive and perceptual impairments.11 In 2009, Smith conducted cognitive training sessions for older adults with normal cognitive function and observed improved auditory memory and attention.19 Similarly, Yusof et al. (2019) examined the benefits of auditory-cognitive training among older adults with and without neurocognitive impairment.20 Participants were trained in auditory perception, such as word and sentence recognition in noise, and auditory-cognitive tasks, such as word span, word order, and word position. Though both groups benefited from the training, improvement was more noticeable among individuals with normal cognitive functions in various domains. Similarly, in 2014 Avila and her colleagues studied the effectiveness of auditory training on the auditory and cognitive skills of older adults with Mild Cognitive Impairment. The training stimulated auditory skills such as auditory memory, selective attention, figure-ground, temporal processing, auditory closure, and binaural integration. The training resulted in the improvement of auditory skills but did not generalize to cognitive skills.21\n\nA recent study by Kawata et al. (2022) investigated the benefits of auditory and cognitive training in healthy older adults.22 They provided auditory-cognitive training (ACT), auditory training (AT), and cognitive training (CT). The results indicated that the ACT group exhibited significant differences in brain structure changes compared to the other groups. It is worth noting that the study had a limitation in that it relied solely on pure tone audiometry as an auditory measure.\n\nMurphy et al. (2011) conducted a study on the effectiveness of auditory training in an adult who had suffered a traumatic brain injury. The patient had difficulties with auditory processing and cognitive skills such as temporal processing, verbal memory, working memory, and verbal fluency. The auditory training not only enhanced auditory skills but also led to improvements in central processes (top-down processing), which consequently had a positive impact on cognitive abilities as well. Both auditory and cognitive training can strengthen neural pathways and circuits through training, leading to improved auditory perception and cognitive abilities.23 Therefore, actively involving older adults in such training can bring about changes in the brain, ultimately enhancing their auditory and cognitive functions.\n\nNumerous studies have demonstrated that cognitive interventions can enhance the quality of life in older adults with and without Mild Cognitive Impairment MCI.24–26 However, there is a dearth of literature on auditory-based cognitive training, and the few existing studies have varying participant selection, training materials, and assessment measures. One study evaluated auditory-based cognitive measures alongside auditory cognitive training, but they used pure tone audiometry as an outcome measure, which is a peripheral test considered to be less influenced by cognitive function.20 Therefore, the current study was designed to evaluate the impact of auditory-based cognitive training on auditory processing skills and cognitive abilities of older adults with cognitive impairment.\n\n\nMethods\n\nThis study was a pilot randomized controlled trial research, conducted at the Department of Speech and Hearing, Manipal College of Health Professions. This study included an experimental group which received cognitive training and a control group who did not receive any treatment. The assessment and training for all the participants were conducted at participants’ home in a silent environment. The procedures of this study were reviewed and approved by the Institutional Ethics Committee, Kasturba Hospital, Manipal (IEC 704/2017) on 15.11.2017, and the Clinical Trials Registry of India CTRI/2019/01/017073, registered on 14.01.2019.\n\nThe participants were recruited from the community (Udupi and nearby districts, Karnataka) through geriatric camps, community visits and screening inmates from old age homes. This preliminary study included 22 older adults with mild cognitive impairment (MCI). The group consisted of 11 males and 11 females, with a mean age of 69.18 (6.35). All participants had a Montreal Cognitive Assessment (MoCA) score between 19 and 25 and had no history of neurological conditions or psychological disorders. The participants were randomly assigned to either the control group (n=11) or the experimental group (n=11). All participants had normal or corrected-to-normal vision in both eyes. They also had a mean (SD) pure tone average of 21.4 (3.61) dBHL in the right ear and 23.4 (4.84) dBHL in the left ear, as assessed across audiometric frequencies (250, 500, 1 kHz, 2 kHz, 4 kHz, and 8 kHz). All participants were native Kannada Speakers with proficiency in reading and writing and had completed at least ten years of education.\n\nThe participants were randomized to either experimental group or control group based on the simple randomization method of picking chits. The enrolled participants were asked to pick a chit and based on that they were assigned to either of the groups. The primary investigator provided intervention to all the participants, however all the three assessments (pre, post and follow up) were conducted by qualified audiologist and speech and language pathologists who were not a part of this study. The statistical analysis was performed by the primary investigator, but the interpretation was made after discussing with other investigators of this study who were unaware of the group allocation including a statistician.\n\nExperimental group\n\nThe group’s participants underwent 15 sessions of Auditory-based cognitive training (AbCT) using Smriti Shravan Software Version 2 (Kumar, 2013)27 [https://sites.google.com/u/0/s/1L2VuSNH1Y6DhrjkLs830TtvUhNjcfmUb/edit?usp=sites_home]. Appropriate permission was obtained for the usage of all the assessment tools, screening checklist and training software for this study. The training was provided to all the participants in a relatively silent environment at their residence based on their preferences. Each session lasted 60 minutes and included various tasks such as Forward Span, Backward Span, Running Span, Ascending Span, Descending Span, and Math Span tasks. The training module for each task consisted of digits from 1 to 9 presented through auditory modality, and the number of digits presented varied from 2 to 9. The stimuli were presented in the Kannada language, and the training was provided through the laptop via speakers set at a comfortable loudness level. Before initiating the training, the baseline of the above-mentioned tasks for all the participants were obtained. For each participant the difficulty level of the training was decided based on their baseline performance. All the participants listened carefully to the digits and repeated them verbally in the required order based on their task.\n\nIn the Forward Span task, participants repeated all the digits they heard in the same order as quickly as possible. In the Backward Span task, they repeated the digits heard in reverse order. The Running Span task used digits from 1 to 9, and participants recalled the last n digits of a set of numbers as quickly as possible, where n varied from 2 to 9. In the Ascending Span task, participants repeated the digits in ascending order, while in the Descending Span task, they repeated the digits in descending order. In the Math Span test, participants memorized and recalled sequences of digits ranging from 2 to 6 while solving simple arithmetic operations.\n\nThe difficulty level of each task was varied by increasing the number of digits from 2 to 9 based on their performance. To progress to the next level, participants had to achieve an accuracy score of 80%. If they did not meet this requirement, they continued training with the same task until they achieved a score of 80%. Only data from participants who attended at least eight sessions (more than 50% of the training) was considered for analysis. All participants’ data were included in the analysis since they attended the minimum required sessions. Assessments were conducted at three time points - baseline, post-training (after 15 days), and follow-up (after one month).\n\nControl group\n\nThe control group did not receive any intervention and was observed for the same duration as the experimental group. They remained passive throughout the study as they were not assigned any activity, unlike the training provided to the experimental group.\n\nThe study used Angel SoundTM, a free PC-based interactive listening rehabilitation program developed by Tiger Speech Technology, to measure individuals’ auditory resolution measures. This measure aimed to assess the listeners’ ability to distinguish subtle acoustic differences in spectral, temporal, and amplitude domains, which form the foundation for complex speech perception. The program uses a two-down/one-up adaptive method presented in a three-alternative-forced-choice paradigm. The adaptive run stops after 30 trials, with at least four reversals. The threshold is calculated as the average response across the reversals, achieving a 71% accuracy convergence.\n\nThe Frequency Discrimination (FD) test was conducted using three pure tones lasting 300 milliseconds each, with a rise and fall time of 10 milliseconds. These tones were separated by an interstimulus interval (ISI) of 500 milliseconds. Two of the three tones had a frequency of 1000 Hz, considered the standard frequency, while one had a different frequency. The initial frequency difference between the standard and different frequencies was 25.6 Hz. The step size was adjusted according to individual subjects.\n\nThe task of detecting temporal modulation (MD) involved three carrier stimuli of broadband noise (BBN), each lasting 350 milliseconds, with an inter-stimulus interval (ISI) of 500 milliseconds. One of the three intervals was modulated at 10 Hz, whereas the other had no modulation. The modulation depth of the stimulus ranged from no modulation (No) to a minimum of 1% modulation depth (-40 dB) and a maximum of 100% modulation (0 dB). The software adopts a 1 dB step size for stimulus presentation.\n\nThe Gap Detection Task (GDT) consisted of three bursts of Broadband Noise (BBN) sounds, each lasting 250 milliseconds, with a 500-millisecond pause between them. One of the three intervals contained a silent gap in the middle of the noise bursts, while the other two contained only noise bursts. The duration of the silent gap varied from trial to trial based on the participant’s response. The software adopts a step size of 1 ms (0 to 10 ms), 2 ms (10 to 20 ms), 5 ms (20 to 50 ms), 10 ms (50 to 100 ms), 20 ms (100 to 200 ms) and 50 ms (200 to 500 ms) respectively between the presentations.\n\nThe stimuli used in the test were played through a MAICO MA53 clinical audiometer calibrated beforehand via speakers in a quiet environment. The intensity of the sounds was adjusted to each participant’s most comfortable level (MCL).\n\nThe study assessed the cognitive abilities of the participants using the Neurocognitive Toolbox (ICMR-NCTB), which The Indian Council of Medical Research developed. For this study, two tests from the toolbox were considered: the Trail Making Test (TMT) and the Verbal Learning Test. The TMT (Black & White) evaluates a person’s executive function through two segments: TMT Part A and TMT Part B. In TMT Part A, the participant must draw a line sequentially connecting 25 numbered circles on a page as quickly as possible. In TMT Part B, the participant must connect circles while alternating between numbers and circles in two colors, black and white. The TMT Part B is more challenging and takes longer time than TMT Part A. Both parts are timed, and the time taken to complete the task is recorded as the response. The difference in time to complete the task between Part A and Part B estimates the person’s executive function index (Part B-A).\n\nThe Verbal Learning Test measures the participants’ episodic memory and records their immediate and delayed recall and recognition memory. The test presents a set of ten unrelated words orally to the participants over three trials. After each trial, the participants are asked to recall the words immediately in any order, and their responses are recorded. After 20 minutes, the participants are asked to recall the set of 10 words and identify the 10 words from a list of similar words.\n\nLinear mixed model analyses were performed on the scores obtained during pre-, post, and follow-up performances. The dependent variables were the responses from Trail Making Tests, auditory resolution tasks, and delayed recall. We added fixed effects of cognitive assessment across time and group and the possible interaction between group and time. We used Jamovi software (version 2.3.28) to compute statistical data.\n\n\nResults\n\nA diagram of participant flow is shown in Figure 1. During the study period, out of 43 participants who were assessed for eligibility, 22 of them were enrolled in the study. All 22 participants completed the training or observation, and their data was included for analysis. Table 1 presents the mean and SD values for auditory resolution tasks, TMT, and DR outcome measures. The study found that AbCT was effective in three outcome measures: MD, TMT-B, and TMT B-A. The MD task showed a significant main effect of group versus time interaction (p=0.038). However, no significant main effect was observed for either group (p=0.497) or time (p=0.186). No significant main effect of time, group, or interaction between time and group was found for the FD and GDT tasks.\n\na Significant between baseline and post-training.\n\nb Significant between post-training and follow-up.\n\nc Significant between baseline and follow-up.\n\nFor the TMT-A task, there were no significant differences in time (p=0.164), group (p=0.733), and the interaction between group and time (p=0.196). However, significant main effects of time and group versus time interaction were observed in Part B and Part B-A, respectively, while the group effect was insignificant. There was a significant difference in the delayed recall tasks over time (p<0.001), but not between groups (p=0.525) or group versus time (p=0.575).\n\nPost hoc analysis revealed a significant score difference between baseline-follow-up and post-follow-up in the Modulation Detection task. Furthermore, TMT-B and TMT B-A had statistically significant differences (p=0.023) during the TMT in the baseline-post and baseline-follow-up conditions.\n\n\nDiscussion\n\nThis study aimed to investigate the benefits of AbCT in improving auditory processing and cognitive functions among older adults with mild cognitive impairment. The results revealed that AbCT positively impacted MD function, but no significant improvements were observed in FD and GDT. Similarly, TMT-B (executive function) showed significant differences compared to TMT-A and DR.\n\nThe positive impact of AbCT can be explained by two mechanisms involved in auditory processing. The first mechanism is the neurocognitive mechanism of acoustic signals, which discriminates and recognizes specific functions. The second mechanism is the attentional process, involving phenomena such as attention and memory.23 Anderson et al. (2013) conducted a study to evaluate the effect of auditory training with six modules designed to increase the speed and accuracy of auditory processing cognitive training on the temporal precision of subcortical speech processing in noise using frequency following response (FFR).17 They observed that the trained group exhibited faster neural timing and experienced improvements in memory, processing speed, and speech-in-noise perception compared to the control group. Song et al. (2012) investigated training-related malleability using a program that included cognitive based listening exercises to enhance speech-in-noise perception.28 The trained individuals showed significant improvements in speech-in-noise perception, sustained even after six months of training. The subcortical responses in noise showed enhancements in the encoding of pitch-related cues, particularly for the time-varying portion of the syllable most susceptible to perceptual disruption. Similarly, Carcagno and Plack (2011) observed that the robustness of FFR neural phase locking to the sound envelope increased significantly more in trained individuals (pitch contour training) than in the control group.29 These studies support the neurocognitive process and suggest that auditory cognitive training, or AbCT, can improve auditory processing.\n\nAttentional processes and working memory are crucial in speech perception, especially in the presence of background noise. A study by Wong et al. (2010) found that activity in the prefrontal cortex and regions associated with memory and attention in speech perception in noisy environments increased, indicating that cognitive compensation may play a crucial role in aiding hearing in noisy environments and that the recruitment of general cognitive areas accompanies declines in sensory processing.30 Similarly, O’Brien et al. (2017) provided auditory cognitive training (Brain fitness) to healthy older adults and observed that a P3b event-related potentials amplitude, latency, and P1-N1-P2 complex significantly improved post-training. However, no advantage was found in auditory perceptual processing.31 Studies have shown that P3b originates from temporal-parietal activity associated with attention and appears related to subsequent memory processing.32 Therefore, our study emphasized that AbCT could improve the efficiency of attention allocation and working memory, which might explain the training-related changes in the auditory processing and neurocognitive processes.\n\nThe differences in performance between the GDT and TMTF tests may be due to the sensitivity and reliability of the training and testing methods. A study by Yusof et al. (2019) investigated the impact of auditory-cognitive training on older adults with normal cognitive function and neurocognitive impairment.20 They found that there was an improvement in some auditory measures such as HINT (quiet), GIN, PPST (humming), and DDT but not in HINT (Composite) and PPST (verbal) for both normal cognitive (NC) and neurocognitive impairment (NCI) groups. Additionally, they observed that the NC group showed more significant improvements than the NCI group, suggesting a higher potential for learning among NC participants. Furthermore, Shen (2014) reported no correlation between GDT and TMTF, and that age and hearing status had no impact on the tests. However, TMTF sensitivity improved as hearing thresholds decreased and worsened with age.33\n\nThe other finding of our study revealed that the AbCT training positively impacted central executive function and attention, as indicated by a significant improvement in TMT-B and TMT B-A, while TMT-A and DR remained unaffected. This suggests that the training primarily influenced cognitive abilities related to attention and executive function rather than psychomotor skills or working memory. This observation agrees with the study by Kawata et al. (2022). They compared four groups - an auditory cognitive training group, an auditory training group, a cognitive training group, and a control group. The results showed that the auditory cognitive training group demonstrated more significant changes in regional gray matter volume in several brain regions than the other groups. The auditory training group significantly improved auditory measures and increased regional gray matter volume and functional connectivity (FC) in the left temporal pole.22 These observations suggest there exists a functional connectivity between the auditory and cognitive processes. Therefore, auditory and cognitive training can improve cognitive and auditory skills in healthy older adults. However, they used a pure tone audiometer as an outcome measure that was less influenced by cognitive and auditory training. A study by Ruscheweyh et al. (2013) reported that executive function is related to regional gray matter volume, also a biomarker, in healthy older individuals.34,35 These studies justify the improvement in executive function. Henceforth, older adults with MCI can benefit from AbCT. No significant difference in digit recall could be attributed to the persistence of benefits for speed of processing/auditory processing but not for memory, which is consistent with the findings of Borella et al. (2010), who showed that older adults maintained training enhancements for fluid intelligence and speed of processing but not for memory.36\n\nThe current study results evaluated the potential of AbCT on the auditory and cognitive skills of older adults with MCI. However, these findings may not be generalized to a wider population due to several concerns. First, the relatively smaller sample size and the absence of electrophysiological tests, which are considered the highest level of evidence for assessing training-related benefits. Second, the characteristics of the participants involved in the study, where recruitment was based on MoCA screening rather than clinical diagnosis of MCI, may have influenced the results. This is mainly due to challenges in obtaining consent from the participants to undergo detailed cognitive and audiological assessment due to practical issues, less motivation, and family consent. Additionally, the number and duration of the training sessions were determined based on a literature search. An interventional study recommended an optimal dose of 12 to 14 sessions for cognitive training and 15 to 20 sessions for multidomain training. Variations in the individual characteristics of the participants were also observed in the study, which directly impacted the optimal dose and dose-response functions.37\n\nThe secondary concern is that the heterogeneity of the MCI population makes it challenging to apply the findings broadly. Though all the participants were recruited based on the cut off score of MCI, their performance on the auditory, cognitive and baseline assessment before training were highly variable. Participants in this study performed slightly poorer in digit span tasks (forward and backward) when compared to a normative data obtained from older adults with MCI.38 We also observed significant variability in the baseline data of the experimental and control groups, which we tried addressing using linear mixed models for statistical analysis, accounting for unbalanced data. As this was a preliminary study, future randomized controlled trials (RCTs) must consider these variations and address these limitations.\n\n\nConclusion\n\nThis current preliminary study suggests that AbCT seems to restore age-related deficits in temporal processing in the brain, promoting better cognitive and perceptual skills, particularly in older adults with MCI. The results also suggest that auditory temporal skills could be adaptable and can be a favorable prognostic indicator. However, further research in this area is warranted with a large sample size to determine whether such auditory cognitive training can change auditory and cognitive functions.\n\n\nEthics and consent\n\nThis study protocol was reviewed and approved by the Institutional Ethics Committee, Kasturba Hospital, Manipal (IEC 704/2017) on 15.11.2017, and the Clinical Trials Registry of India (CTRI/2019/01/017073). Written informed consent was obtained from all the participants who participated in this study.", "appendix": "Data availability\n\nName of the repository: Open Science Framework\n\nProject Title: Influence of Auditory-Based Cognitive Training on Auditory Resolution, Executive function, and Working Memory Skills in individuals with Mild Cognitive Impairment – A Preliminary study, DOI: 10.17605/OSF.IO/3J67R. 39\n\nThis project contains the following underlying data:\n\n• Data for repository.xlsx\n\n• Clinical Trial Protocol.pdf\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nName of the repository: Open Science Framework\n\nProject Title: Influence of Auditory-Based Cognitive Training on Auditory Resolution, Executive function, and Working Memory Skills in individuals with Mild Cognitive Impairment – A Preliminary study, DOI: 10.17605/OSF.IO/3J67R. 39\n\nThis project contains the following underlying data:\n\n• CONSORT 2010 Checklist & Flowchart.pdf\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgements\n\nThe authors express their gratitude to all the participants of this study.\n\n\nReferences\n\nDeal JA, Betz J, Yaffe K, et al.: Hearing impairment and incident dementia and cognitive decline in older adults: the health ABC study. J. Gerontol. A Biol. Sci. Med. Sci. 2017; 72(5): 703–709.\n\nWorld Health Organization: World report on hearing. World Health Organization; 2021.\n\nJayakody DM, Friedland PL, Martins RN, et al.: Impact of aging on the auditory system and related cognitive functions: a narrative review. Front. Neurosci. 2018; 12: 125. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nEshkoor SA, Hamid TA, Mun CY, et al.: Mild cognitive impairment and its management in older people. Clin. Interv. Aging. 2015; 10: 687–693. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nJanoutová J, Serý O, Hosák L, et al.: Is mild cognitive impairment a precursor of Alzheimer’s disease? Short review. Cent. Eur. J. Public Health. 2015; 23(4): 365–367. PubMed Abstract \| Publisher Full Text\n\nKawata NY, Nouchi R, Saito T, et al.: Subjective hearing handicap is associated with processing speed and visuospatial performance in older adults without severe hearing handicap. Exp. Gerontol. 2021; 156: 111614. PubMed Abstract \| Publisher Full Text\n\nShechter Shvartzman L, Lavie L, Banai K: Speech perception in older adults: an interplay of hearing, cognition, and learning? Front. Psychol. 2022; 13: 816864. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBisogno A, Scarpa A, Di Girolamo S, et al.: Hearing loss and cognitive impairment: epidemiology, common pathophysiological findings, and treatment considerations. Life. 2021; 11(10): 1102. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMcClannahan KS, Mainardi A, Luor A, et al.: Spoken word recognition in listeners with mild dementia symptoms. J. Alzheimers Dis. 2022; 90(2): 749–759. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSchow RL, Nerbonne MA: Introduction to audiologic rehabilitation. (No Title). 2002.\n\nPichora-Fuller MK, Levitt H: Speech comprehension training and auditory and cognitive processing in older adults.2012.\n\nFerguson MA, Henshaw H: Auditory training can improve working memory, attention, and communication in adverse conditions for adults with hearing loss. Front. Psychol. 2015; 6: 137455. Publisher Full Text\n\nLampit A, Hallock H, Valenzuela M: Computerized cognitive training in cognitively healthy older adults: a systematic review and meta-analysis of effect modifiers. PLoS Med. 2014; 11(11): e1001756. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHe W, Wang M, Jiang L, et al.: Cognitive interventions for mild cognitive impairment and dementia: an overview of systematic reviews. Complement. Ther. Med. 2019; 47: 102199. Publisher Full Text\n\nZhang H, Huntley J, Bhome R, et al.: Effect of computerised cognitive training on cognitive outcomes in mild cognitive impairment: a systematic review and meta-analysis. BMJ Open. 2019; 9(8): e027062. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nChan AT, Ip RT, Tran JY, et al.: Computerized cognitive training for memory functions in mild cognitive impairment or dementia: a systematic review and meta-analysis. NPJ Digit. Med. 2024; 7(1): 1. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAnderson S, White-Schwoch T, Parbery-Clarka A, et al.: Reversal of age-related neural timing delays with training. Proc. Natl. Acad. Sci. USA. 2013; 110: 4357–4362. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAthilingam P, Edwards JD, Valdes EG, et al.: Computerized auditory cognitive training to improve cognition and functional outcomes in patients with heart failure: results of a pilot study. Heart Lung. 2015; 44: 120–128. PubMed Abstract \| Publisher Full Text\n\nSmith GE, Housen P, Yaffe K, et al.: A cognitive training program based on principles of brain plasticity: results from the Improvement in Memory with Plasticity-based Adaptive Cognitive Training (IMPACT) Study. J. Am. Geriatr. Soc. 2009; 57(4): 594–603. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nYusof Y, Mukari SZMS, Dzulkifli MA, et al.: Efficacy of a newly developed auditory–cognitive training system on speech recognition, central auditory processing and cognitive ability among older adults with normal cognition and with neurocognitive impairment. Geriatr. Gerontol. Int. 2019; 19(8): 768–773. PubMed Abstract \| Publisher Full Text\n\nÁvila RRDA, Murphy CFB, Schochat E: Effects of auditory training in elderly with mild cognitive impairment. Psicologia: Reflexão e Crítica. 2014; 27: 547–555.\n\nKawata NY, Nouchi R, Oba K, et al.: Auditory cognitive training improves brain plasticity in healthy older adults: Evidence from a randomized controlled trial. Front. Aging Neurosci. 2022; 14: 826672. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMurphy CFB, Fillippini R, Palma D, et al.: Auditory training and cognitive functioning in adult with traumatic brain injury. Clinics. 2011; 66: 713–715. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHill NT, Mowszowski L, Naismith SL, et al.: Computerized cognitive training in older adults with mild cognitive impairment or dementia: a systematic review and meta-analysis. Am. J. Psychiatry. 2017; 174(4): 329–340. Publisher Full Text\n\nYun S, Ryu S: The effects of cognitive-based interventions in older adults: a systematic review and meta-analysis. Iran. J. Public Health. 2022; 51(1): 1–11. PubMed Abstract \| Publisher Full Text\n\nLi F, Parsons J, Peri K, et al.: Effects of cognitive interventions on quality of life among adults with mild cognitive impairment: A systematic review and meta-analysis of randomised controlled trials. Geriatr. Nurs. 2022; 47: 23–34. PubMed Abstract \| Publisher Full Text\n\nKumar AU, Sandeep M: Auditory cognitive training module. Mysore: ARF funded departmental project submitted to All India Institute of Speech and Hearing; 2013.\n\nSong JH, Skoe E, Banai K, et al.: Training to improve hearing speech in noise: biological mechanisms. Cereb. Cortex. 2012; 22(5): 1180–1190. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCarcagno S, Plack CJ: Subcortical plasticity following perceptual learning in a pitch discrimination task. J. Assoc. Res. Otolaryngol. 2011; 12: 89–100. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWong PC, Ettlinger M, Sheppard JP, et al.: Neuroanatomical characteristics and speech perception in noise in older adults. Ear Hear. 2010; 31(4): 471–479. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nO’Brien JL, Lister JJ, Fausto BA, et al.: Cognitive training enhances auditory attention efficiency in older adults. Front. Aging Neurosci. 2017; 9: 322. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPolich J: Updating P300: an integrative theory of P3a and P3b. Clin. Neurophysiol. 2007; 118(10): 2128–2148. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nShen Y: Gap detection and temporal modulation transfer function as behavioral estimates of auditory temporal acuity using band-limited stimuli in young and older adults. J. Speech Lang. Hear. Res. 2014; 57(6): 2280–2292. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nRuscheweyh R, Deppe M, Lohmann H, et al.: Executive performance is related to regional gray matter volume in healthy older individuals. Hum. Brain Mapp. 2013; 34(12): 3333–3346. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCristofori I, Zhong W, Chau A, et al.: White and gray matter contributions to executive function recovery after traumatic brain injury. Neurology. 2015; 84(14): 1394–1401. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBorella E, Carretti B, Riboldi F, et al.: Working memory training in older adults: evidence of transfer and maintenance effects. Psychol. Aging. 2010; 25(4): 767–778. PubMed Abstract \| Publisher Full Text\n\nBelleville S, Cloutier S, Mellah S, et al.: Is more always better? Dose effect in a multidomain intervention in older adults at risk of dementia. Alzheimers Dement. 2022; 18(11): 2140–2150. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nTripathi R, Kumar K, Bharath S, et al.: Indian older adults and the digit span A preliminary report. Dement. Neuropsychol. 2019; 13: 111–115. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPriya G, Krishnan G, Kishan MM, et al.: Influence of Auditory-Based Cognitive Training on Auditory Resolution, Executive function, and Working Memory Skills in individuals with Mild Cognitive Impairment – A Preliminary study.2024. Publisher Full Text" }	[ { "id": "329238", "date": "25 Oct 2024", "name": "Karen Banai", "expertise": [ "Reviewer Expertise Cognitive hearing science", "perceptual learning of speech." ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this preliminary study, the potential contribution of auditory-cognitive training to auditory processing and to performance on two cognitive tasks (recall and trail making) was studied using a RCT. Participants were 22 older adults with MCI randomized to an intervention and a control group. The intervention group participated in 15 1-hour training sessions focused on auditory span tasks using digits. All participants were tested on the auditory and cognitive outcome measures at three time points: pre- post- and follow-up. Some improvements in the outcome measures were observed over time , but it is unclear whether they can be consistently attributed to training.\nThe study is generally well designed, and used tester-blinding to minimize researcher-related bias. Note that my review did not cover the inclusion criteria and the diagnosis of MCI. Comments on specific aspects of the study are listed below. These should be addressed to make the study sounder.\nGeneral 1) Although are-related hearing loss and MCI often co-occur, no model of the potential causal associations is presented. Therefore, it is not clear why auditory memory training should have influenced auditory processing as assessed by the gap, frequency and modulation tasks.\n\n2) On a related note, one of the motivations for this study was that only few previous studies delivered cognitive training via the auditory modality to people with MCI. However, if auditory processing is one of the contributing factors to the cognitive profile of people with MCI, why is it desirable to deliver training via the auditory modality? 3) One recent systematic review on the effects of cognitive training in MCI is cited, but others are not (e.g., Kudlicka, A., Martyr, A., Bahar-Fuchs, A., Sabates, J., Woods, B., & Clare, L. (2023 [Ref - 1]). Cognitive rehabilitation for people with mild to moderate dementia. The Cochrane database of systematic reviews, 6(6), CD013388. https://doi.org/10.1002/14651858.CD013388.pub2).\nMethods 1) Age, hearing and MOCA are not reported separately for each group, making it hard to determine whether the randomization yielded well matched groups. This is a concern given some of the data reported in Table 1 which would suggest that the two groups may not have been well matched on the outcome measures at the onset of the study. 2) It is not clear whether the same versions of the cognitive outcome measures were used across the pre- post- and follow-up tests or if parallel forms were used. 3) Whereas the title and the abstract of the paper suggest that auditory working memory was targeted as an outcome measure, a verbal learning test is described in the methods, which has a working memory component, but may not be as clear index of working memory as other tests. 4) Although testers during the pre- post- and follow-up tests were blind to whether participants received training or not, the use of an untrained group that received no alternative or sham intervention would make it hard to determine whether outcomes are a byproduct of the specific intervention or of participants having received any sort of intervention (see Jacoby, N., & Ahissar, M. (2013 [Ref - 2]). What does it take to show that a cognitive training procedure is useful? A critical evaluation. Progress in brain research, 207, 121–140. https://doi.org/10.1016/B978-0-444-63327-9.00004-7). 5) How were the training session distributed? Daily? Weekly? Some other schedule? 6) What was the schedule for the pre- post- and follow-up tests? Did the two groups follow the same schedule?\nData presentation and analysis 1) The statistical model used is not fully reported. (a) What were the random effects? (b) What kind of follow-up or planned comparisons were used to obtain the effects between test times that are reported with the a,b,c indices in Table 1? (c) It is not clear whether the F-values in Table 1 describe group, time or interaction effects. (d) Table 1 suggests that the significance in modulation detection may have been driven by pre- to post- changes in the control group. In the absence of a more detailed description of the statistical outcomes and tests, it is hard to justify the discussion statement that “The results revealed that AbCT positively impacted MD function...”.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [] }, { "id": "332064", "date": "24 Dec 2024", "name": "Sandeep Maruthy", "expertise": [ "Reviewer Expertise Audiology" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntroduction The introduction is well-written, with the authors providing a strong justification for the study by critically evaluating existing research in the field. Method Rephrase: to 'The participants were randomly assigned to either the experimental group or the control group using a simple randomization method involving the drawing of chits.'\nSmriti Shravan Software Version 2 was developed by (Kumar & Maruthy, 2013). Correct it.\n\npost-training (after 15 days): after 15 days of what? follow-up (after one month): after 1 month of what?\nThe authors' decision to use 8 sessions as the criterion for considering data for analysis should be justified.\nThe time points at which the control group was tested should be defined\nThe control group did not receive any training. In such a case how do you judge that auditory-cognitive training made the difference in the performance. It could be mere training of any form. Include explanation for this.\nGive an operational definition of ' Auditory resolution measures' 'ms' is a standard abbreviation for milliseconds. Consider using the abbreviation. The authors state that 'The step size was adjusted according to individual subjects.' - how was it adjusted? please provide more details.\n\nIn the sentence 'The task of detecting temporal modulation (MD) involved three carrier stimuli of broadband noise (BBN), each lasting 350 milliseconds, with an inter-stimulus interval (ISI) of 500 milliseconds.', it is not clear as to what is the task of the subject. Please rephrase.\n\nResults Figure 1 can be moved to the end of Method section. It is appreciated that the subjects were randomly assigned to the control and experimental groups. However, it is recommended to statistically confirm that there is no significant difference between the two groups in the baseline assessment.\nIt is stated that \"All 22 participants completed the training or observation,\" which is incorrect. Only 11 participants underwent the training.\nDiscussion The discussion is well-written; however, using this research design makes it challenging for the authors to attribute the observed improvements solely to auditory cognitive training. This limitation will remain a caveat of the study.\nGeneral comment: The manuscript would benefit from a more thorough proofreading to enhance its readability.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13061", "date": "13 Jan 2025", "name": "Gopee Krishnan", "role": "Author Response", "response": "Revision 1: Reviewer Comments 1.Method Rephrase: to 'The participants were randomly assigned to either the experimental group or the control group using a simple randomization method involving the drawing of chits.' Corrections: Comments accepted and modified Location: Methods section, Randomization and Blinding paragraph 2.Smriti Shravan Software Version 2 was developed by (Kumar & Maruthy, 2013). Correct it. Corrections: Comments accepted and incorporated Location: Methods section, Experimental group 1st paragraph 3.The authors' decision to use 8 sessions as the criterion for considering data for analysis should be justified. Clarification: It was the minimum criterion set earlier for inclusion of data for analysis and to minimize loss of data due to attrition. All participants completed fifteen training sessions. Therefore, the phrase “8 sessions as the criterion for considering data for analysis” can be removed. Location: Methods section, Experimental group 3rd paragraph 4.post-training (after 15 days): after 15 days of what? follow-up (after one month): after 1 month of what? Corrections: Comments accepted and modified as [post-training (after 15 days of training) Follow-up (after one month of post-training assessment)] Location: Methods section, Experimental group 3rd paragraph 5.The time points at which the control group was tested should be defined Corrections: Suggestion accepted and incorporated. Assessments were conducted for the control group at three-time points: baseline, post-observation (15 days after the baseline assessment), and follow-up observation (one month after the post-observation assessment). Location: Methods section, Control group paragraph 6.Give an operational definition of 'Auditory resolution measures' Corrections: The auditory resolution measure refers to an individual's ability to detect the smallest variations in a given stimulus, such as variations in frequency (Hz) and time (dB or ms). Location: Methods section, Auditory resolution measures paragraph 7.'ms' is a standard abbreviation for milliseconds. Consider using the abbreviation. Corrections: Comments accepted and modified Location: Auditory resolution measures, 2nd paragraph 8.The authors state that 'The step size was adjusted according to individual subjects.' - how was it adjusted? please provide more details. Corrections: The software adjusted the step size based on participant responses. It gradually increased the step size for incorrect responses and decreased it for correct responses. Location: Auditory resolution measures, 2nd paragraph 9.In the sentence 'The task of detecting temporal modulation (MD) involved three carrier stimuli of broadband noise (BBN), each lasting 350 milliseconds, with an inter-stimulus interval (ISI) of 500 milliseconds.', it is not clear as to what is the task of the subject. Please rephrase. Corrections: Suggestion accepted and modified. “The temporal modulation task involved three carrier stimuli consisting of broadband noise (BBN). Each stimulus lasted for 350 milliseconds, and there was an inter-stimulus interval (ISI) of 500 milliseconds. Participants were instructed to identify the stimulus that was different (modulated) from the other two stimuli”. Location: Auditory resolution measures, 3rd paragraph 10.Results Figure 1 can be moved to the end of Method section. Corrections: Accepted and moved. Location: Methods section 11.It is stated that \"All 22 participants completed the training or observation,\" which is incorrect. Only 11 participants underwent the training. Corrections: All 11 participants in the experimental group completed the training, and their data was included in the analysis. Location: Results section, 1st paragraph 12.It is appreciated that the subjects were randomly assigned to the control and experimental groups. However, it is recommended to statistically confirm that there is no significant difference between the two groups in the baseline assessment. Corrections: Suggestion accepted. A table for Baseline Demographic Information is included below. The explanation related to the table is included in the text. “The statistical analysis indicated no significant differences in baseline assessments between the control and experimental groups for most outcome measures, except for TMT Part B-A”. Location: Results section, 1st paragraph Given the significant differences observed at baseline for TMT Part B-A, post-training significance should be interpreted cautiously before generalizing. Location: Discussion section, 5th paragraph 13.Discussion The discussion is well-written; however, using this research design makes it challenging for the authors to attribute the observed improvements solely to auditory cognitive training. This limitation will remain a caveat of the study. Corrections: Thank you for the suggestion. This limitation is included in the revised manuscript. 14.The control group did not receive any training. In such a case how do you judge that auditory-cognitive training made the difference in the performance. It could be mere training of any form. Include explanation for this. Corrections: We agree that the difference in performance of the control group needs explanation. Including an active control group in this study would have eliminated the possibility of a placebo effect in the experimental group. Additionally, various factors, such as participant motivation and health condition on the day of assessment, could have influenced their performance. Furthermore, the literature supports the absence of evidence indicating differences between the active and passive control groups in cognitive interventions (Au et al., 2024). Location: Discussion section, 7th paragraph General comment: The manuscript would benefit from a more thorough proofreading to enhance its readability. Table 1 Baseline Demographic Information Variables Experimental group (n=11) Mean (SD) Control group (n=11) Mean (SD) p-value Age (years) EG: 70.4 (5.71) CG: 68.0 (7.18) p-value: 0.403 MoCA EG: 22.2 (1.99) CG: 21.5 (2.16) p-value: 0.481 FD EG:129.36 (119.20) CG: 56.45 (41.45) p-value: 0.070 MD EG: -13.75 (2.32) CG: -14.02 (3.83) p-value: 0.847 TGD EG: 22.71 (42.48) CG: 9.65 (3.88) p-value: 0.322 TMT Part A EG: 98.27 (46.29) CG: 99.27 (29.15) p-value: 0.952 TMT Part B EG: 289.73 (120.36) CG: 217.73 (47.82) p-value: 0.080 TMT Part B-A EG: 191.45 (80.71) CG: 118.45 (33.09) p-value: 0.012* DR EG: 4.55 (3.45) CG: 5.55 (2.30) p-value: 0.433 *Level of Significance (p<0.05)" } ] } ]	1	https://f1000research.com/articles/13-1022
https://f1000research.com/articles/13-392/v1	25 Apr 24	{ "type": "Research Article", "title": "Injury incidence and associated factors among soccer players during the 2021 African Cup of Nations competition", "authors": [ "Amr Chaabeni", "Amine Kalai", "Helmi Ben Saad", "Yacine Zerguini", "Montassar Tabben", "Karim Chamari", "Anis Jellad", "Amr Chaabeni", "Amine Kalai", "Helmi Ben Saad", "Yacine Zerguini", "Montassar Tabben", "Karim Chamari" ], "abstract": "Background Understanding the epidemiology of soccer injuries during specific international competitions is essential for customizing preventive strategies. Several studies have reported outcomes related to international competitions but, to the best of our knowledge, there has been no investigation into the injury patterns during any African Cup of Nations (AFCON) tournaments. This study aimed to analyse the incidence and the characteristics of soccer injuries during the 2021 African Cup of Nations (AFCON), which took place in Cameroon from January 9 to February 6, 2022.\n\nMethods A video-based analysis covering 52 matches was conducted by two independent consultant physicians. They reviewed injury replays to determine incidence and characteristics ( i.e. ; mechanisms, body location, match moment, player substitution, absence in the next match, and referee decisions).\n\nResults The tournament involved 519 male players, comprising 275 African (ALP) and 244 Non-African (NALP) league players. Eighty-seven injuries occurred, with incidences of 1.7 and 48.8 injuries per match and per 1000 match hours, respectively. Injury incidence rose with competition stages, particularly contact mechanism injuries. Non-contact injuries (23/87) predominantly occurred after 60 minutes of play (19/23), with the thigh being the most frequently affected body part (18/87). Older age and playing time significantly correlated with injury occurrence (p=0.032 and p<0.001, respectively). NALP midfielders and forwards were notably injured by contact mechanisms (36/45) in the attacking zone. Although non-contact mechanisms were more common in ALP than NALP (13/42 vs. 9/45), the difference lacked statistical significance (p=0.240), with a higher rate of muscle injuries (13/42 vs. 10/45, p=0.001).\n\nConclusion Muscle injuries prevailed among professional soccer players in the 2021 AFCON, with older age and playing time identified as key associated factors. Muscle injuries were more prevalent in ALP compared to NALP.", "keywords": [ "Africa", "Epidemiology", "On-field injury", "Athletes", "Football", "Sport" ], "content": "Introduction\n\nSoccer is a universally popular sport, boasting over 265 million licensed players globally, of which 46 million reside in Africa.1 According to the Federation International de Football Association (FIFA), there are 128983 soccer professional players worldwide, with Africa contributing 22525, as per the Professional Football 2019 Report.2 The physical demands of soccer, characterized by repetitive and high-impact movements, put players at a high risk of injuries.3 Epidemiological studies play a crucial role in sports medicine, both for enhancing athletic performance and for serving as the foundational first phase in developing and implementing effective injury prevention programs.4,5 Importantly, injury characteristics can vary depending on geographical factors, such as climate and competition type.6,7 The reason why region-specific data are necessary for more effective preventive measures.\n\nInjury rates differ significantly across competitions. For instance, the rate is 32.3 injuries per 1000 hours of exposure in national leagues, whereas it rises to 41.1 in international tournaments.8 Even within Africa, there is significant variability; the South African league reports 24.8 injuries per 1000 match hours,9 in contrast to 113.4 in the Nigerian league.10 The study of Zerguini et al.11 investigating the EPFKIN league in Congo RDC revealed an alarming six injuries per game, equivalent to 182 injuries per 1000 hours of competition. Indeed, some regional competitions, such as the West Africa Football Union, exhibit even higher incidences up to 289 injuries per 1000 match hours.12\n\nUnderstanding the epidemiology of injuries is crucial for tailoring preventive measures to local contexts. Surprisingly, to the best of the authors’ knowledge, no study has yet delved into injury characteristics during any African Cup of Nations (AFCON) competitions. Therefore, the aim of this study was to analyze the incidence and factors associated with injuries among soccer players during the 2021 AFCON competition.\n\n\nMethods\n\nThis was an analytical study (i.e.; a video-based analysis) related to the 2021 AFCON, which took place in Cameroon from January 9 to February 6, 2022. The 2021 competition was postponed to 2022 because of the coronavirus disease 2019 pandemic. Twenty-four national team have participated in this competition (Box 1) with 519 players (i.e.; 275 African (ALP) and 244 Non-African (NALP) league players). The 52 matches were kicked off at four different times: 14:00 (n=5), 16:00 (n=1), 17:00 (n=22), and 20:00-h (n=24) (Box 2).\n\nAlgeria; Burkina Faso; Cameroon; Cape Verde; Comoros; Ivory Coast; Egypt; Equatorial Guinea; Ethiopia; Gabon; Gambia; Ghana; Guinea; Guinea-Bissau; Malawi; Mali; Mauritania; Morocco; Nigeria; Senegal; Sierra Leone; South Africa; Sudan; Tunisia.\n\n\n\n* Match with extra-time\n\nThere was no need for an ethical committee approval as the data were taken from publicly available video footages. The study was conducted following the guidelines established by the STROBE statement.13\n\nTwo independent consultant physicians, (AJ and AC in the authors’ list, with 17 and 4 years’ experience in sports medicine and physical rehabilitation, respectively), followed the live streaming of matches (Box 2) and collected data related to every match. Furthermore, the two physicians reviewed the replay of injuries moment.\n\nAn injury incident was defined as any situation in which the match was interrupted by the referee, a player remained on the ground for more than 15 seconds, or the participant seemed to be in pain or got medical attention, regardless of the consequences with respect to absence from the match or training.14–16 Each injury was characterized according to the characteristics of the:\n\ni) Player’s age, playing position, the league where the footballer was playing in at the moment of the competition (i.e.; NALP or ALP);\n\nii) Injury: Mechanism (contact vs. non-contact), body location (upper extremity, head and neck, trunk, thigh, knee, ankle), moment during the match, replacement after injury, absence next match, and eventual referee’s sanction;\n\niii) Match: Time, temperature and humidity (displayed at the presentation of each match just before the kick-off), and competition stage (e.g.; round of groups, round of 16, quarterfinals, semi-finals, and finals (the third-place and final matches)).\n\nInjury with contact mechanism was defined with any “physical contact with other player or object”,14,17 otherwise it was considered as non-contact mechanism. Body location was classified by anatomical regions based on previous studies.8,18\n\nThe moment of the injury was categorized into six “15-min” periods of standard match19,20 (i.e.; 0-15, 16-30, 31-45, 46-60, 61-75, and 76-90 minutes), as the added extra-time was considered as a seventh period (i.e.; > 90 min).\n\nThe Kolmogorov–Smirnov test was used to analyze the distribution of quantitative data. All quantitative data (except for time played) were normally distributed, and therefore were presented as means ± standard-deviation, and time played was expressed as median (interquartile). Mean difference (95% confidence interval) between two groups was calculated for the quantitative data. Categorical data were expressed as frequencies. For the analytical study, Student t test and Mann-Whitney U test were used for means and medians comparison, respectively. The 2-sided Chi squared test was used to compare the categorical data and rates between groups.\n\nThe calculation of the incidence of injuries followed the recommendations of previous studies.15–17 Injury frequencies are represented by the number of injuries per match played and by number of injuries per 1000 match hours. We have calculated the total hours of ‘match play’ as follows: 22 players × match duration using the factor 1.5, based on standard 90 min match play.15,16 We decided to consider the 30 minutes possible extra-time during play offs (i.e.; rounds of 16, quarterfinal, semi-finals, and finals), we added the factor 0.5 for the matches requiring extra-time. Therefore, in this case we used the formula as follows: 22 players × match duration using factor 2.\n\nThe collected data were analyzed using a statistical software (StatSoft, Inc. (2014). STATISTICA (data analysis software system), version 12. www.statsoft.com, RRID: SCR_014213). The significance level was set at p<0.05.\n\n\nResults\n\nDuring the 2021 AFCON competition, 52 matches were played, among which seven required the addition of extra-time (Box 2). The total number of players who effectively participated in the AFCON was 519 (244 (47%) were NALP) (Table 1). All NALP were European league players.\n\nDuring the competition, 87 injuries were recorded, with 45 (51.7%) in NALP and 42 (48.2%) in ALP. These injuries occurred in 77 players, with 34 (44%) NALP and 43 (56%) ALP. The overall injury incidences were 1.7 and 48.8 injuries per match and per 1000 match hours, respectively. The average age of injured players was 26±4 years. The injury mechanisms were contact in 64 (74%) and non-contact in 23 (26%) cases. When analyzed by match time, 9 (10%) injuries occurred at 14:00, 43 (49%) at 16:00 and 17:00, and 35 (40.2%) at 20:00. Injury rates also varied by the round of the competition. A higher rate of injuries was recorded in playoff (2.5±1.5) compared to groups’ stage (1.3±1.2) (p=0.002).\n\nInjuries resulting from contact mechanisms were mainly observed during the 16-30- and 76-90-minute intervals of the game (17/65 (26%) and 14/65 (21.5%) of injuries, respectively) (Figure 1). Most non-contact injuries were observed after 60 minutes of play (19/23; 82.6%) (Figure 1). The percentage of injuries due to contact mechanism compared to non-contact mechanism was significantly higher during the intervals of 0-15, 16-31 minutes, and 46-60 minutes (Figure 1). Lower extremity injuries accounted for 65.5% of the total injuries (57/87). The most common injury locations were the thigh (20.7%), ankle (17.2%), and knee (16%).\n\n#p-value (2-sided Chi squared test test) < 0.05: Comparison between the 2 groups.\n\nThe rate of injuries per match increased with the competition stage, especially those caused by contact mechanism (Figure 2). The highest rate was noticed during the finals (Figure 2).\n\nTable 2 displays the factors associated with injuries. Compared to the group of non-injured players, the group of injured players was significantly older, had played longer than the non-injured ones, and included a higher percentage of goalkeepers.\n\n* p-value (Student t test or Mann-Witney U test) < 0.05: Comparison of quantitative data between the 2 groups.\n\n# p-value (2-sided Chi squared test test) < 0.05: Comparison of categorical data between the 2 groups.\n\nTable 3 displays the comparison between NALP and ALP players in terms of injury characteristics. The injured NALP were significantly younger than the ALP. Non-contact mechanisms and muscle injuries were more common in the ALP compared to the NALP. In the NALP group, injuries were more frequent for midfielders and forwards than goalkeepers and defenders.\n\n* p-value (Student t test or 2-sided Chi squared test) < 0.05: comparison between the 2 groups.\n\n\nDiscussion\n\nThe present study identified injury rates of48.8 injury per 1000 match hours and 1.7 per match during the 2021 AFCON, and the rate of injuries per match increased with the competition stage. Injuries occurred mostly in goalkeepers. Non-contact injuries occurred mainly during the last third of the game. Injuries involved mainly lower extremity with the thigh being the most common concerned location. Injured players were significantly older and had longer amount of time played compared to those non-injured. NALP were injured mainly by contact mechanism, in the attacking zone of the field and injuries involved especially midfielders and forwards. Non-contact mechanism was more common in ALP with a higher rate of muscle injuries compared to NALP.\n\nThe documented incidence of injuries per 1000 match hours in the present study (i.e.; 48.8) is comparable to the 50.8 reported during the 2014 FIFA World Cup,17 but is higher than those reported by Waldén et al.21 during the 2004 European Football Championship (EURO) (36 per 1000 match hours) and by Bengtsson et al.22 during the 2015/2016 and 2016/2017 Champions League seasons (20.3 per 1000 match hours) and 2016 Copa Libertadores (20.9 per 1000match hours). The documented incidence is lower than those reported during the FIFA World Cup hold in Korea/Japan 2002, Germany 2006, and South Africa 2010, respectively 81, 68.7, and 61.1 per 1000 match hours.15,16,23 Moreover, the incidence of injuries per match we report (i.e.; 1.7 injuries) is comparable to the 1.68 reported during the 2014 FIFA World Cup17 but (i) Lower than those noticed during FIFA World Cup (2.3 per match), Olympic Games (2.3 per match) and FIFA confederation cups (2.8 per match) from 1998 to 201224; and (ii) Higher than those noticed during the 2017 Gold Cup14 and EURO 2004,21 1.22 and 1.04 per match respectively. This discrepancy may potentially be due to the different type of competition/environment, the improvement in injuries prevention programs and the strict referees’ interventions. Indeed, the decrease in the injuries’ incidence in recent years was noticed by Junge et Dvořák17 and explained by the referee sanctions’ evolution and the greater fair play by players.\n\nThe increase of the rate of injuries with competition stages in our study is aligned with the conclusions of Yoon et al.25 This can be explained by the cumulative fatigue during playoffs and the fact that physical commitment on the field is increasingly important as players approach the finals. Discordantly, Junge et al.15 reported no significant association between the incidence of injuries and the competition stages. The latter study investigated the 2002 FIFA World Cup, which included a higher number of matches and a different organization than continental competitions.\n\nIn accordance with our findings, the literature reported that, the incidence of injury within a match time increases especially after 60-min of the game.14,26 As players spent more time on the field, the incidence of muscle injuries increased significantly. This is comparable to the results of Pangrazio and Forriol26 and Chahla et al.14 In fact, Pangrazio and Forriol26 reported during the 2015 America cup that muscle strains happened in the last quarter of the match. Chahla et al.14 reported an increase of injuries’ incidence with play time, especially between the 60th and 75th minute of play. Physical fatigue is the main explanatory factor according to some authors.14,27 Other studies have reported the increase of injuries during the end of each half15,19,20,28 with the high intensity of the match as possible explanation.15 In contrasts with our results, Dvořák et al.23 identified no differences in injuries’ distribution between the two halves.\n\nStudies about soccer injuries identified that lower extremity is by far the most affected body part. Similarly to our findings, the thigh has previously been reported as the most commonly injured body part.8,17,19,26,29 Soccer injuries epidemiology studies identified the older age as one of the main risk factors for muscle injuries.20,30–32 In concordance with Pangrazio and Forriol26 and Arnason et al.,30 we found that players who played for longer times were more exposed to injuries. Thus, the longer the exposure was (related to the long-time of practice), the higher the rate of injuries was.26\n\nThere is no agreement in the literature about the rate of injuries by player position. We found that goalkeepers had the highest rate of injuries. Chahla et al.14 and Arliani et al.33 reported that forward players had the highest rate of injuries, while Chomiac et al.34 reported the defenders as the most injured. This divergence in findings between studies may be explained by the difference of competitions type with the playing style potentially exposing specific player’s positions to a higher risk of being injured.\n\nNo previous study has investigated the injuries characteristics between players belonging to different continental leagues at the same competition. The higher rate of contact injuries noticed in the present study among NALP may be explained by the fact that these players are essentially forward and midfielder players with high level of skills, commonly injured in the attacking zone of the field. The fact that ALP in the present study had the highest rate of muscle injuries may be explained by the difference in training cultures between continents as it was reported between South American and Asian competitions and European competition.22,25 Furthermore, NALP are exposed to higher intensity practice and probably less likelihood to get injured than ALP who are used to lower intensity and/or less dense match schedule than in Europe.\n\nThe video-based analysis approach used in the present study did not include training and potential match’ warm-up-related injuries. Furthermore, due to the study design, injury severity and recovery duration are not reported, missing an important piece of information of the recent epidemiological studies, i.e. injury burden.29,35\n\n\nConclusion\n\nWe report an injury incidence of 48.8 per 1000 match hours and a rate of 1.7 injuries per match during the 2021 AFCON. Older age and longer playing time were the main factors associated with injury. NALP players were mostly injured by contact mechanisms, while ALP players were mainly injured by non-contact mechanisms. ALP players had the highest rate of muscle injuries. These findings may highlight the importance of preventive interventions, especially targeting muscle injuries in ALP players.\n\n\nEthics and consent\n\nEthical approval and written consent were not required.", "appendix": "Data availability statement\n\nZenodo: Excel data of the study titled: Injury incidence and associated factors among male soccer players during the 2021 African Cup of Nations competition: a pilot study. DOI: https://doi.org/10.5281/zenodo.10465671. 36\n\nThe project contains the following underlying data:\n\n- Excel Data with description of injuries, matches and players’ characteristics.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nZenodo: STROBE of the paper titled: Injury incidence and associated factors among soccer players during the 2021 African cup of nations’ competition. DOI: https://doi.org/10.5281/zenodo.10944493. 37\n\n\nAcknowledgments\n\nIn memory of Yacine ZERGUINI, a dedicated contributor to this article whose passion for sports science and commitment to advancing our understanding of athlete health and performance was truly inspiring. Yacine’s invaluable insights and contributions to the research on injury incidence among soccer players during the 2021 African Cup of Nations competition will forever remain a testament to his expertise and dedication to the field. However, he is no longer with us, his impact on this work and on the broader sports science community will continue to be felt.\n\n\nReferences\n\nKunz M: 265 Million Playing Football. Zurich: FIFA Magazine; 2007; 10–15.\n\nFIFA: Professional football report 2019: 91% of member associations implementing club licensing. (Last visit: April 12, 2024). Reference Source\n\nEkstrand J, Walden M, Hagglund M: Hamstring injuries have increased by 4% annually in men’s professional football, since 2001: a 13-year longitudinal analysis of the UEFA Elite Club injury study. Br. J. Sports Med. 2016 Jun; 50(12): 731–7. Epub 20160108. eng. PubMed Abstract\n\nvan Mechelen W : Sports injury surveillance systems. ‘One size fits all’? Sports Med. 1997 Sep; 24(3): 164–8. eng. PubMed Abstract\n\nEirale C, Ekstrand J: Epidemiology of injury in football. Aspetar Sports Med. J. 2013; 2: 144–9.\n\nOrchard JW, Walden M, Hagglund M, et al.: Comparison of injury incidences between football teams playing in different climatic regions. Open Access J. Sports Med. 2013; 4: 251–60. Epub 20131205. eng. PubMed Abstract \| Free Full Text\n\nWalden M, Hagglund M, Orchard J, et al.: Regional differences in injury incidence in European professional football. Scand. J. Med. Sci. Sports. 2013 Aug; 23(4): 424–30. Epub 20111103. PubMed Abstract\n\nLopez-Valenciano A, Ruiz-Perez I, Garcia-Gomez A, et al.: Epidemiology of injuries in professional football: a systematic review and meta-analysis. Br. J. Sports Med. 2020 Jun; 54(12): 711–8. Epub 20190606. PubMed Abstract \| Free Full Text\n\nBayne H, Schwellnus M, van Rensburg DJ , et al.: Incidence of injury and illness in South African professional male soccer players: a prospective cohort study. J. Sports Med. Phys. Fitness. 2018 Jun; 58(6): 875–9. Epub 20170509. PubMed Abstract\n\nOwoeye OB, Aiyegbusi AI, Fapojuwo OA, et al.: Injuries in male and female semi-professional football (soccer) players in Nigeria: prospective study of a National Tournament. BMC. Res. Notes. 2017 Mar 21; 10(1): 133. Epub 20170321. PubMed Abstract \| Free Full Text\n\nZerguini Y, Bungu Kakala J-P, Junge A, et al.: Étude des blessures lors d’une Compétition nationale africaine de football. À propos du championnat EPFKIN 2006–2007 à Kinshasa (RD Congo). Journal de Traumatologie du Sport. 2010; 27(4): 171–6.\n\nAkodu AK, Owoeye OB, Ajenifuja M, et al.: Incidence and characteristics of injuries during the 2011 West Africa Football Union (WAFU) Nations’ Cup. Afr. J. Med. Med. Sci. 2012 Dec; 41(4): 423–8. PubMed Abstract\n\nvon Elm E , Altman DG, Egger M, et al.: The Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007 Oct 20; 370(9596): 1453–1457. PubMed Abstract\n\nChahla J, Sherman B, Cinque M, et al.: Epidemiological findings of soccer injuries during the 2017 gold cup. Orthop. J. Sports Med. 2018 Aug; 6(8): 2325967118791754. Epub 20180820. PubMed Abstract \| Free Full Text\n\nJunge A, Dvorak J, Graf-Baumann T: Football injuries during the World Cup 2002. Am. J. Sports Med. 2004 Jan-Feb; 32(1 Suppl): 23S–27S. PubMed Abstract\n\nJunge A, Dvorak J, Graf-Baumann T, et al.: Football injuries during FIFA tournaments and the Olympic Games, 1998-2001: development and implementation of an injury-reporting system. Am. J. Sports Med. 2004 Jan-Feb; 32(1 Suppl): 80S–89S. PubMed Abstract\n\nJunge A, Dvorak J: Football injuries during the 2014 FIFA World Cup. Br. J. Sports Med. 2015 May; 49(9): 599–602. PubMed Abstract \| Free Full Text\n\nAndersen TE, Larsen O, Tenga A, et al.: Football incident analysis: a new video based method to describe injury mechanisms in professional football. Br. J. Sports Med. 2003 Jun; 37(3): 226–32. PubMed Abstract \| Free Full Text\n\nDvorak J, Junge A, Derman W, et al.: Injuries and illnesses of football players during the 2010 FIFA World Cup. Br. J. Sports Med. 2011 Jun; 45(8): 626–30. Epub 20110121. PubMed Abstract PubMed Abstract\n\nEkstrand J, Hagglund M, Walden M: Epidemiology of muscle injuries in professional football (soccer). Am. J. Sports Med. 2011 Jun; 39(6): 1226–32. Epub 20110218. PubMed Abstract\n\nWalden M, Hagglund M, Ekstrand J: Football injuries during European Championships 2004-2005. Knee Surg. Sports Traumatol. Arthrosc. 2007 Sep; 15(9): 1155–62. Epub 20070321. PubMed Abstract\n\nBengtsson H, Ortega Gallo PA, Ekstrand J: Injury epidemiology in professional football in South America compared with Europe. BMJ Open Sport Exerc. Med. 2021; 7(4): e001172. Epub 20211001. PubMed Abstract \| Free Full Text\n\nDvorak J, Junge A, Grimm K, et al.: Medical report from the 2006 FIFA World Cup Germany. Br. J. Sports Med. 2007 Sep; 41(9): 578–81. Epub 20070517. discussion 81. PubMed Abstract \| Free Full Text\n\nJunge A, Dvorak J: Injury surveillance in the world football tournaments 1998-2012. Br. J. Sports Med. 2013 Aug; 47(12): 782–8. Epub 20130430. PubMed Abstract \| Free Full Text\n\nYoon YS, Chai M, Shin DW: Football injuries at Asian tournaments. Am. J. Sports Med. 2004 Jan-Feb; 32(1 Suppl): 36S–42S. eng. PubMed Abstract\n\nPangrazio O, Forriol F: Epidemiology of soccer players traumatic injuries during the 2015 America Cup. Muscles Ligaments Tendons J. 2016 Jan-Mar; 6(1): 124–30. Epub 20160519. PubMed Abstract \| Free Full Text\n\nDambroz F, Clemente FM, Teoldo I: The effect of physical fatigue on the performance of soccer players: A systematic review. PLoS One. 2022; 17(7): e0270099. Epub 20220714. PubMed Abstract \| Free Full Text\n\nPedrinelli A, Filho G, Thiele ES, et al.: Epidemiological study on professional football injuries during the 2011 copa America, Argentina. Rev. Bras. Ortop. 2013 Mar-Apr; 48(2): 131–6. Epub 20130620. PubMed Abstract \| Free Full Text\n\nTabben M, Eirale C, Singh G, et al.: Injury and illness epidemiology in professional Asian football: lower general incidence and burden but higher ACL and hamstring injury burden compared with Europe. Br. J. Sports Med. 2022 Jan; 56(1): 18–23. Epub 20210105. PubMed Abstract\n\nArnason A, Sigurdsson SB, Gudmundsson A, et al.: Risk factors for injuries in football. Am. J. Sports Med. 2004 Jan-Feb; 32(1 Suppl): 5S–16S. PubMed Abstract\n\nBisciotti GN, Chamari K, Cena E, et al.: Hamstring injuries prevention in soccer: A narrative review of current literature. Joints. 2019 Sep; 7(3): 115–26. Epub 20200525. PubMed Abstract \| Free Full Text\n\nMcGregor JC, Rae A, Melvin WD: A three year review of injuries to professional footballers (1995-98) and comparison with previous observations (1990-93). Scott. Med. J. 2000 Feb; 45(1): 17–9. PubMed Abstract\n\nArliani GG, Lara PHS, Margato GF, et al.: Prospective Study of Injuries Occurred during Brazilian Football Championship in 2019. Acta Ortop. Bras. 2021 Jul-Aug; 29(4): 207–10. PubMed Abstract \| Free Full Text\n\nChomiak J, Junge A, Peterson L, et al.: Severe injuries in football players. Influencing factors. Am. J. Sports Med. 2000; 28(5 Suppl): S58–S68. PubMed Abstract\n\nBahr R, Clarsen B, Derman W, et al.: International Olympic Committee consensus statement: methods for recording and reporting of epidemiological data on injury and illness in sport 2020 (including STROBE Extension for Sport Injury and Illness Surveillance (STROBE-SIIS)). Br. J. Sports Med. 2020 Apr; 54(7): 372–89. Epub 20200218. PubMed Abstract \| Free Full Text\n\nChaabeni A, Kalai A, Jellad A, et al.: Excel data of the study titled: Injury incidence and associated factors among male soccer players during the 2021 African Cup of Nations competition: a pilot study. [Data set]. Zenodo. 2024. (Last visit: April 12, 2024). Publisher Full Text\n\nChaabeni A, Kalai A, Ben Saad H, et al.: STROBE of the paper titled: Injury incidence and associated factors among soccer players during the 2021 African cup of nations’ competition. (Last visit: April 12, 2024). 2024. Reference Source" }	[ { "id": "281561", "date": "14 Jun 2024", "name": "Fouad Chiha", "expertise": [ "Reviewer Expertise Training methodology –football- physical preparation- exercise physiology- monotoring.." ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nKnowing the epidemiology of footballer injuries during international competitions is essential for developing preventive strategies. The study compared its results to those linked to other international competitions. This study aimed to characterize injuries contracted during the African Cup of Nations (AFCON) in Cameroon from January 9 to February 6, 2021.\nThe study reports an injury incidence of 48.8 per 1000 match hours and a rate of 1.7 injuries per match. Muscle injuries were the highest and the main factors being advanced age and length of play.\nIn conclusion, the study highlights the importance of preventive interventions. Addressing the use of preventive sessions (the FMS test is the best example) and recognized prophylactic means would have been relevant to put forward practical recommendations based on the results of the study. When discussing the results, we must pay attention to the characteristics of the competitions to be compared (climate, timing, match schedule, number of participating teams, number of matches played) to better appreciate the comparisons.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] }, { "id": "300243", "date": "13 Sep 2024", "name": "Pablo Prieto González", "expertise": [ "Reviewer Expertise Sports training and injury prevention" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you very much for giving me the opportunity to review this study. Below, I share my observations regarding the manuscript in each of its sections:\nINTRODUCCIÓN: The introduction of the article \"Injury incidence and associated factors among soccer players during the 2021 African Cup of Nations competition\" presents strengths and areas for improvement. Among the strengths, it provides relevant context, highlighting the popularity of soccer and the large number of registered players both in Africa and worldwide, establishing the importance of the study within the global soccer landscape. Additionally, the introduction underscores the relevance of epidemiological studies in sports medicine, both for enhancing athletic performance and for developing injury prevention programs. It also mentions that injury characteristics can vary according to geographical factors such as climate and competition type, reinforcing the need for specific data to implement effective preventive measures. A comparative analysis of injury rates in various competitions, both national and international, contextualizes the severity and variability of the issue. Finally, the introduction identifies a research gap: the lack of studies on injury characteristics in African Cup of Nations (AFCON) tournaments, justifying the study's objective.\nHowever, the introduction has several weaknesses. Some parts of the introduction could be clearer to improve understanding. Although geographical differences in injury incidence are mentioned, the study could developed deeper into how these differences influence the nature of injuries and the need for specific studies in different regions. It would be beneficial to provide more specific background on AFCON, highlighting its importance in the context of African and global soccer, to strengthen the study's justification. The transition to the study objectives could be smoother, improving the connection between identifying the research gap and the study's objectives for a more natural flow. There is room to improve clarity and particularly in depth in key aspects. Additionally, studying a previously unexamined population (players participating in the African Cup of Nations) does not constitute a novelty in itself unless it provides new insights into scientific knowledge.\nMETHODS: Regarding the type of study, it is indicated as an analytical study. While this is not incorrect, it would be more accurate to specify that this is a video-based descriptive observational study. The STROBE-SIIS guidelines recommend providing a clear and detailed description of the study design, including the process for selecting injury events.\nRegarding the statement that \"there was no need for an ethical committee approval,\" it is important to emphasize that ethical approval is necessary to protect the privacy and rights of the players, ensure informed consent, minimize potential harm, and comply with ethical regulations and guidelines. Review by an ethics committee provides an independent evaluation and ensures that the study is conducted in an ethical and responsible manner.\nInclusion and Exclusion Criteria: Specific inclusion and exclusion criteria for injury events are not detailed. It is essential to specify these criteria to understand how it was determined which injuries were included in the analysis.\nClearly Defined Outcomes: The definition of an injury incident is relatively general. STROBE-SIIS suggests clearly defining specific outcomes and justifying the criteria used. In this study, the definition of a \"situation in which the match was interrupted\" may be ambiguous.\nSample Size Rationale: No justification is provided for the sample size or the formula used to calculate it. STROBE-SIIS recommends describing how the sample size was determined and providing adequate statistical justification for this.\nVariable Details: While some characteristics of the injuries and players are mentioned, a detailed description of all variables considered in the analysis is missing. STROBE-SIIS emphasizes the importance of accurately specifying and categorizing all variables. I consider that one of the main limitations of the study is the small number of variables studied, and the absence of a clear criterion to analyze in depth the mechanisms that cause injuries.\nData Collection Methodology: The data collection methodology is based on observing live broadcasts and replays, but specific tools or methods used to ensure consistency and accuracy in data collection are not detailed. STROBE-SIIS suggests providing a detailed description of data collection methods, including any standardized tools or protocols used.\nData Validation and Reliability: There is no mention of how the reliability of the data collected by the consulting physicians was validated. STROBE-SIIS recommends describing any validation processes or reliability tests applied to the data.\nData Analysis and Statistical Considerations: Although some statistical analyses are described, there is a lack of justification for the choice of statistical tests used. STROBE-SIIS suggests providing a clear justification for the statistical techniques employed and explaining how potential confounders were addressed.\nBias Information: Possible sources of bias and how they were addressed are not discussed. STROBE-SIIS recommends identifying and discussing potential sources of bias in the study and the strategies used to minimize them.\nContext and Confounding Data: Not enough information is provided on potential confounding factors, such as exact weather conditions or the previous physical condition of the players. STROBE-SIIS suggests considering and adjusting for potential confounders in the analysis.\nRESULTS The lack of clear definitions and criteria in the methodology section affects the results section. Although data on injuries are presented, there is no clear definition of the criteria used for injury categorization. While it specifies that injuries were either contact or non-contact and further breaks down the analysis by injury location and timing, the specific criteria for including injuries in the dataset are not detailed. This lack of clarity may hinder the evaluation of the validity and reliability of the findings.\nInconsistent Data Presentation: Some data are presented as means with standard deviations while others are presented as medians with interquartile ranges, and the rationale for choosing these methods is not explained. For example, the choice of using the median for playing time should be justified, as the standard deviation is used for other continuous variables. The inconsistency in data presentation could affect the interpretability and comparability of the results.\nAbsence of Statistical Power Analysis: The results section lacks information on statistical power analysis, which is essential to determine whether the sample size was adequate to detect significant differences. There is no mention of how the sample size was determined or justified, which could raise concerns about the validity of the statistical comparisons made.\nPotential Bias in Injury Reporting: The results indicate that injuries were recorded and analyzed, but there is no discussion of potential biases in injury reporting. For example, whether all injuries were uniformly reported and categorized, or if there was any observer bias in the injury assessment process, is not addressed.\nLimited Information on Contextual Factors: Factors such as weather conditions, listed as temperature and humidity, are mentioned but not thoroughly analyzed in relation to injury incidence. The impact of these variables should be examined more comprehensively to understand their effect on injury rates. Additionally, there is a lack of analysis regarding confounding factors such as player fatigue or previous injuries.\nInadequate Analysis of Injury Mechanisms: While the results provide a general breakdown of injury mechanisms (contact vs. non-contact) and their occurrence by match time, there is a lack of detailed analysis of how different mechanisms relate to specific injury types or player positions. A more detailed examination could help in understanding injury patterns more comprehensively.\nInadequate Analysis of Injury Impact: Although the results show variations in injury rates by match round and time, there is limited analysis of how these injuries affected player performance and match outcomes. The study does not explore how injuries impacted player availability or team performance, which could provide valuable insights into the broader implications of the findings.\nDISCUSSION AND CONCLUSION One of the main shortcomings is the lack of consideration for injuries occurring during training sessions, warm-ups, and cool-downs. This is a significant limitation, as injuries during these periods can substantially contribute to the overall injury burden. Excluding these injuries from the study may lead to an underestimation of the total incidence and severity of injuries, affecting the comprehensiveness of the findings.\nAdditionally, the study does not report on the severity of the injuries or the duration of recovery. This omission is critical, as understanding the severity and recovery time of injuries provides crucial information on the injury burden and the long-term impact on players' health and performance.\nThe study compares injury rates with several previous studies but does not delve deeply into the potential differences in study methodologies, such as variations in injury definitions, data collection methods, or competitive environments. These differences may introduce inconsistencies in comparative findings, making it difficult to draw definitive conclusions.\nThe video-based analysis used in the study may introduce selection bias if certain injuries were less likely to be recorded or if injuries involving some players were not reported. Dependence on video footage may also overlook injuries that occurred off-camera or were inadequately captured, affecting the accuracy of reported injury rates.\nWhile the study reports injury rates by player position, it does not explore how different playing styles or positional demands might contribute to the observed injury patterns. Understanding these factors could provide a more nuanced view of injury risks associated with different player positions.\nThe study highlights differences between players from different leagues (NALP vs. ALP) but does not thoroughly investigate how geographical or cultural differences in training practices might influence injury patterns. These differences could contribute to variations observed in injury mechanisms and types, but are not fully explored.\nThe study also does not address whether players or teams had access to specific injury prevention measures, such as strength and conditioning programs or medical interventions. The presence or absence of such measures could influence injury rates and should be considered when interpreting the results.\nDespite presenting important limitations, the study does not thoroughly address the need for future research to address these shortcomings.\nAs for the conclusion, it must be taken into account that the findings are specific to the 2021 AFCON competition, and may not be generalizable to other tournaments or leagues. Factors such as competition level, player conditioning, and environmental conditions may vary, impacting the applicability of the conclusions to different contexts.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "13096", "date": "13 Jan 2025", "name": "Anis Jellad", "role": "Author Response", "response": "Reviewer comments Response Comment: Although geographical differences in injury incidence are mentioned, the study could developed deeper into how these differences influence the nature of injuries and the need for specific studies in different regions. Response: As suggested, we added an example illustrating the influence of climate differences on injury nature. Comment: It would be beneficial to provide more specific background on AFCON, highlighting its importance in the context of African and global soccer, to strengthen the study's justification. Response: As suggested, we have added additional details about AFCON's significance, positioning it as a key tournament that features both local talent and international stars. Its importance for African football and global soccer development is emphasized, supporting the study's relevance. Comment: The transition to the study objectives could be smoother, improving the connection between identifying the research gap and the study's objectives for a more natural flow. There is room to improve clarity and particularly in depth in key aspects. Additionally, studying a previously unexamined population (players participating in the African Cup of Nations) does not constitute a novelty in itself unless it provides new insights into scientific knowledge. Response: We appreciate the reviewer's feedback on improving the flow and clarity. In response, we have refined the transition to better connect the identified research gap with the study’s objectives. We have also emphasized how this study contributes novel insights into injury epidemiology within the unique context of AFCON, offering valuable information for both regional and international injury prevention strategies. Comment: Regarding the type of study, it is indicated as an analytical study. While this is not incorrect, it would be more accurate to specify that this is a video-based descriptive observational study. Response: As suggested, the study design has been clearly redefined as a \"video-based descriptive observational study\" to align with reviewer recommendations and clarify the methodology. Comment: The STROBE-SIIS guidelines recommend providing a clear and detailed description of the study design, including the process for selecting injury events. Response: According to the STROBE-SIIS guidelines: “SIIS-4.1. Clearly specify which health problems are being observed”: this item is explained lines 122-125. SIIS-4.2. State explicitly which approach was used to record the health problem data, including all outcome measures or tools: this item is detailed lines 117-121. SIIS-4.3.State explicitly which coding system was used to classify the health problems: lines 129-131 SIIS-4.4. Where relevant, clearly describe how athletes were categorised: players were categorised based Player's age, playing position, and the league where the footballer was playing in at the moment of the competition (NALP or ALP); lines 127-128. Comment: Regarding the statement that \"there was no need for an ethical committee approval,\" it is important to emphasize that ethical approval is necessary to protect the privacy and rights of the players, ensure informed consent, minimize potential harm, and comply with ethical regulations and guidelines. Review by an ethics committee provides an independent evaluation and ensures that the study is conducted in an ethical and responsible manner. Response: We stated that ethical approval was not required as the data were sourced from publicly available video footage. Additionally, the identities of the players were not disclosed (lines 114–115). Comment: Inclusion and Exclusion Criteria: Specific inclusion and exclusion criteria for injury events are not detailed. It is essential to specify these criteria to understand how it was determined which injuries were included in the analysis. Response: As suggested, we added an inclusion/exclusion criteria. Comment: Clearly Defined Outcomes: The definition of an injury incident is relatively general. STROBE-SIIS suggests clearly defining specific outcomes and justifying the criteria used. In this study, the definition of a \"situation in which the match was interrupted\" may be ambiguous. Response: As suggested, we reformulated the injury definition in order to raise ambiguity. Comment: Sample Size Rationale: No justification is provided for the sample size or the formula used to calculate it. STROBE-SIIS recommends describing how the sample size was determined and providing adequate statistical justification for this. Response: Sample size calculation was unnecessary, as all players participating in the tournament were included. In our case we conducted a population study. Comment: Variable Details: While some characteristics of the injuries and players are mentioned, a detailed description of all variables considered in the analysis is missing. STROBE-SIIS emphasizes the importance of accurately specifying and categorizing all variables. I consider that one of the main limitations of the study is the small number of variables studied, and the absence of a clear criterion to analyze in depth the mechanisms that cause injuries. Response: As suggested, we added a detailed description of missing variables. We reviewer for his valuable remark. Comment: Data Collection Methodology: The data collection methodology is based on observing live broadcasts and replays, but specific tools or methods used to ensure consistency and accuracy in data collection are not detailed. STROBE-SIIS suggests providing a detailed description of data collection methods, including any standardized tools or protocols used. Response: We thank the reviewer for their remark. Injuries were registered by the two authors (AJ and AC) independently and outcomes were compared at the end of each competition day. Comment: Data Validation and Reliability: There is no mention of how the reliability of the data collected by the consulting physicians was validated. STROBE-SIIS recommends describing any validation processes or reliability tests applied to the data. Response: Injuries were registered by the two authors (AJ and AC) independently and outcomes were compared at the end of each competition day. In case of discrepancy, the intervention of a third author (AK) was required. Details were added in the text (lines 121-122) Comment: Data Analysis and Statistical Considerations: Although some statistical analyses are described, there is a lack of justification for the choice of statistical tests used. STROBE-SIIS suggests providing a clear justification for the statistical techniques employed and explaining how potential confounders were addressed. Response: The authors thank the reviewer for their remark. For clarity, we have added a justification for the choice of statistical tests used. Comment: Bias Information: Possible sources of bias and how they were addressed are not discussed. STROBE-SIIS recommends identifying and discussing potential sources of bias in the study and the strategies used to minimize them. Response: A section has been added to address potential biases, such as selection bias in video-based injury analysis, and how these were mitigated. Comment: Context and Confounding Data: Not enough information is provided on potential confounding factors, such as exact weather conditions or the previous physical condition of the players. STROBE-SIIS suggests considering and adjusting for potential confounders in the analysis. Response: We acknowledge the lack details about potential confounding factors like player fatigue are now addressed. Comment: Although data on injuries are presented, there is no clear definition of the criteria used for injury categorization. While it specifies that injuries were either contact or non-contact and further breaks down the analysis by injury location and timing, the specific criteria for including injuries in the dataset are not detailed. This lack of clarity may hinder the evaluation of the validity and reliability of the findings. Response: We thank the reviewer for their valuable remark. This issue has been addressed in the Methods section under the inclusion criteria. Comment: Inconsistent Data Presentation: Some data are presented as means with standard deviations while others are presented as medians with interquartile ranges, and the rationale for choosing these methods is not explained. For example, the choice of using the median for playing time should be justified, as the standard deviation is used for other continuous variables. The inconsistency in data presentation could affect the interpretability and comparability of the results. Response: The mean and standard deviation are used when the distribution of data is approximately symmetrical. In contrast, the median and interquartile range are employed for skewed distributions, such as playing time, to better represent central tendency and variability. This approach ensures that the most appropriate statistical measures are used, enhancing the interpretability of the results. Comment: Absence of Statistical Power Analysis: The results section lacks information on statistical power analysis, which is essential to determine whether the sample size was adequate to detect significant differences. There is no mention of how the sample size was determined or justified, which could raise concerns about the validity of the statistical comparisons made. Response: We acknowledge the reviewer's comment regarding the absence of a statistical power analysis. Due to the nature of the study, which analyzed all available injury data from the 2021 AFCON, conducting a formal power analysis was not feasible. The study sample reflects the entire population of players and matches from the tournament, providing a comprehensive dataset. While this limits our ability to perform a prospective power calculation, we believe that analyzing the complete dataset ensures that the study captures all relevant injury patterns and associations. Comment: Potential Bias in Injury Reporting: The results indicate that injuries were recorded and analyzed, but there is no discussion of potential biases in injury reporting. For example, whether all injuries were uniformly reported and categorized, or if there was any observer bias in the injury assessment process, is not addressed. Response: A section has been added to address potential biases, such as selection bias in video-based injury analysis, and how these were mitigated. Comment: Limited Information on Contextual Factors: Factors such as weather conditions, listed as temperature and humidity, are mentioned but not thoroughly analyzed in relation to injury incidence. The impact of these variables should be examined more comprehensively to understand their effect on injury rates. Additionally, there is a lack of analysis regarding confounding factors such as player fatigue or previous injuries. Response: Weather conditions (temperature and humidity) have been analyzed, we haven’t find a relationship with injury incidence. We acknowledge the lack of analysis regarding confounding factors such as player fatigue or previous injuries Comment: Inadequate Analysis of Injury Mechanisms: While the results provide a general breakdown of injury mechanisms (contact vs. non-contact) and their occurrence by match time, there is a lack of detailed analysis of how different mechanisms relate to specific injury types or player positions. A more detailed examination could help in understanding injury patterns more comprehensively. Response: The analysis of injury mechanisms has been expanded to explore how different player positions and match contexts influence injury patterns. Comment: Inadequate Analysis of Injury Impact: Although the results show variations in injury rates by match round and time, there is limited analysis of how these injuries affected player performance and match outcomes. The study does not explore how injuries impacted player availability or team performance, which could provide valuable insights into the broader implications of the findings. Response: As suggested, we included a discussion on how injuries impacted player availability and potential performance in subsequent matches. Comment: One of the main shortcomings is the lack of consideration for injuries ocurring during training sessions, warm-ups, and cool-downs. This is a significant limitation, as injuries during these periods can substantially contribute to the overall injury burden. Excluding these injuries from the study may lead to an underestimation of the total incidence and severity of injuries, affecting the comprehensiveness of the findings. Response: We acknowledge this limitation and discuss how it may underestimate the total injury burden, suggesting it as an area for future research. Comment: Additionally, the study does not report on the severity of the injuries or the duration of recovery. This omission is critical, as understanding the severity and recovery time of injuries provides crucial information on the injury burden and the long-term impact on players' health and performance. Response: We address this limitation, indicating the need for future studies to incorporate data on injury severity and recovery time to better understand the overall burden. Comment: The study compares injury rates with several previous studies but does not delve deeply into the potential differences in study methodologies, such as variations in injury definitions, data collection methods, or competitive environments. These differences may introduce inconsistencies in comparative findings, making it difficult to draw definitive conclusions. Response: A discussion has been added to compare methodologies between this study and others, including how different definitions of injury and data collection techniques may influence findings. Comment: The video-based analysis used in the study may introduce selection bias if certain injuries were less likely to be recorded or if injuries involving some players were not reported. Dependence on video footage may also overlook injuries that occurred off-camera or were inadequately captured, affecting the accuracy of reported injury rates. Response: As suggested, some injuries may be not recorded, this discussion is added in limitation section Comment: While the study reports injury rates by player position, it does not explore how different playing styles or positional demands might contribute to the observed injury patterns. Understanding these factors could provide a more nuanced view of injury risks associated with different player positions. Response: As suggested, we provide a more detailed discussion of how different playing styles and positional demands may explain variations in injury patterns across player roles. Comment: The study highlights differences between players from different leagues (NALP vs. ALP) but does not thoroughly investigate how geographical or cultural differences in training practices might influence injury patterns. These differences could contribute to variations observed in injury mechanisms and types, but are not fully explored. Response: we acknowledge that differences in training loads, intensity, and preparation between African and non-African league players (ALP vs. NALP) could contribute to variations in injury mechanisms, this was beyond the scope of our current analysis. However, we have added a discussion in the manuscript, noting that future research should explore how regional training practices, competition schedules, and recovery protocols may impact injury risk and mechanisms, potentially contributing to the observed differences between ALP and NALP players. Comment: The study also does not address whether players or teams had access to specific injury prevention measures, such as strength and conditioning programs or medical interventions. The presence or absence of such measures could influence injury rates and should be considered when interpreting the results. Response: While detailed data on prevention measures were unavailable, we recommend that future studies investigate the influence of training and medical interventions on injury rates. Comment: Despite presenting important limitations, the study does not thoroughly address the need for future research to address these shortcomings. Response: A section on future research is included, emphasizing the need to study injury prevention strategies, the role of training, and to include training and warm-up injury data." } ] } ]	1	https://f1000research.com/articles/13-392
https://f1000research.com/articles/13-265/v1	15 Apr 24	{ "type": "Policy Brief", "title": "Ambient Air Pollution and Chronic kidney disease risk in Deltan communities: A Policy Brief, 2023", "authors": [ "Ogochukwu Okoye", "Elaine Carnegie", "Luca Mora", "Elaine Carnegie", "Luca Mora" ], "abstract": "Chronic kidney disease (CKD) is a persistent, devastating, yet neglected, non-communicable disease in developing and emerging countries. National, regional, and international agencies’ communications and reports on non-communicable diseases intentionally or non-intentionally do not feature CKD. The traditional risk factors for CKD, such as hypertension and diabetes, which have received relatively ample attention, do not sufficiently explain the high burden of CKD in these countries. Ambient air pollution is an emerging significant environmental risk factor for CKD; however, epidemiological data and evidence are lacking for susceptible populations in developing countries. The Niger Delta region of Nigeria is a petrochemical hub known for environmental degradation, including air pollution, and thus, serves as a good case study for investigating the association between air pollution and CKD. This brief is based on the results of a mixed-methods study conducted in four communities situated near an oil and gas refinery in Warri, Nigeria. Air pollutant concentrations measured in partnership with citizen scientists showed that all except one air pollutant (ozone) exceeded the WHO acceptable limits in all four communities. The overall prevalence of CKD was high (12.3%) but even higher (18%) in a socially deprived semi-urban community closest to the oil refinery. Hypertension, diabetes, other behavioral risk factors, and exposures associated with CKD were prevalent among the inhabitants of the four communities. However, public environmental health information and education are lacking. A multifaceted approach is required to mitigate air pollution and the associated health risks in the state. Public inclusion is strongly recommended for the planning and implementation of future interventions. Kidney disease prevention and treatment should be emphasized in health policies and insurance schemes.", "keywords": [ "air pollution", "chronic kidney disease", "petrochemical industry", "particulate matter", "environmental health" ], "content": "Introduction\n\nChronic kidney disease (CKD) is a persistent, devastating, yet neglected non-communicable disease (NCD) especially in developing and emerging countries (Vanholder et al., 2021). Chronic kidney disease is responsible for 3.4 million deaths worldwide and ranks 10th among the risk factors for global deaths and DALYs (Global Burden of Disease Collaboration, 2019). However, national, regional, and international agency communications and reports on non-communicable diseases intentionally or non-intentionally do not feature CKD. Traditional risk factors for CKD, such as hypertension and diabetes, which receive relatively ample attention, do not sufficiently explain the high burden of CKD in these countries (Garcia-Garcia et al., 2015; Stanifer et al., 2016).\n\nThe disproportionately higher prevalence and severity of CKD in the young population of low- or middle-income countries (LMIC), despite preventive interventions, is a matter of global concern. Since the traditional risk factors for CKD, such as hypertension and diabetes mellitus, do not sufficiently explain the CKD epidemiology in LMIC, attention is shifting towards other environmental exposures, such as air pollution, which is the leading environmental risk factor for NCD (World Health Organization, 2018). Systematic reviews and meta-analyses have shown that air pollution increases the risk of kidney dysfunction by 4–70%, and persons residing or working near point sources of air pollution are at an increased risk (Okoye et al., 2022; Wu et al., 2020; Ye et al., 2021). However, these reviews were based on methodologically heterogeneous studies. In contrast, there is a proliferation of epidemiological and toxicological evidence of air pollution-associated respiratory and cardiovascular diseases. Evidence for air pollution associated with CKD is almost non-existent in Nigeria and Sub-Saharan Africa, and environmental epidemiological researchers from the Niger Delta region have stressed the general paucity of scientific evidence, advocating for research support to examine and assess the health risks associated with petroleum-related exposure (Ordinioha & Brisibe, 2013; Orisakwe, 2021).\n\nCoincidentally, similar to CKD, air pollution and its negative health consequences are worse in disadvantaged countries, placing an additional burden on already-strained health systems. Few reliable epidemiological studies on air pollution and kidney disease have been conducted among susceptible people living in the Niger Delta, Nigeria’s greatest petroleum hub, with CKD prevalence exceeding 10% (Chukwuonye et al., 2018). The irreversible and progressive nature of CKD, the high prevalence and incidence rates, adverse outcomes, enormous costs of treatment, and the strain on individual and collective health costs should prompt all stakeholders to take action. The persistence of a combination of CKD and ambient air pollution (two top-ten risk factors for global deaths) despite existing environmental health regulations is concerning and deserves attention.\n\nThis document provides epidemiological evidence of air pollution associated CKD in susceptible communities in Niger Delta, Nigeria, the implications for policy and recommendations for action. The Ethical Review Committee of the Hospital Management Board, Warri, Delta State, Nigeria (CHW/ECC VOL 1/226) and the School of Health and Social Care Research Integrity Committee, Edinburgh Napier University (2782647) approved the study.\n\n\nPolicy outcomes and implications\n\nDespite the high burden of CKD in Nigeria, there is currently no renal care policy, plan or programme. Although the updated National Health Policy published in 2016 (Federal Ministry of Health, 2016) explicitly states that all tiers of government and private sectors should commit to attaining health and good quality of life for all citizens, CKD was surprisingly not identified as one of the major NCDs requiring attention. The implication of this grave omission is that while resources are channelled towards the prevention and control of NCDs such as hypertension, cardiovascular disease, stroke and asthma, the prevalence of CKD remains high and outcomes, abysmal.\n\nThe nephrology research community are well place to generate the needed evidence that may persuade policy makers to action. This brief therefore provides epidemiological evidence of high CKD burden in susceptible communities in the Niger Delta, Nigeria and the possible association with the greatest environment risk factor for diseases - air pollution.\n\nNo air monitoring data existed in the State at the time this study was conducted. Ambient air pollutants were measured in collaboration with eight citizen scientists from four communities at varying distances from the petrochemical refinery: A (3 km/semi-urban), B (3.5 km/urban), C (10 km/urban), and D (13 km/rural). The mean concentrations of PM2.5, PM10, and volatile organic compounds (VOCs) exceeded the WHO acceptable limits in all four communities, whereas CO2 was acceptable only in the communities farthest from the refinery (Table 1). Ozone (O3) was within the acceptable limits in all communities. The mean PM10 concentration was highest in the two communities closest to the refinery (A and B), while PM2.5 was highest in the urban community closest to the refinery (B). Higher than acceptable levels of NO2 were recorded on certain days in all communities, whereas for most other days, it was negligible. Table 1 shows the estimated hazard quotient (HQ) of the air pollutants in the four communities. The HQ was estimated by dividing the mean concentration of the individual air pollutants by their respective WHO minimum acceptable limits. An HQ ≤1 is considered a negligible hazard, while >1 indicates exposure concentrations exceeding the reference limit, but not necessarily a statistical probability of harm occurring. The calculated HQ for PM2.5, PM10, VOC, and CO2 based on the WHO minimum allowable limits, were elevated in all four communities.\n\n* Indoor threshold limit, which is typically higher than outdoor.\n\nA health survey was conducted over a period of six months to assess the prevalence and risk factors of CKD among 1460 community members selected by multi-stage sampling from the four communities. Adults aged 18-64 years who had resided in their respective communities for at least 5 years were recruited.\n\nThe overall prevalence of CKD, defined as dipstick proteinuria and/or an eGFR <60 ml/min was 12.3%. The prevalence was highest in community A closest to the refinery (17.9%) compared with 13.1%, 10.5%, and 8.0% in communities B, C, and D, respectively (X2=18.292, p≤.001). Proteinuria alone was detected in 6.8% of all participants, while 6.6% had a reduced eGFR of <60 ml/min. Two-fifths of the participants with CKD were in stage 3A (i.e. eGFR 45-59 mls/min) which represents a mild to moderate decrease in kidney function requiring monitoring (Figure 1).\n\nThe risk factors significantly associated with CKD were older age, low level of education, proximity to the refinery, residence in urban/semi-urban areas compared to rural areas, use of hair dyes, spending more time indoors, hypertension, and diabetes. However, after adjusting for confounding factors, the independent risk factors for CKD were older age, low level of education, proximity to the refinery and hypertension. The overall prevalence of hypertension, obesity, and diabetes was 33%, 28.5%, and 6.0%, respectively.\n\nOne-third (31.5%) of the population had less than secondary-level education, and 50.5% earned less than the minimum wage. Although 86% of the population was employed, 68% were self-employed, and only 3.8% were employed by the government. Of the 68% self-employed, the majority were petty traders. Several social risk factors and toxic environmental exposures associated with CKD and NCDs were prevalent among residents of the four communities. Behavioural factors included grossly inadequate fruit (90%) and vegetable ingestion (70%), low physical activity (47.2%), use of kerosene (44%), alcohol consumption (41%), use of herbal concoctions (40.8%), and cooking with solid fuel (37.1%). Four-fifths of the population was regularly exposed to petrochemical products as part of their daily lives, 72% used household chemicals regularly, 53.2% were regularly exposed to pesticides, and 49% were exposed to toxic chemicals or dust in their jobs. Other risk factors that were relatively less prevalent included hair dye use (19%), excess salt intake (15%), use of mothballs (14.4%), use of skin lighteners (12.7%), and current smoking (3.8%).\n\nTwo-fifths of the 1460 survey participants perceived that their outdoor air was polluted, and the proportion was significantly higher (65%) among those residing near the refinery. Heightened perception of air pollution was significantly more common among young people, those who lived near refineries and urban areas, those who spent more time outdoors, and those who cooked with propane gas. Refinery activities were cited as the most popular source of air pollution. A higher proportion of those residing near the refinery attributed air pollution to the refinery/gas plant: 40.6% and 18.0% for communities A and B, respectively, compared to 7.2% and 6.1% for the furthest away communities C and D, respectively. Other perceived sources of air pollution include poor environmental sanitation, traffic emissions, generator fumes, open waste burning, and illegal oil refining (Figure 2).\n\nOthers=Bakery, other industries, dust, overcrowding, sawmills, septic pits, swamps.\n\nMost participants (70.1%) perceived that air pollution is associated with health risks, 13.4% responded negatively, and 16.4% did not know. The majority of study participants (60.1%) were unaware of any medical conditions associated with air pollution. Figure 3 shows the participants’ responses when asked about the specific health conditions associated with air pollution.\n\nOnly 12.3% of the participants agreed that the ambient air environment was well controlled and up to 60% placed responsibility solely on the government. Among those who agreed that they had a role to play, the responses included maintaining environmental sanitation (53%), complaining to the government and advocacy (32%), and using personal protective measures (3.7%).\n\n\nImplications for policy\n\nThere is currently no renal care policy in Nigeria or Delta State, and the most recent National Health Policy does not capture CKD among NCDs. This critical omission needs to be urgently addressed as the enormous burden of CKD is not debatable. Furthermore, CKD is often associated with mortality in patients with both NCDs and chronic infections.\n\nIn the broadest policy terms, increasing efforts towards environmental risk protection, including environmental risk communication and transparency, and reducing poverty and investment in public health services, would improve population health and reduce inequalities in general, but more so for susceptible persons. Specifically, poverty and ignorance of health-promoting information increase the burden of CKD via mechanisms related to access to health care, unhealthy behaviors, biological factors (e.g., low birth weight, inadequate nutrition), and environmental factors (e.g., exposure to pollutants, communicable diseases, lack of clean water, and sanitation). Therefore, multisector integration, interdisciplinarity, and public inclusion in shaping policies and planning health interventions are needed to ensure effectiveness and reduce inequalities.\n\nThis study reveals that communities in Warri are simultaneously exposed to household, community, and global environmental risks, depicting a Triple Risk Overlap (Smith & Ezzati, 2005). Due to the high prevalence of CKD risk factors and low awareness of CKD and NCD status among the study participants, it appears that health literacy is low, and the public is yet to embrace routine health screening. The implication is that current public health education interventions are not persuasive enough or effective. Out-of-pocket payments are an additional hindrance to positive health-seeking behaviors.\n\n\nActionable recommendations\n\n\n\n• A National Renal Care Policy is needed and should be integrated with the existing National Health Care Policy.\n\n• Kidney health prevention and treatment should be covered by National and State health insurance schemes. Re-introducing the Delta State haemodialysis subsidy should be considered to address the suffering of people already living with kidney failure.\n\n• All primary health centers (public and private) should be equipped to carry out basic kidney screening tests, including blood pressure monitors, urinalysis dipsticks, and portable point-of-care serum creatinine or cystatin C analyzers.\n\n• The public requires more persuasion to adopt healthy behaviors and routine annual health screenings. For instance, a medical certificate of fitness should be required before a driver’s licence or international passport renewals.\n\n• Environmental risk factors such as air pollution should feature prominently in strategic plans for NCD prevention. The current National Health Policy does not explicitly highlight the role of mitigating environmental exposures such as air pollution in achieving sustainable health.\n\n• Public environmental health education is needed and should be planned and executed in collaboration with all stakeholders, including relevant government agencies, public health professionals, educators, environmental scientists, sociologists, industries, non-profit organizations, and community leaders/members. Training is required for trainers who are environmental health champions that will sustain the campaign for clean air at the community level.\n\n• Nigeria lacks continuous air monitoring data and has met only one out of the nine Clean Air Targets (United Nations Environment Programme, 2021).\n\nThere is an urgent need to invest in air monitoring services and data, cleaner technologies (e.g., electric transportation, solar, and wind power), and environmental risk communication through various media channels.\n\n• Preserve forests and green spaces. Encourage and support citizens to maintain green spaces around their homes. The Delta State Ministry of Environment has initiated a number of tree-planting campaigns, which are commendable and should be sustained.\n\n• There is a need for socially empowering policies to improve the indices of susceptible populations that have suffered long-term environmental exposure. Job creation and skill acquisition training is required in these areas.\n\n• All tiers of government, regulatory bodies, and urban planners should commit to improving air quality by enforcing stringent air pollution standards, regulations, and legislation. Environmental impact assessments should be conducted in accordance with ethical standards.\n\n• There is a need to support the research community through grants to generate robust, credible, and reliable evidence that will inform effective health and social interventions. Although the National Health Policy stated the importance of “strengthening the evidence”, this can only be achieved by partnering with the experts and providing the resources to support credible research in areas of need.\n\nAir monitoring was conducted for a period of 4 weeks only, due to the high financial implications and tenure of the research. Urine protein was tested using dipsticks rather albumin: creatinine ratio which is more reliable, due to high cost of the test. However, dipsticks test is highly specific though less sensitive in detecting low levels of proteinuria. Lastly, the diagnosis of CKD was based on a spot- assessment due to the participants’ unwillingness to repeat their test and possibly confirm a new disease. The lack of a repeat test may have led to an over- or under-diagnosis of CKD.\n\n\nConclusion\n\nThe main purpose of this briefing is to draw attention to the seriousness of chronic kidney disease, the possible causative role of environmental exposures such as air pollution, and to provide information that may support decision makers in developing and implementing policies and strategies to address the problem.\n\nThe evidence presented strongly suggests that long-term exposure to ambient air pollution increases the risk of chronic kidney disease and hypertension, which is consistent with previously published evidence. In addition, there is evidence of the socioeconomic and indirect health impacts of air pollution in an already vulnerable population with poor environmental health literacy. Environmental injustices such as disparities in access to clean air and environmental health information are significant threats to sustainable health and require urgent attention. Therefore, the co-benefits of effective air pollution mitigation surpass environmental sustainability to include improvements in health, social well-being, and reduction in health inequalities.\n\nAddressing air pollution-associated CKD requires a multifaceted approach involving decision makers, health care professionals, the academic community, industries, and the general public. By incorporating the issue of air pollution-associated health risks into policymaking, practice, health professionals, and public education, it is possible to reduce the burden of CKD and other NCDs and improve public health outcomes.", "appendix": "Data availability statement\n\nEdinburgh Napier University: Ambient Air Pollution near Petrochemical Industries and Chronic Kidney Disease Risk: Integrating Citizen Science within an Exploratory Mixed Methods Study (dataset) https://doi.org/10.17869/enu.2024.3559366.\n\nThis project contains the following underlying data:\n\n• AIR MONITORING DATA.xlsx\n\n• Codebook - air pollution - 17-03-2022.docx\n\n• GFR.xlsx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgements\n\n\n\n• Management of Delta State University, Abraka, and Delta State University Teaching Hospital, Oghara.\n\n• The management of Central Hospital Warri, Delta State.\n\n• School of Health and Social Care, Edinburgh Napier University.\n\n• Leaders and members of the study community.\n\n• Research Assistants and volunteer health care professionals: Dr. Ejiro Orhewere, Dr. Oritseweyinmi Edema, Dr. Toritseju Ereku, Miss Chigozie Offiah, Miss Osarumen Uwadiae, and Mr. Clement Ugbunu.\n\n• Community volunteers (citizen scientists)\n\n• Dr Mininim Oseji, Permanent Secretary, Ministry of Environment, Delta State.\n\n\nReferences\n\nChukwuonye II, Ogah OS, Anyabolu EN, et al.: Prevalence of chronic kidney disease in Nigeria: systematic review of population-based studies. Int. J. Nephrol. Renov. Dis. 2018; 11: 165–172. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nFederal Ministry of Health: National Health Policy 2016: Promoting the Health of Nigerians to Accelerate Socio-economic Development.2016.Reference Source\n\nGarcia-Garcia G, Jha V; World Kidney Day Steering, C: Chronic kidney disease in disadvantaged populations: The case of Africa. Afr. J. Prim. Health Care Fam. Med. 2015, Apr 28; 7(1): e1–e2. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nGlobal Burden of Disease Collaboration: Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study.2019.\n\nOkoye OC, Carnegie E, Mora L: Air Pollution and Chronic Kidney Disease Risk in Oil and Gas- Situated Communities: A Systematic Review and Meta-Analysis. Int. J. Public Health. 2022; 67: 1604522. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nOrdinioha B, Brisibe S: The human health implications of crude oil spills in the Niger delta, Nigeria: An interpretation of published studies. Niger. Med. J. 2013; 54(1): 10–16. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nOrisakwe OE: Crude oil and public health issues in Niger Delta, Nigeria: Much ado about the inevitable. Environ. Res. 2021, Jan 9; 194: 110725. PubMed Abstract \| Publisher Full Text\n\nSmith KR, Ezzati M: HOW ENVIRONMENTAL HEALTH RISKS CHANGE WITH DEVELOPMENT: The Epidemiologic and Environmental Risk Transitions Revisited. Annu. Rev. Environ. Resour. 2005; 30(1): 291–333. Publisher Full Text\n\nStanifer JW, Muiru A, Jafar TH, et al.: Chronic kidney disease in low- and middle-income countries. Nephrol. Dial. Transplant. 2016, Jun; 31(6): 868–874. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nUnited Nations Environment Programme: Actiona on Air Quality: A global summary of policies and programmes to reduce air pollution. U. N. E. Program; 2021. Reference Source\n\nVanholder R, Annemans L, Bello AK, et al.: Fighting the unbearable lightness of neglecting kidney health: the decade of the kidney. Clin. Kidney J. 2021, Jul; 14(7): 1719–1730. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWorld Health Organization: Ambient (outdoor) air pollution.2018. December 11th. Reference Source\n\nWu MY, Lo WC, Chao CT, et al.: Association between air pollutants and development of chronic kidney disease: A systematic review and meta-analysis. Sci. Total Environ. 2020, Mar 1; 706: 135522. PubMed Abstract \| Publisher Full Text\n\nYe J, Wang S-S, Fang Y, et al.: Ambient air pollution exposure and risk of chronic kidney disease: A systematic review of the literature and meta-analysis [Article]. Environ. Res. 2021; 195: 110867. PubMed Abstract \| Publisher Full Text" }	[ { "id": "268338", "date": "08 May 2024", "name": "Chao Yang", "expertise": [ "Reviewer Expertise Public health" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study provides insights into the association between air pollution and CKD risk in Niger Delta communities. Comprehensive policy interventions and public education are needed to mitigate the CKD risk and improve overall health outcomes in these communities. Here are several specific comments for the paper:\n1) The authors should provide a more detailed description of the mixed-methods approach used in the study. Clarify the specific quantitative and qualitative methods employed, sample sizes, and data collection techniques.\n2) The paper mentions that air pollutant concentrations were measured and compared to WHO limits. However, the analysis of these data and their statistical significance is lacking. The authors should include a more thorough analysis of the air pollution data.\n3) The paper discusses the association between ambient air pollution and CKD risk, but does not claim causality. The authors should clarify this distinction and discuss potential confounders or alternative explanations for the observed association.\n4) The paper should acknowledge other limitations of the study, such as sample size, data availability, or methodological constraints. Additionally, the authors should discuss potential directions for future research to build upon the current findings.\n5) The authors should discuss the generalizability of their findings to other communities and regions with similar industrial activities.\n\nDoes the paper provide a comprehensive overview of the policy and the context of its implementation in a way which is accessible to a general reader? Partly\n\nIs the discussion on the implications clearly and accurately presented and does it cite the current literature? Partly\n\nAre the recommendations made clear, balanced, and justified on the basis of the presented arguments? Partly", "responses": [ { "c_id": "11795", "date": "24 Jun 2024", "name": "Ogochukwu Okoye", "role": "Author Response", "response": "Thank you for your kind critique of the manuscript. All your comments are valid and appreciated. Being a policy brief, the manuscript was intentionally shortened to provide the basic information in a simple way for the intended audience, which includes policy makers. More detailed Original manuscripts for a scientific audience have been written and are currently undergoing peer review. However, the link to the Study Thesis was provided with this submission. Thank you." }, { "c_id": "12543", "date": "21 Nov 2024", "name": "Ogochukwu Okoye", "role": "Author Response", "response": "REVIEWER 1 We are grateful for your detailed and constructive critique which has helped to significantly improve the merit and quality of our manuscript 1) The authors should provide a more detailed description of the mixed-methods approach used in the study. Clarify the specific quantitative and qualitative methods employed, sample sizes, and data collection techniques. Thank you for your observations. Extensive methodological and statistical details were deliberately omitted as the manuscript was targeted at policymakers. However, we have provided additional details in the text. The underlying study was an exploratory mixed methods study with an embedded citizen science inquiry. Details of the first strand which was a focus group has been published and we have provided a reference to the article. In the current brief, we focus on findings from the other strands of the study. (Pages 2,3,5) 2) The paper mentions that air pollutant concentrations were measured and compared to WHO limits. However, the analysis of these data and their statistical significance is lacking. The authors should include a more thorough analysis of the air pollution data. For the reasons mentioned above, we omitted these details. However, some additional data have been provided in the text and as supplementary files. (Page 5, suppl 1, Figure 1) 3) The paper discusses the association between ambient air pollution and CKD risk, but does not claim causality. The authors should clarify this distinction and discuss potential confounders or alternative explanations for the observed association. We agree with your observations. We have provided details of confounding factors considered and a supplementary file containing updated results from a binary mixed effects logistic model conducted to account for clustering effects. We report that long-term exposure to ambient air pollution is associated with CKD risk, but does not independently increase its risk, after adjusting for clustering effects and confounders (age, gender, hypertension, level of education and diabetes). (Page 6, suppl 2) 4) The paper should acknowledge other limitations of the study, such as sample size, data availability, or methodological constraints. Additionally, the authors should discuss potential directions for future research to build upon the current findings. The section on limitation of the study has been improved and suggestions for future research as follows: “More research is required from under-served areas to explore: this exposure-effect relationship, the mechanism of air pollution associated CKD and potential interventions to reverse it; and to develop educational interventions that would effectively improve public awareness of environmental health risks”. (Page 11) 5) The authors should discuss the generalizability of their findings to other communities and regions with similar industrial activities. This has been included. “…. our findings are generalisable to similar vulnerable populations across the globe who reside near point emission sources” (Page 7)" } ] }, { "id": "292274", "date": "11 Sep 2024", "name": "Nikola M Pavlović", "expertise": [], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAmbient Air Pollution and Chronic kidney disease risk in Deltan communities: A Policy Brief, 2023. Abstract\nComments:\nThe abstract effectively highlights the importance of the study by addressing an issue that is often overlooked: CKD in developing countries. However, it could refine its focus on the study's objectives, methods, key findings, and specific policy recommendations.\n\nSuggestions:\nObjective Clarification: Include a brief statement that clearly outlines the study's objective. Methodology Mention: Explicitly mention that a mixed-methods approach was used. Specific Findings: Highlight specific data points, such as the exact levels of pollutants that exceed WHO limits. Policy Recommendations: Summarize one or two key policy recommendations for a clear takeaway.\n\nIntroduction\nComments:\nThe introduction is comprehensive, providing a strong background on CKD and air pollution, particularly in the context of developing countries. However, it somewhat repeats itself by discussing traditional CKD risk factors.\n\nSuggestions:\nStreamlining: Consider consolidating the discussion on traditional CKD risk factors to avoid redundancy. Focused Transition: Ensure a smooth transition from discussing CKD globally to the specific context of the Niger Delta. Identification of Gap: Introduce the research gap on the link between air pollution and CKD in the Niger Delta earlier in the section.\n\nPolicy Outcomes and Implications\nComments:\nThis section succinctly outlines the critical issue of lacking renal care policies in Nigeria. However, the link between CKD and air pollution could be articulated more forcefully to emphasize urgency.\n\nSuggestions:\nDirect Link: Explicitly connect the absence of CKD in national health policy to the study’s findings on air pollution and CKD prevalence. Broader Implications: Discuss the broader public health implications if this policy gap continues, including potential long-term consequences.\n\nEvidence of High Ambient Air Pollutant Levels in Warri\nComments:\nThis section is rich in data and provides a clear picture of pollution levels. The use of a table to present hazard quotients is effective, but the narrative could be enhanced for better flow and readability.\n\nSuggestions:\nNarrative Flow: Integrate the table with the narrative by referencing key figures directly in the text. Benchmark Against Global Standards: Briefly compare the findings with global or regional averages for context. Graphical Representation: Consider using a graph to visualize the levels of pollutants across communities for greater impact.\n\nHigh Prevalence of CKD and the Risk Factors\nComments:\nThis section effectively presents prevalence data and associated risk factors. The statistical significance is clearly noted, strengthening the findings.\n\nSuggestions:\nRisk Factor Hierarchy: Present the risk factors in order of their strength of association with CKD. Visual Aids: While the current figure is useful, additional visual aids, such as bar charts or scatter plots, could further clarify the distribution of CKD stages across communities. Contextualization: Briefly contextualize the CKD prevalence data with national or regional statistics to highlight the severity.\n\nSocial Determinants of CKD Risk\nComments:\nThe social determinants are well-captured, providing a comprehensive picture of contributing factors. However, the section could benefit from a more concise presentation.\n\nSuggestions:\nCondensation: Consider condensing the list of behavioral factors by grouping similar items, such as unhealthy dietary habits. Clearer Connections: Draw clearer connections between these social determinants and the higher CKD prevalence, emphasizing the compounding effect of multiple risk factors. Implications: Discuss the potential public health implications of these social determinants in more depth.\n\nLow Air Pollution Health Risk Literacy in Warri\nComments:\nThis section addresses an important issue but could be more impactful if it connected low health literacy directly with CKD prevalence.\n\nSuggestions:\nDirect Linkage: Explicitly link low literacy levels to poor health outcomes, particularly in the context of CKD and air pollution. Awareness Campaigns: Suggest potential public health campaigns or educational interventions to improve awareness based on the findings.\n\nImplications for Policy\nComments:\nThis section provides a strong call to action. The identified policy gaps are critical and well-presented.\n\nSuggestions:\nStructured Recommendations: Present the policy implications in a more structured format, possibly using bullet points or numbered lists for clarity. Evidence Integration: Integrate specific study findings more directly into the policy recommendations to strengthen the argument for immediate action.\n\nActionable Recommendations\nComments:\nThe recommendations are comprehensive and relevant but could be more prioritized or categorized.\n\nSuggestions:\nPrioritization: Consider categorizing the recommendations into short-term, medium-term, and long-term actions. Stakeholder Engagement: Emphasize the role of specific stakeholders (e.g., government, NGOs, the public) in implementing these recommendations. Feasibility: Briefly discuss the feasibility of these recommendations, particularly in the context of existing infrastructure and resources.\n\nLimitations of the Study\nComments:\nThe limitations are transparently discussed, which is commendable. However, there is a risk that some of these might overshadow the study's strengths.\n\nSuggestions:\nStrengths Emphasis: Counterbalance the limitations with a brief discussion of the study’s strengths, particularly its novel approach and the involvement of citizen scientists. Future Directions: Suggest specific areas for future research that could address these limitations, enhancing the study's impact.\n\nConclusion\nComments:\nThe conclusion effectively summarizes the key points but could be more emphatic in calling for urgent action.\n\nSuggestions:\nStronger Call to Action: End with a more forceful call to action directed at policymakers, highlighting the urgency of addressing CKD in the Niger Delta. Summary of Key Points: Briefly summarize the most critical findings and recommendations to leave a lasting impression.\n\nOverall Document Comments:\nConsistency: Ensure consistency in the use of terms (e.g., CKD vs. chronic kidney disease) throughout the document. Clarity: While the document is generally clear, some sections, particularly those with dense data, could benefit from simpler language and clearer transitions. Visual Aids: Consider the strategic use of additional visual aids to break up text-heavy sections and improve reader engagement. Proofreading: A thorough proofreading is recommended to correct any minor grammatical errors and ensure a polished final submission.\nI believe these suggestions will assist the authors in refining their policy brief to make it more impactful and ensure it effectively communicates the urgency of the issue to both policymakers and the broader public.\n\nDoes the paper provide a comprehensive overview of the policy and the context of its implementation in a way which is accessible to a general reader? Yes\n\nIs the discussion on the implications clearly and accurately presented and does it cite the current literature? Yes\n\nAre the recommendations made clear, balanced, and justified on the basis of the presented arguments? Yes", "responses": [ { "c_id": "12544", "date": "31 Jan 2025", "name": "Ogochukwu Okoye", "role": "Author Response", "response": "We are grateful for your detailed and constructive critique which has helped to improve the merit and quality of our manuscript. ABSTRACT Reviewer comment: Objective Clarification: Include a brief statement that clearly outlines the study's objective. Author response: The objective has been clarified as follows: “This brief is based on a mixed-methods study conducted in four communities situated near an oil and gas refinery in Warri, Nigeria to explore perceived and actual air pollution risk and determine whether long-term exposure to AAP increases NCD risk” (Page 2) Reviewer comment: Methodology Mention: Explicitly mention that a mixed-methods approach was used. Author response: Done as stated above Reviewer comment: Specific Findings: Highlight specific data points, such as the exact levels of pollutants that exceed WHO limits. Author response: Included as follows: “Measured PM2.5 ranged from 22.8 – 28.0 μg/m3, PM10, 40.6 - 55.5 μg/m3, and CO2, 584-652ppm”. 2 Reviewer comment: Policy Recommendations: Summarise one or two key policy recommendations for a clear takeaway. Author response: Included as follows: “The government needs to urgently invest in air monitoring services and data, cleaner technologies and environmental risk communication through various media channels. We strongly recommend public inclusion in planning, designing and implementing future environmental interventions. Lastly, environmental risk factors such as air pollution should feature prominently in strategic plans for NCD prevention”. (Page 2) Introduction Reviewer comment: Streamlining: Consider consolidating the discussion on traditional CKD risk factors to avoid redundancy. Focused Transition: Ensure a smooth transition from discussing CKD globally to the specific context of the Niger Delta. Identification of Gap: Introduce the research gap on the link between air pollution and CKD in the Niger Delta earlier in the section. Author response: Thank you for your suggestions. We have reviewed this section accordingly. (Page 3) Reviewer comment: Policy Outcomes and Implications Author response: This section has been improved accordingly Reviewer comment: Direct Link: Explicitly connect the absence of CKD in national health policy to the study’s findings on air pollution and CKD prevalence. Author response: This has been revised as follows: “This lack of recognition of CKD and the environmental risk factors important in the disease epidemiology, may explain why CKD and related NCDs are persistent.” (Page 4) Reviewer comment: Broader Implications: Discuss the broader public health implications if this policy gap continues, including potential long-term consequences. Author response: “The long-term consequences of continually neglecting CKD in health policies include the persistence of hypertension and CKD with associated considerable morbidity and mortality; high health care expenditure which further impoverishes the affected members of society and their families”. (Page 4) Reviewer comment: Evidence of High Ambient Air Pollutant Levels in Warr Narrative Flow: Integrate the table with the narrative by referencing key figures directly in the text. Author response: This section has been improved accordingly and highlighted in the text (Page 4-5) Reviewer comment: Benchmark Against Global Standards: Briefly compare the findings with global or regional averages for context. Author response: This section has been improved as follows: “The PM2.5 concentrations for three of the communities are higher than Nigeria’s 2023 average of 23.9 μg/m3 (IQAIR) and five times higher than the WHO acceptable limit. Furthermore, these levels are much higher than 7.8μg/m3 achieved in Angola, the least polluted African country which ranked 114th out of 134 countries, while Nigeria was ranked the 35th most polluted”.( Page 4-5) Reviewer comment: Graphical Representation: Consider using a graph to visualize the levels of pollutants across communities for greater impact. Author response: A bar chart showing air pollutant levels in the 4 communities have been included. (Figure 1) Reviewer comment: High Prevalence of CKD and the Risk Factors Risk Factor Hierarchy: Present the risk factors in order of their strength of association with CKD. Author response: Included as follows: “The independent risk factors for CKD were proximity to the refinery [OR=2.00 (1.43 – 2.81], increasing age [OR=1.02(1.005-1.04)], hypertension [OR=1.61(1.12-2.31)], and level of education [OR=0.63(0.44-0.91)]. In a further logistic mixed model, which accounted for clustering effects at household level, only increasing age was an independent risk factor for CKD [OR=1.16 (1.07-1.25)]”, (Page 6) Reviewer comment: Visual Aids: While the current figure is useful, additional visual aids, such as bar charts or scatter plots, could further clarify the distribution of CKD stages across communities. Author response: A new figure showing the information requested has been included. (Figure 3) Reviewer comment: Contextualization: Briefly contextualize the CKD prevalence data with national or regional statistics to highlight the severity. Author response: Revised as follows: The prevalence of CKD reported across Nigeria and Sub-Saharan Africa varies greatly depending on the population studied, CKD definition and methodology; from as low as 2% to >20% (Abd ElHafeez et al., 2018; Chukwuonye et al., 2018). However, our findings demonstrate a higher CKD prevalence in the nearest/semiurban community A, compared with a pooled prevalence of 10% and 13.7% reported for Africa and Nigeria, respectively (Abd ElHafeez et al., 2018; Raji et al., 2024). (Page 5) Social Determinants of CKD Risk Reviewer comment: Condensation: Consider condensing the list of behavioral factors by grouping similar items, such as unhealthy dietary habits. Author response: Revised as follows: ‘Behavioural factors included unhealthy dietary habits (70-90%), low physical activity (47.2%), habitual exposure to potential nephrotoxins (37-44%)’. (Page 6) Reviewer comment: Clearer Connections: Draw clearer connections between these social determinants and the higher CKD prevalence, emphasizing the compounding effect of multiple risk factors. Author response: Revised as follows: “The concentration of multiple social and environmental risk factors in the studied population may explain the high prevalence of CKD and other NCDs. These findings support the multicasuation theory, drawing attention to the need for a multi-faceted approach to CKD prevention.” (Page 6) Reviewer comment: Implications: Discuss the potential public health implications of these social determinants in more depth. Author response: Done as above. These points were further discussed in the section on implications for policy. (Pages 6,7) Reviewer comment: Low Air Pollution Health Risk Literacy in Warri Direct Linkage: Explicitly link low literacy levels to poor health outcomes, particularly in the context of CKD and air pollution. Author response: Revised as follows: “This low literacy level suggests that the necessary preventive measures such as individual behavioral changes, are lacking and this may contribute to the high burden of air pollution associated NCDs in the community”. (Page 7) Reviewer comment: Awareness Campaigns: Suggest potential public health campaigns or educational interventions to improve awareness based on the findings. Author response: These have been suggested. “The high prevalence of CKD risk factors and low awareness of CKD and NCD status among the study participants suggests low health literacy and poor health-seeking behavior which necessitates more persuasive and inclusive public health educational interventions.” (Page 7) Implications for Policy Reviewer comment: Structured Recommendations: Present the policy implications in a more structured format, possibly using bullet points or numbered lists for clarity. Author response: This section has been reviewed accordingly. (Page 7,8) Reviewer comment: Evidence Integration: Integrate specific study findings more directly into the policy recommendations to strengthen the argument for immediate action. Prioritization: Consider categorizing the recommendations into short-term, medium-term, and long-term actions. Author response: We appreciate your comments. This section has been improved as is shown in Table 1. (Page 8-11) Reviewer comment: Stakeholder Engagement: Emphasize the role of specific stakeholders (e.g., government, NGOs, the public) in implementing these recommendations. Feasibility: Briefly discuss the feasibility of these recommendations, particularly in the context of existing infrastructure and resources. Author response: These points have all been considered in the revised table of recommendations. (Page 8-11) Limitations of the Study Reviewer comment: Strengths Emphasis: Counterbalance the limitations with a brief discussion of the study’s strengths, particularly its novel approach and the involvement of citizen scientists. Author response: This has been included as follows: “Despite the limitations, the strength of the underlying study lies in the relatively large sample size, the extensive consideration and adjustment for confounding factors, the innovative combination of multiple research methods and involving citizen scientists in addressing a public health problem”. (Page 11) Reviewer comment: Future Directions: Suggest specific areas for future research that could address these limitations, enhancing the study's impact. Author response: This has been included as follows: “More research is required from under-served areas to explore: this exposure-effect relationship, the mechanism of air pollution associated CKD and potential interventions to reverse it; and to develop educational interventions that would effectively improve public awareness of environmental health risks”. (Page 110) Conclusion Reviewer comment: Stronger Call to Action: End with a more forceful call to action directed at policymakers, highlighting the urgency of addressing CKD in the Niger Delta. Author response: Thank you for your suggestions. The section has been improved. (Page 11,12) Reviewer comment: Summary of Key Points: Briefly summarize the most critical findings and recommendations to leave a lasting impression. Author response: Thank you for your suggestions. The section has been improved. (Page 11, 12) Overall Reviewer comment: Consistency: Ensure consistency in the use of terms (e.g., CKD vs. chronic kidney disease) throughout the document. Author response: CKD is now used consistently throughout the text, except for where it was first mentioned. Reviewer comment: Clarity: While the document is generally clear, some sections, particularly those with dense data, could benefit from simpler language and clearer transitions. Author response: Thank you. The authors have made significant efforts to improve the clarity and readability of the document using a proof reader. Reviewer comment: Visual Aids: Consider the strategic use of additional visual aids to break up text-heavy sections and improve reader engagement. Author response: Additional visual aids have been introduced. e.g., more figures and the recommendations have been tabulated." } ] }, { "id": "279715", "date": "14 Sep 2024", "name": "Nicholas Osborne", "expertise": [ "Reviewer Expertise Environmental epidemiology" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall comments This study proposes to discover association between air pollution and CKD. Unfortunately an accurate measure of air pollution was not available. Similarly an accurate measure of the health outcome, kidney function was not available. Diagnosis of CKD requires two measures of kidney function (usually by eGRF) at least 3 months apart. Consequently attempts to examine the relationship do not have data of sufficient quality to make the linkage. The paper was not conducted as a policy brief. Large amounts of extant literature were missing from the evidence base presented. The paper has a limited data reference list.\nSpecific comments Abstract mentions CKDu in passing without mentioning its prevalence in certain LMIC settings. The disease CKDu in Sri Lankan and Mesoamerican settings.\n\nDoes the paper provide a comprehensive overview of the policy and the context of its implementation in a way which is accessible to a general reader? No\n\nIs the discussion on the implications clearly and accurately presented and does it cite the current literature? No\n\nAre the recommendations made clear, balanced, and justified on the basis of the presented arguments? No", "responses": [ { "c_id": "12545", "date": "21 Nov 2024", "name": "Ogochukwu Okoye", "role": "Author Response", "response": "We are grateful for your detailed and constructive critique which has helped to significantly improve the merit and quality of our manuscript. Comment: This study proposes to discover association between air pollution and CKD. Unfortunately, an accurate measure of air pollution was not available. Consequently, attempts to examine the relationship do not have data of sufficient quality to make the linkage. Response: Extensive methodological and statistical details were deliberately omitted as this document was targeted at policymakers. However, we have provided additional information in the text to describe how air pollution was measured and other details are available in the link to the underlying study. Page 4 Comment: Similarly, an accurate measure of the health outcome, kidney function was not available. Diagnosis of CKD requires two measures of kidney function (usually by eGRF) at least 3 months apart. Response: We agree with your observation. The authors initially set out to obtain at least two measurements from participants who have abnormalities but encountered challenges with participant retention. This limitation has been highlighted in more detail. However, all biological samples were handled and processed by a reputable independent laboratory with documented standard operating procedures to ensure accuracy and reliability. Page 11 Comment: The paper was not conducted as a policy brief. Large amounts of extant literature were missing from the evidence base presented. Response: Thank you for your valid observation. We structured the paper according to the journal's template for a policy brief. Our intention was to provide a brief summary of the underlying study before delving into the policy implications and recommendations. We deliberately excluded excessive statistical information to enhance readability for the non-academic audience. However, we have now included more data in the text figures and supplementary files. Comment: The paper has a limited data reference list. Response: The short reference list was to adhere to the limits of a policy brief. More references have been included in specific sections. Pages 3,5,6,7,14 Comment: Abstract mentions CKDu in passing without mentioning its prevalence in certain LMIC settings. The disease CKDu in Sri Lankan and Mesoamerican settings. Response: Thank you for your comment. There may have been a mix up. CKDu was not mentioned in the abstract. -" } ] } ]	1	https://f1000research.com/articles/13-265
https://f1000research.com/articles/13-1118/v1	03 Oct 24	{ "type": "Opinion Article", "title": "Knee strengthening after surgery: A comprehensive analysis using key performance indicators", "authors": [ "Florian Forelli", "Jean Mazeas", "Mathias Nielsen-Le Roux", "Ayrton Moiroux Sahraoui", "Nicholas Miraglia", "Maciej Bialy", "Ismail Bouzekraoui Alaoui", "Georgios Kakavas", "Andreas Bjerregaard", "Maurice Douryang", "Jean Mazeas", "Mathias Nielsen-Le Roux", "Ayrton Moiroux Sahraoui", "Nicholas Miraglia", "Maciej Bialy", "Ismail Bouzekraoui Alaoui", "Georgios Kakavas", "Andreas Bjerregaard", "Maurice Douryang" ], "abstract": "This article provides a comprehensive analysis of knee strengthening post-surgery, focusing on key performance indicators (KPIs) essential for recovery and performance enhancement. The study delves into the importance of range of motion (ROM), load management through repetitions maximum (RM) and velocity-based training (VBT), speed variations, repetition schemes for hypertrophy and strength, and the assessment of pain, inflammation, and effusion. Emphasis is placed on dynamic alignment, muscle activation, and rate of perceived exertion (RPE) to tailor individualized rehabilitation programs. The integration of these KPIs ensures a balanced approach, enhancing muscle strength and joint integrity while minimizing injury risk. Regular monitoring and adjustments based on these indicators are recommended to optimize outcomes and ensure sustained progress in knee function and overall mobility.", "keywords": [ "Knee Strengthening", "Rehabilitation", "Velocity-Based Training", "Range of Motion" ], "content": "Introduction\n\nThe knee joint is crucial for many movements in daily life and athletic activities, making strength training essential for performance, injury prevention and rehabilitation. This article delves into the scientific foundations of knee strengthening, focusing on key performance indicators (KPIs) such as range of motion (ROM), load (repetitions maximum and velocity-based training), speed, repetitions (hypertrophy and strength), pain assessment, inflammation and effusion evaluations (stroke test), biomechanics of movement (dynamic alignment of the lower limb), muscle activation (patient’s perception), and rate of perceived exertion (RPE).\n\n\nRange of motion\n\nROM is a critical factor in knee health, influencing the efficacy of strengthening exercises. ROM refers to the degree of movement a joint can achieve in a certain plane or direction. For the knee, symmetrical to the uninvolved side in full extension (0 degrees) to full flexion (approximately 135 degrees) is considered normal. Achieving and maintaining this range is vital for joint function and overall mobility. Manske et al. highlights that achieving full ROM post-surgery or injury is necessary for optimal recovery and function.1 Exercise targeting the knee should prioritize regaining and maintaining this range, with progressive loading to ensure joint and muscle adaptation without compromising joint integrity. This is especially important kneeling sports activities or praying position where weighted full knee flexion are required. Consistent monitoring and assessment of ROM can help tailor exercise programs to individual needs, ensuring that any limitations are addressed promptly to avoid long-term deficits.\n\nTo enhance ROM, dynamic stretching and flexibility exercises should be incorporated into a knee strengthening regimen. Techniques such as proprioceptive neuromuscular facilitation (PNF) stretching can be particularly effective. PNF stretching involves both stretching and contracting the muscle group targeted, which can help improve both flexibility and strength. Additionally, incorporating low-impact activities such as swimming or cycling can help maintain and enhance ROM without placing excessive stress on the knee joint. Assisted manual technique such a mobilization with movement may potential contribute to increased ROM.\n\n\nLoad: Repetitions maximum and velocity-based training\n\nThe load used in knee strengthening exercises is a fundamental aspect of training effectiveness. Strength training is typically prescribed as load relative percentage to an individual’s maximal ability repetitions maximum (1RM) or measured the maximum weight a person can lift for a given number of repetitions. For knee strengthening, 1RM and 10RM are commonly used benchmarks. The 1RM test, while effective, may pose a risk of injury if not supervised properly. Conversely, 10RM offers a safer alternative, balancing load and repetition to enhance muscle endurance and strength. Using these metrics allows for the precise prescription of exercise intensity, ensuring that the muscles are adequately stimulated for growth and adaptation. However, estimating a daily RM can be challenging, if the 1RM intended for the particular session or over a given period has changed prior to the session due to daily fluctuations.\n\nVelocity-Based Training (VBT) utilizes the speed of movement to regulate training load. When the load increased an equal relationship in reduction of lifting speed occurs. This loss of velocity continues until 1RM is achieved. This method ensures that athletes train at optimal intensities, maximizing power output while minimizing injury risk. VBT also allows for real-time adjustments, making it highly adaptable to the individual’s performance on any given day. Banyard et al. demonstrated that VBT could optimize strength gains by allowing real-time adjustments to training loads based on movement velocity, ensuring that muscles are consistently challenged while reducing the likelihood of overtraining.2,3 By incorporating both RM and VBT, a comprehensive training program can be developed that maximizes strength gains while maintaining safety (Table 1).\n\nAn effective knee strengthening program should include both heavy resistance training (based on percentage of 1RM). However, coaches should be aware of normal daily fluctuations may change with previously established 1RM. Therefore, by using VBT, daily variability of 1RM should be easier to adjust. Also more experienced and stronger athletes knows how to perform a maximum lift, and therefore their 1RM velocities may be lower than non-experienced lifter.4 While heavy resistance training close to 1RM are focuses on maximizing muscle strength and muscle size, VBT is focusing on ensuring that the knee muscles are trained across a spectrum of intensities and speeds either within the same session or over time (Table 2).\n\n\nSpeed\n\nSpeed in knee strengthening exercises refers to the tempo at which movements are performed. Faster speeds can enhance power and neuromuscular coordination, while slower speeds often emphasize muscle hypertrophy and neural drive. Balancing these different tempos can lead to more well-rounded strength development. Behm et al found that varying exercise speed can lead to different adaptations. Fast concentric movements with a high velocity are effective for developing explosive strength 1.3-0.75 m/s, whereas slower eccentric movements 0.75-<0.5 m/s are beneficial for hypertrophy and tendon health.7 Integrating both fast and slow tempos into a training regimen can therefore enhance overall knee function and resilience (Figure 1).\n\nWhen designing a knee strengthening program, incorporating speed variations can help supporting the performance goal by appropriate exercise selection towards either more force production or more velocity. From a clinical perspective tracking the same weight being moving with a faster speed over time will also indicate increase performance and equally a decrease in speed can indicate fatigue. Also manipulating load and velocity in plyometric exercises such as jump squats or box jumps can improve explosive power and neuromuscular coordination. Equally, controlled, slow movements like eccentric squats or leg presses will focus more on muscle hypertrophy and tendon health. Implementing VBT training approach ensures comprehensive knee strengthening and functional improvements.\n\n\nRepetitions: Hypertrophy and strength\n\nRepetition schemes play a significant role in determining the outcome of a knee strengthening program. Hypertrophy is typically achieved with 6-12 repetitions per set at 60-75% of 1RM, focusing on muscle growth.9 This rep range balances load and volume to promote muscle fiber size increase. On the other hand, strength is developed through lower repetitions (1-6 reps per set at 75-90% of 1RM), geared towards maximizing muscular strength. This approach ensures sufficient load to stimulate neural and muscular adaptations without causing excessive fatigue. Schoenfeld suggests that combining hypertrophy and strength training within a periodized program can lead to optimal muscle growth and strength improvements, offering a balanced approach to knee strengthening.10 Alternating between these repetition schemes can prevent plateaus and maintain continuous progress.\n\nPeriodization is a key concept in strength training, involving the systematic planning of training to optimize performance and recovery. By cycling through different phases of hypertrophy and strength training, the knee muscles can be continually challenged and stimulated for growth and adaptation. This approach also helps in preventing overuse injuries and mental burnout, ensuring sustained progress and motivation.\n\n\nPain assessment\n\nPain assessment is vital in knee strengthening programs, particularly for individuals recovering from injury. Utilizing pain scales help monitor patient discomfort and adjust exercises accordingly. Regular pain assessment can prevent the exacerbation of injuries and guide the progression of exercise intensity. Eitzen et al. emphasize that pain should be monitored to prevent exacerbation of injuries.11 They recommend that patients report pain levels consistently, with modifications to exercises made when pain exceeds a mild threshold. This approach ensures that the training remains within a safe and effective range.\n\nIncorporating pain assessment into a knee strengthening program allows for individualized adjustments based on patient feedback. This can include modifying exercise intensity, volume, or type to ensure that the knee is not being overstressed. Additionally, integrating recovery strategies such as cryotherapy, compression (or compressive cryotherapy in combination), and rest days can help manage pain, reduced medication consumption, and facilitate swelling reduction.12\n\n\nInflammation and effusion evaluation\n\nIdentifying and managing knee effusion may preventing long-term joint damage and ensuring effective rehabilitation. The stroke test is a commonly test used to assess the presence of joint effusion by performing an upward stroke from the medial joint line towards the suprapatella pouch followed by a downward stroke on the distal thigh from the suprapatellar pouch towards the lateral joint line. If a wave of fluid is observed at the medial knee the test is considered positiv.13 The stroke test grades the swelling into five grades from zero where no swelling to 3+ where there are such much fluid that it is not possible to move the effusion out of the medial aspect of the knee. Precautions in exercise progression should be taken when identifying joint effusion to ensure they do not aggravate the knee.13 Regularly conducting the stroke test can help track the knee’s response to training and make necessary adjustments.\n\nMonitoring joint effusion through the stroke test provides valuable information about the knee’s condition and response to exercise for example when returning to running. If effusion is detected, it may indicate an inflammatory response that requires modification of the training program. Rest, anti-inflammatory treatments, and low-impact exercises can be incorporated to allow the knee recover without exacerbating the condition.\n\n\nBiomechanics of movement: Dynamic alignment of the lower limb\n\nProper biomechanical alignment is essential to minimize injury risk and maximize exercise efficiency. Dynamic alignment refers to maintaining proper knee, hip, and ankle positioning during movement. Ensuring correct alignment can prevent common knee injuries and enhance the effectiveness of strengthening exercises. Powers8 discusses the role of dynamic alignment in preventing conditions like patellofemoral pain syndrome. Exercises that enhance lower limb alignment can improve functional outcomes and reduce injury incidence. Emphasizing biomechanical education and motor control or neuromuscular exercises. exercises can significantly improve dynamic alignment during physical activity. Single-leg exercises, such as single-leg squats or lunges, challenge the muscles to stabilize the knee joint and maintain proper alignment in the different planes. Additionally, incorporating balance and vibration training with tools such as balance boards or water bags can enhance proprioception and neuromuscular control.\n\n\nMuscle activation: Patient’s perception\n\nMuscle activation refers to the engagement of muscles during exercise. Muscle activation can be directly assessed using electromyography (EMG) or through subjective feedback of the patient. Understanding muscle activation patterns helps in designing exercises that target the intended muscles effectively. Escamilla et al.14 found that exercises like squats and lunges have varying levels of muscle activation in the quadriceps and hamstrings. Incorporating patient feedback on muscle activation can help tailor programs to individual goals. Ensuring optimal muscle activation can enhance the benefits of strengthening exercises by getting quicker results and prevent compensatory movements that may lead to undesired delay in the rehabilitation. An example, if a patient reports low quadriceps activation during squats, adjustments in technique or additional exercises such as leg extensions can be incorporated to enhance activation. This personalized approach ensures that the knee strengthening program is effective and aligned with the patient’s specific goals.\n\n\nRate of Perceived Exertion (RPE)\n\nRPE is a subjective measure of exercise intensity, typically rated on a scale from 1 to 10. It provides insight into how hard an individual feels they are working, allowing for adjustments in training load. Using RPE in conjunction with objective measures such as RM and VBT can create a comprehensive understanding of training intensity. Foster et al. validated the use of RPE in monitoring training intensity.15 They found that RPE correlates well with physiological measures of exercise intensity, making it a useful tool for autoregulating training loads. This allows for a more personalized approach to training, adjusting for daily variations in performance and ensuring consistent progress without overtraining.16 Another way for autoregulating is by using repetition in reserve (RIR). RIR is a measure of how many more repetitions an individual could perform before reaching failure, offering a practical and intuitive way to gauge training intensity and manage fatigue.4,17\n\nIntegrating RPE and RIR into a knee strengthening program helps to balance training load with recovery when VBT is not available. By regularly assessing RPE and RIR, physiotherapists can adjust the intensity and volume of exercises to match the patient’s current condition and prevent overtraining. This dynamic approach ensures that the knee muscles are continuously challenged while allowing for adequate recovery, optimizing long-term progress.\n\n\nConclusion\n\nStrengthening the knee is a multifaceted process that requires attention to various KPIs. When designing individualized knee strengthening programs the focus should be on manipulate on ROM, load, velocity, repetitions, pain assessment, biomechanics, muscle activation, and RPE/RIR. These principles, backed by scientific evidence, ensure that knee strengthening not only enhances performance but also mitigates injury risks as well as long-term joint health.\n\nThe integration of clear and well communicated KPIs creates a comprehensive framework for knee strengthening, ensuring that all boxes are checked if any issue to the knee arise during the rehabilitation. Regular assessment and adjustment based on these KPIs allow for personalized and effective training programs that cater to individual needs and goals.\n\nEthical approval and consent were not required.", "appendix": "Data availability statement\n\nNo data are associated with this article.\n\n\nAcknowledgements\n\nNone.\n\n\nReferences\n\nManske RC, Prohaska D, Lucas B: Recent advances following anterior cruciate ligament reconstruction: rehabilitation perspectives: Critical reviews in rehabilitation medicine. Curr. Rev. Musculoskelet. Med. 2012 Mar; 5(1): 59–71. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBanyard HG, Tufano JJ, Delgado J, et al.: Comparison of the Effects of Velocity-Based Training Methods and Traditional 1RM-Percent-Based Training Prescription on Acute Kinetic and Kinematic Variables. Int. J. Sports Physiol. Perform. 2019 Feb; 14(2): 246–255. PubMed Abstract \| Publisher Full Text\n\nForelli F, Riera J, Marine P, et al.: Implementing Velocity-Based Training to Optimize Return to Sprint After Anterior Cruciate Ligament Reconstruction in Soccer Players: A Clinical Commentary. Int. J. Sports Phys. Ther. 2024 Mar 1 [cited 2024 Mar 5]; 19(3): 355–365. PubMed Abstract \| Publisher Full Text \| Free Full Text Reference Source\n\nHelms ER, Byrnes RK, Cooke DM, et al.: Percentage 1RM Loading in Periodized Programs Matched for Sets and Repetitions. Front. Physiol. 2018 Mar 21; 9: 247. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBalsalobre-Fernández C, Torres-Ronda L: The Implementation of Velocity-Based Training Paradigm for Team Sports: Framework, Technologies, Practical Recommendations and Challenges. Sports. 2021 Mar 30; 9(4): 47. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWeakley J, Mann B, Banyard H, et al.: Velocity-Based Training: From Theory to Application. Strength Cond. J. 2021 Apr; 43(2): 31–49. Publisher Full Text\n\nBehm DG, Sale DG: Intended rather than actual movement velocity determines velocity-specific training response. J. Appl. Physiol. 1993 Jan 1; 74(1): 359–368. PubMed Abstract \| Publisher Full Text\n\nHernández-Belmonte A, Alegre LM, Courel-Ibáñez J: Velocity-Based Resistance Training in Soccer: Practical Applications and Technical Considerations. Strength Cond. J. 2023 Apr; 45(2): 140–148. Publisher Full Text\n\nCarvalho L, Junior RM, Truffi G, et al.: Is stronger better? Influence of a strength phase followed by a hypertrophy phase on muscular adaptations in resistance-trained men. Res. Sports Med. 2021 Nov 2; 29(6): 536–546. PubMed Abstract \| Publisher Full Text\n\nSchoenfeld BJ: The Mechanisms of Muscle Hypertrophy and Their Application to Resistance Training. J. Strength Cond. Res. 2010 Oct; 24(10): 2857–2872. PubMed Abstract \| Publisher Full Text\n\nEitzen I, Moksnes H, Snyder-Mackler L, et al.: A Progressive 5-Week Exercise Therapy Program Leads to Significant Improvement in Knee Function Early After Anterior Cruciate Ligament Injury. J. Orthop. Sports Phys. Ther. 2010 Nov; 40(11): 705–721. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKotsifaki R, Korakakis V, King E, et al.: Aspetar clinical practice guideline on rehabilitation after anterior cruciate ligament reconstruction. Br. J. Sports Med. 2023 May; 57(9): 500–514. PubMed Abstract \| Publisher Full Text\n\nSturgill LP, Snyder-Mackler L, Manal TJ, et al.: Interrater Reliability of a Clinical Scale to Assess Knee Joint Effusion. J. Orthop. Sports Phys. Ther. 2009 Dec; 39(12): 845–849. PubMed Abstract \| Publisher Full Text\n\nEscamilla RF, Fleisig GS, Zheng N, et al.: Effects of technique variations on knee biomechanics during the squat and leg press. Med. Sci. Sports Exerc. 2001 Sep; 33(9): 1552–1566. PubMed Abstract \| Publisher Full Text\n\nFoster C, Rodriguez-Marroyo JA, De Koning JJ: Monitoring Training Loads: The Past, the Present, and the Future. Int. J. Sports Physiol. Perform. 2017 Apr; 12(s2): S2-2–S2-8. PubMed Abstract \| Publisher Full Text\n\nLovegrove S, Hughes LJ, Mansfield SK, et al.: Repetitions in Reserve Is a Reliable Tool for Prescribing Resistance Training Load. J. Strength Cond. Res. 2022 Oct; 36(10): 2696–2700. PubMed Abstract \| Publisher Full Text\n\nZourdos MC, Klemp A, Dolan C, et al.: Novel Resistance Training–Specific Rating of Perceived Exertion Scale Measuring Repetitions in Reserve. J. Strength Cond. Res. 2016 Jan; 30(1): 267–275. PubMed Abstract \| Publisher Full Text" }	[ { "id": "343352", "date": "16 Dec 2024", "name": "Ismail Laher", "expertise": [ "Reviewer Expertise Pharmacology and physiology" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors seem not to have identified a target audience that this review aimed at--and this is a major weakness. The article is fragmented and contains many typographical and grammatical errors.\n\nHow many KPIs are needed for recovery? Are the KPIs the same when one see or both knees are affected? Differentiate between 1RM vs 10RM--and explain the differences? Why would it be useful to to know \"daily RM\"?\n\nWhat are the determinants of recovery of ROM?\n\nThe article is very cryptic. The section on Pain Management is quite weak and adds little value to the article.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Partly\n\nAre all factual statements correct and adequately supported by citations? Partly\n\nAre arguments sufficiently supported by evidence from the published literature? Partly\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Partly", "responses": [ { "c_id": "12993", "date": "10 Jan 2025", "name": "florian forelli", "role": "Author Response", "response": "The authors seem not to have identified a target audience that this review aimed at--and this is a major weakness. The article is fragmented and contains many typographical and grammatical errors. We changed the title to target the audience: Knee strengthening after orthopedics surgery: A comprehensive analysis using key performance indicators to Guide Physical Therapists How many KPIs are needed for recovery? Response: We added at the end of the introduction \"The number of KPIs required depends on the patient's overall condition and specific rehabilitation needs.\" Are the KPIs the same when one see or both knees are affected? Response: In orthopedic rehabilitation, it is common for only one knee to be operated on; therefore, our focus is primarily on this aspect. We have clarified this point in the title. Differentiate between 1RM vs 10RM--and explain the differences? Response: We added \"The 1RM represents the maximum weight an individual can lift once with proper form, primarily used to assess maximal strength and prescribe training loads in strength-focused programs. In contrast, the 10RM measures the maximum weight that can be lifted ten times consecutively, emphasizing muscular endurance and hypertrophy. While 1RM provides precise data for maximal strength, it poses a higher risk of injury, making it less suitable for rehabilitation. The 10RM, with its lower loads, is safer and more appropriate for progressive recovery programs, offering a balance between load and repetition to promote both strength and endurance.\" Why would it be useful to to know \"daily RM\"? Response: We have already written in the text: \"However, estimating a daily RM can be challenging, if the 1RM intended for the particular session or over a given period has changed prior to the session due to daily fluctuations.\" What are the determinants of recovery of ROM? Response: We added: The recovery ROM is influenced by various factors, including the severity of the injury or surgery, the healing process, and the presence of inflammation or pain. Muscle strength, flexibility, and scar tissue formation also play a significant role, as do external interventions such as manual therapy and adherence to rehabilitation programs. Psychological factors, like fear of movement or low motivation, and overall health conditions, such as age or pre-existing illnesses, can further impact progress. The article is very cryptic. The section on Pain Management is quite weak and adds little value to the article. Response: We added: It is essential to maintain pain levels within a range of 2-3/10 on the pain scale, as this level is optimal for stimulating collagen production. However, if pain exceeds 4/10, the strengthening program must be adapted to prevent overloading the knee and to ensure safe and effective recovery." } ] } ]	1	https://f1000research.com/articles/13-1118
https://f1000research.com/articles/13-1480/v1	04 Dec 24	{ "type": "Case Report", "title": "Case Report: A giant ruptured splenic hydatic cyst in a patient with a complete situs inversus: Diagnostic challenge and intra-operative difficulties", "authors": [ "Amina Chaka", "Wael Boujelbène", "Amin Chaabouni", "Mohamed Ali Bahloul", "Nizar Kardoun", "Salah Boujelben", "Amina Chaka", "Amin Chaabouni", "Mohamed Ali Bahloul", "Nizar Kardoun", "Salah Boujelben" ], "abstract": "The splenic localization of hydatid cysts is extremely rare. A 50-year-old obese female who consults with a painful and febrile syndrome of the right hypochondrium. Abdominal ultrasound and a CT scan computed tomography revealed a complete situs inversus, a mass of the right hypochondrium measuring 152 mm with membrane detachment, and infiltration of the surrounding fat, evoking a type II complicated splenic hydatic cyst. The patient was operated on in an emergency via midline laparotomy. Exploration revealed situs inversus, an angiant cyst of the spleen. Exposition of the splenic pedicle is difficult. The samples were then infected. Total splenectomy was performed. The postoperative period was unproblematic, and the patient was discharged with antibiotic and antiparasitic treatment and habitual vaccination.", "keywords": [ "spleen", "hydatid cyst", "echinococcosis", "situs inversus", "splenectomy", "case report" ], "content": "Introduction\n\nSplenic hydatic localization is extremely rare, with a worldwide incidence rate of 0.5%-4%.1 Abdominal left hypochondrium pain, mass, and fortuitous discoveries are the most frequently discovered complications1,2. However, right hypochondrium pain due to a splenic hydatic cyst associated with situs inversus is an exceptional finding. Here, we report the case of a 50-year-old female, who underwent surgery in our department for a complicated splenic hydatic cyst with situs inversus.\n\n\nObservation\n\nA 50-year-old female, without no medical history presented to the emergency department with right hypochondrium pain.\n\nOn physical examination, the patient was febrile at 38,4°C; anicteric, with tenderness of the right hypochondrium on abdominal examination.\n\nBlood analysis showed a biological inflammatory syndrome. The liver test was normal.\n\nIn the face of a 50-year-old obese female who consulted for a painful and febrile syndrome of the right hypochondrium, an abdominal ultrasound was performed, which showed a complete situs inversus and a mass of the right hypochondrium with a membrane detachment, measuring 152 mm, evoking a type II splenic hydatic cyst.\n\nComputed tomography (CT) revealed a splenic cystic formation, containing a membrane detachment, measuring 15 cm, evoking a type II splenic hydatic cyst with an infiltration of the surrounding fat, evoking a complication: hydatid cyst cracking (Figure 1, 2).\n\nThe patient underwent an emergency midline laparotomy. The exploration revealed a situs inversus, a voluminous splenic cyst occupying over 80% of the splenic volume. Exposition of the splenic pedicle is difficult. The cysto-parietal and cysto-visceral adherences, giant size of the cyst, and obesity prevented good exposure, which led to the decision to empty the cyst content after protecting the operating field with a field soaked in hypertonic serum. The samples were then infected.\n\nEqually, the choice of the type of surgery, whether a total splenectomy or a protruding dome resection in an emergency context with complications such as cracking and surinfection, was not easy.\n\nHowever, in the face of an emergency, the primary localization in the spleen, we performed a total splenectomy that allowed healing of the infested organ and avoided recurrence and surinfection of the residual cavity.\n\nThe overture of the cyst objectified the proligere membrane (Figure 3).\n\nThe post-operative period was unproblematic, and the patient was discharged with antibiotic and antiparasitic treatment and habitual vaccination.\n\n\nDiscussion\n\nHydatic cysts are a common pathology in endemic countries. The most frequent locations are the liver and lungs.2 Splenic localization is extremely rare, with a worldwide incidence rate of 0.5%-4%.1\n\nBased on the literature of some published cases of splenic primary localization, the pain, discovery of a left hypochondrium mass, and fortuitous discoveries are the most frequent discovery circumstances or during complications such as infection and splenic abscess, rupture with an anaphylactic shock, and dissemination to other organs.1,2\n\nUltrasound, computed tomography, and magnetic resonance imaging of the abdomen allow for diagnosis by objectifying membrane detachment and calcifications on the daughter vesicle wall.2,3\n\nThe treatment of splenic hydatic cysts is surgical. Total splenectomy has the advantage of avoiding recurrences. Protruuding dome resection has the advantage of being a conservative intervention of the organ and its functions and is slightly hemorrhagic at the cost of a considerable rate of residual cavity surinfection.4–6\n\nThe surgical approach depends on the localization of the splenic hydatic cyst(s) and its association with other cystic localizations.4,7 The laparoscopic approach is realizable in almost all cases, with good short-term and long-term results.6–8\n\nTo our knowledge, this is the first case of a giant splenic hydatic cyst and situs inversus.\n\n\nConclusion\n\nIsolated splenic hydatid cysts are uncommon and present significant challenges in both diagnosis and surgical intervention. Advanced imaging techniques, particularly computed tomography (CT), play a pivotal role in accurately identifying the condition and planning the appropriate treatment strategy. In this case, preoperative imaging not only confirmed the diagnosis but also provided valuable insights into the cyst’s size, location, and relationship with adjacent structures, which were critical for minimizing intraoperative risks and guiding the surgical approach.\n\n\nPatient perspective\n\nThe patient was satisfied with treatment with good follow-up after one year.\n\n\nInformed consent statement\n\nWritten informed consent for publication of their clinical details and clinical images was obtained from the patient.", "appendix": "Data availability statement\n\nNo data are associated with this article.\n\n\nReferences\n\nHassan A, Azhar A, Mazhar S, et al.: A rare case of recurrent hydatid cyst of the spleen: A case report. Radiol Case Rep. oct 2023; 18(10): 3406–3409. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSingh S, Kisee S, Amatya S, et al.: A case of giant primary splenic hydatid cyst: Case report. Ann. Med. Surg. déc 2022 [cité 28 déc 2023]; 84. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPukar MM, Pukar SM: Giant solitary hydatid cyst of spleen—A case report. Int. J. Surg. Case Rep. 2013; 4(4): 435–437. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nOumar TA, Ibrahima K, Sitor SI, et al.: Kyste hydatique de la rate: à propos d’un cas. Pan Afr. Med. J. 2013 [cité 28 déc 2023]; 14. PubMed Abstract \| Publisher Full Text \| Free Full Text Reference Source\n\nOusadden A, Raiss M, Hrora A, et al.: Kystes hydatiques de la rate: chirurgie radicale ou conservatrice?\n\nAl-Hakkak SMM, Muhammad AS, Mijbas SA-R, et al.: Splenic-preserving surgery in hydatid spleen: a single institutional experience. J. Med. Life. janv 2022; 15(1): 15–19. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMejri A, Arfaoui K, Ayadi MF, et al.: Primitive isolated hydatid cyst of the spleen: total splenectomy versus spleen saving surgical modalities. BMC Surg. déc. 2021; 21(1): 46. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAksakal N, Kement M, Okkabaz N, et al.: Unusually located primary hydatid cysts. Turk J Surg. 14 juin 2016; 32(2): 130–133. PubMed Abstract \| Publisher Full Text \| Free Full Text" }	[ { "id": "349375", "date": "28 Dec 2024", "name": "Selmy Awad", "expertise": [ "Reviewer Expertise acute care", "trauma", "laparoscopy" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThanks for the novel case as an incidence and location. many typos and grammar mistakes are abundant. What is the role of medical treatment in preoperative preparation and post-operative regimens? please follow the standards for writing case reports\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly", "responses": [ { "c_id": "13095", "date": "10 Jan 2025", "name": "Wael Boujelbène", "role": "Author Response", "response": "Dear Dr. Selmy Awad: Thank you for your valuable feedback on the case report. I appreciate your thoughtful insights and constructive criticism. 1. Typos and Grammar Mistakes: We acknowledge that there were some typos and grammatical errors in the manuscript. These will be carefully reviewed and corrected to ensure clarity and professionalism in the final version. 2. Role of Medical Treatment in Preoperative and Postoperative Regimens: You have raised an important point regarding the role of medical treatment in both preoperative preparation and postoperative regimens. We will include a more comprehensive discussion on the medical management, emphasizing its significance in patient preparation before surgery, as well as in the postoperative care to enhance recovery and prevent complications. 3. Standards for Writing Case Reports: We will ensure that the case report is fully aligned with the standards for writing case reports. This will involve revising the structure and adding any missing sections to enhance the clarity and scientific rigor. 4. Importance of Findings and Relevance to Disease Understanding: We appreciate your observation about the lack of a detailed discussion regarding the importance of the findings and their relevance to future disease understanding. We will expand this section to explain the significance of the case in relation to broader disease processes, diagnosis, and treatment. This will help contextualize the findings for future research and clinical practice. 5. Sufficiency of Details for Other Practitioners: We will review the report to ensure that enough practical insights and relevant details are provided for it to be a useful reference for others in the field. Thank you again for your review. We will address these concerns thoroughly in the revised version of the manuscript." } ] }, { "id": "349374", "date": "07 Jan 2025", "name": "Silvio Buscemi", "expertise": [ "Reviewer Expertise internal medicine", "obesity", "metabolic disease" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe case described is very interesting and well-written. I have some general considerations for you below. It is appropriate to discuss cystic echinococcosis in female with obesity. Given the unique nature of this case with situs inversus, including descriptive arrows in the CT images is essential and reassuring. This will provide clear visual guidance for the reader, enhancing their confidence in the case report. Please elaborate on the antiparasitic treatment used, including the specific regimen followed (it is important to continue the treatment after the cyst spontaneously ruptures to avoid possible dissemination). It is essential to document the changes in antibody titers and blood chemistry tests following surgical treatment and therapy (it would be appropriate to document how in the article, that could also be mentioned: Ref 1). This will not only inform the reader but also enhance their knowledge about the progression of the disease.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly", "responses": [ { "c_id": "13094", "date": "10 Jan 2025", "name": "Wael Boujelbène", "role": "Author Response", "response": "Dear Dr. Silvio Buscemi, Thank you for your insightful comments and positive feedback regarding our case report. We appreciate your valuable suggestions, which have significantly improved the quality of our work. Please find our responses to your considerations below: 1. Discussion of cystic echinococcosis in females with obesity In the surgical treatment of abdominal cystic echinococcosis, obesity can complicate operative exposure due to increased intra-abdominal fat, making visualization and access to the surgical field more challenging. This raises the risk of spillage or injury to adjacent structures and may prolong operative time. Obesity-related comorbidities can further increase perioperative risks, highlighting the need for careful preoperative planning and surgical expertise. 2. Inclusion of descriptive arrows in CT images We acknowledge the importance of providing clear visual guidance in the CT images. Descriptive arrows have been added to highlight key findings, especially given the unique presentation of situs inversus. 3. Details of the antiparasitic treatment regimen We have expanded the description of the antiparasitic treatment regimen, specifying the protocol followed, including dosages, treatment duration, and intervals. This addition highlights the importance of continuing medical therapy after cyst rupture to prevent dissemination and recurrence. 4. Documentation of antibody titers and blood chemistry changes We have included detailed data on the evolution of antibody titers and blood chemistry tests post-surgery and during therapy. These additions are presented in the results sections to provide a comprehensive view of disease progression and response to treatment. 5. References We have incorporated your suggested reference to complement our discussion and to underline the importance of prolonged treatment with albendazole in managing disseminated cystic echinococcosis. 6.Additional improvements We have ensured that the background, physical examination findings, diagnostic tests, and treatment outcomes are presented in greater detail. The discussion has also been expanded to highlight the importance of our findings for future understanding and management of similar cases.We hope these revisions address your comments and enhance the quality and utility of our case report for other practitioners. Thank you for your time, expertise, and valuable feedback. Sincerely," } ] } ]	1	https://f1000research.com/articles/13-1480
https://f1000research.com/articles/13-282/v1	17 Apr 24	{ "type": "Research Article", "title": "Prognostic significance of tumor budding in pancreatic carcinoma: Digitalized image approach evaluation using artificial intelligence.", "authors": [ "Sarra Ben Rejeb", "Jasser Yaacoubi", "Jasser Yaacoubi" ], "abstract": "Introduction Pancreatic carcinoma (PC) is a highly malignant and lethal tumor characterized by a dismal prognosis which raised the need to identify other prognostic factors for better patient risk stratification. This study investigated the prognostic significance of tumor budding (TB) in pancreatic carcinoma using artificial intelligence.\n\nMethods In this retrospective multicenter study, we collected all cases of PC diagnosed (2008-2022). TB was assed using 2methods: manuel on hematoxylin-eosin (HE) slides and semi-automated using QUPATH software. The selected slide for each case was digitalized using NIS software version 4.00 connected to the microscope NIKON (Eclipse Ni-U). The pathological images were then incorporated into QUPATH. The budds were counted using cell count functionality based on the nucleus size and pixel variability, and TB scores were categorized as BUDD1(0-4), BUDD2(5-9) and BUDD3(≥10). We analyzed the association between the TB score and prognostic clinicopathological factors and overall survival.\n\nResults 25patients were included (mean age:62.3years;male-to-female ratio:2.57). TB was found in 100%of cases and a high TB score (BUDD2-3) was observed in 56%of cases (using QUPATH versus 48% using HE slides); statistical analysis showed no significant difference between the two methods(p=0.589). A high TB score was associated with older age(>72 years), ductal histological subtype and advanced stage (pT>2).53.8% of patients with lymph node metastasis or advanced stage had high TB score. Multivariate analysis revealed that TB score was strongly and independently associated with overall survival (OS), with a hazard ratio of 2.35.\n\nConclusion TB is an additional prognostic factor in PC, and using artificial intelligence via QUPATH software offers a promising and accessible tool for pathologists to evaluate TB and to improve risk stratification in patients with PC.", "keywords": [ "Pancreatic cancer (PC)", "tumor budding (TB)", "prognosis", "overall survivor (OS)", "artificial intelligence." ], "content": "Introduction\n\nPancreatic carcinoma (PC) is an aggressive malignancy with a high rate of recurrence and a 5-year survival rate of <10% even after complete resection and negative lymph nodes status.1 Although tumor resecability and stage remain the most relevant prognostic factors, there is an increasing need to focus on novel histo-prognostic factors that would enable better risk stratification for patients.\n\nTumor budding (TB), defined as the presence of isolated single cancer cells or clusters of up to four cancer cells at the invasive tumor front, has been recognized as an emerging marker of aggressiveness related to the epithelial to mesenchymal process in patients with colorectal cancer. Thus, TB has been introduced as a routine prognostic marker in colorectal cancer to stratify patients for adjuvant chemotherapy for stage II tumors.2,3\n\nIn PC, although it has been reported that TB has a clear association with adverse prognosis, TB is still not systematically reported by pathologists, and there are no clearly defined recommendations on TB counting in PC.\n\nThis study aimed to assess the tumor budding score in PC using artificial intelligence and to explore the association of TB clinicopathological prognostic factors.\n\n\nMethods\n\nThis retrospective, bicentric, cross-sectional study was approved by the Biomedical Research Ethics Committee of our institution (Approval number12/23).\n\nWe included all cases of pancreatic carcinoma diagnosed in the pathology departments of the Security Forces and Charles Nicolles Hospitals over a period of 14 years (March 2008-December 2022).\n\nWe included both biopsies and surgical specimens and excluded patients with other histological subtypes and those for whom large pathological sections were not available. Clinical characteristics of the patients were retrieved from their medical records. Pathological data were collected from pathological reports.\n\nPathological HE slides analysis\n\nAll hematoxylin and eosin (HE)-stained slides were reviewed by two pathologists to select the most representative slides for tumor budding assessment.\n\nTumor budding was assessed according to the recommendations of the International Tumor Budding Consensus Conference (ITBCC) for colorectal cancer.4 TB was identified as a single tumor cell or a cluster of <5 cells. For each selected HE-stained slide, hotspot areas either at the invasion front or within the tumor center were identified at 10-fold magnification. TB was counted by two pathologists over a field of 0.785 mm2 at 20-fold magnification.\n\nDigital assessed approach\n\nThe slides that were selected for TB counting at 20-fold magnification were digitalized using NIS image scope software, which was connected to a Nikon microscope (Eclipse Ni-U) (Figure 1).\n\nThese images were exported in GIF format and then uploaded to open-source software QUPATH (version v0.4.3, https://qupath.github.io/) for digital pathology.5 TB was assessed and evaluated using a semi-automated method according to the methodology of Budeau et al.6 In this study, the author’s assessed TB in a cohort of 92 patients with intrahepatic cholangiocarcinoma. Firstly, Tumor budding was identified in one tissue slide on the basis of the recommendations of the International Tumor Budding Consensus Conference 2016.4 The HE slides were then digitalized and all images were analyzed in QuPath 16 (Version 0.1.2) (https://qupath.github.io/). Ten rectangles of H&E stained tissue slides were evaluated for both, the tumor-host interface and the tumor center. Each rectangle was standardized for an area of 0.785 mm2 as recommended. The function “cell detection” facilitates the manual differentiation of tumor buds from larger tumor groups by detecting individual cells and only having to assess the number of cells.6 In the present study, according to this methodological approach, we used the annotation functionality of QUPATH to highlight tumor cells (red color). Each 20-fold magnification digitalized slide was segmented into five rectangles, each rectangle corresponded to an area of 0.785 mm2. We used the “cell detection” functionality to circumscribe tumor cells based on nucleus sigma between 3 and 8. The TB score was counted manually for each rectangle, and the final TB score for each case was defined as the average of the five rectangles (Figure 2a, b and c).\n\nClassification of tumor budding\n\nFor both morphological and semi-automated methods, the final TB score for each case was categorized into four groups according to the recommendations of ITBCC4:\n\n✓ BD0: no budds\n\n✓ BD1: 1-4 Budds\n\n✓ BD2: 5-10 Budds\n\n✓ BD3:>10Budds\n\n→ The final TB score is calculated as follows:\n\n➢ Low: BD0-BD1\n\n➢ High: BD2-BD3\n\nStatistical analysis was performed using SPSS21 software [(IBM Corp. Released 2021. IBM SPSS Statistics for Windows, Version 28.0. Armonk, NY: IBM Corp) The statistical analyses performed in this article using SPSS21 software can be conducted using the freely accessible software Jamovi https://www.jamovi.org. The user manual is available at the following link. https://lsj.readthedocs.io/ru/latest/Ch03/Ch03_jamoviIntro_1.html. We first used the Kolmogorov-Smirnov test to evaluate the normal distribution and variance homogeneity tests on all continuous variables. Qualitative variables were summarized using frequencies and percentages. Quantitative parameters were summarized using medians and standard deviations. We used Fisher’s exact test to assess the relationship between TB and clinical and pathological parameters. A p-value of less than 5% was considered statistically significant or nearly significant for p [0.05-0.08], considering the small sample size.\n\n\nResults\n\n25 cases patients were included in this study. The mean age of the patients was 62.3years old the male-to-female ratio was 2.57. Alcohol consumption and smoking were found in 36% and 56% of the patients, respectively. Clinical signs included abdominal pain (96%), loss of body weight and condition (80%), jaundice (72%), transit disorder (28%), dark urine (64%), discolored stool (44%), pruritus (36%), and fever (16%). On physical examination, a palpable gallbladder was found in 36% and ascites in 12% of patients. Laboratory tests revealed anemia in 64%, elevated CA19.9 in 76%, cytolysis in 52%, and cholestasis in 76%. Surgery was performed in 80% of the cases: cephalic duodeno-pancreatectomy (75%), caudal pancreatectomy (20%), and double bypass (5%). Neoadjuvant therapy was performed in 12% of patients, adjuvant treatment in 56%, and palliative care in 28%. Local recurrence occurred in 44% of patients, distant metastases in 38.9%, and death in 72%. The pathological findings are summarized in Table 1.\n\nTumor budding was found in 100% of cases using the morphological method and 84% using the digitalized approach. The number varied from 1 to 37 (mean: 8.04, median:4) using the morphological method and from 0 to 19 (mean: 5.92, median: 6) using the QUPATH software. Tumor budding counts are summarized in Table 2.\n\nA high TB score (BUDD2-3) was found in 48% of the cases using the morphological method and 56% using the semi-automated QUPATH method. No statistically significant differences were observed between the two methods (p=0.589).\n\nUsing morphological TB score, a statistically significant association was found between high TB score and advanced age >72 ans (p=0.03). Considering the small sample size, 84.6% of tumors with the ductal subtype had a high TB score, and the difference was nearly statistically significant (p=0.07).\n\n53.8% of patients with lymph node invasion or advanced pT stage had high TB score (p=0.53 and p=0.32).\n\n76.9 Of the patients with perineural invasion, 76.9% had high TB scores. The association between tumor budding and clinicopathological features of pancreatic carcinoma is summarized in Table 3.\n\nOn multivariate analysis, tumor grade, vascular invasion, and tumor budding affected overall survival (p=0.04, p=0.07, p=0.016, respectively) (Figures 3, 4, 5).\n\n\nDiscussion\n\nIn the present study, tumor budding was found in 100%of cases using morphological methods and 84% of cases using the digitalized approach; these findings are consistent with previous reports indicating that TB is reported in approximately 85-100% of specimens with pancreatic carcinoma.8–10 This fact raises the hypothesis that TB is a relatively constant finding that could also be a pervasive feature of pancreatic carcinoma, especially in biopsy specimens.10\n\nIn our study, a high TB score was found in 48% (VS 56% using QUPATH), which is slightly lower than that reported in previous studies reporting a high TB score in about 56 to 80% of cases.8–10 These disparities may be partly explained by the differences in TB counting methods, the surface of the HPF, and the use of immunohistochemistry in some studies to identify CK+-stained tumor cells. TB is defined as single cells or clusters of <5 cells at the tumor invasion front.2,4 This quantifiable histological feature has gained attention over the last 10years and has proven its prognostic value in many cancers. The International Tumor Budding Consensus Conference (ITBCC) proposed a scoring system for tumor buds in colorectal carcinomas that was later applied to other cancers such as hepatocellular, oral squamous cell, and bladder cancers.4,6 However, there is still no standardized method for reporting tumor budding in PC, and various approaches are available to count tumor buds either on HE slides or using pathological image analysis softwares.6,11 In the present study, we first assessed tumor budding in pancreatic carcinoma specimens according to the recommendations of the ITBCC at 20-fold magnification for a field of 0.785 mm2, either at the tumor front or within the tumor center. Then, similar to the published study of Budeau et al.,6 we extrapolated the ITBCC counting approach on an optic microscope to a digital image analysis system using QUPATH, an open-access software for digital image analysis. QUPATH is completely free, which enables pathologists in low-income countries to have access to digital pathology analysis.5 The tumor cell detection functionality of the QUPATH software facilitates distinguishing between tumor cells and small clusters from a larger group of cells. In addition, compared to “analog” microscopy, QUAPTH offers the possibility of re-evaluating tumor buds at anytimes higher than those of other pathologists.6 Although a high TB score was found in 48% of patients using the first method compared with 56% using the digitalized approach, the difference was not statistically significant (p=0.589). Hence, QUPATH could be an interesting, costless, and accurate alternative for pathologists, which would considerably reduce the work time and facilitate TB counting.\n\nAccording to the recommendations of ITBCC, the TB score is categorized as a three-tier grading system for patient risk stratification.4,6 In the present study, similar to the study published by Tanaka et al.,12 we first graded the TB score as low (BUDD1), intermediate (BUDD2), and high (BUDD3) but later combined BUDD2 and BUDD3 groups into high TB scores for statistical analysis purpose. Consequently, we compared the high and low TB score groups using clinicopathological and survival data.\n\nUsing the morphological method results, we demonstrated a statistically significant (or nearly significant) association between high tumor budding and advanced age >72 years (p=0.03), ductal subtype (p=0.07), and advanced-stage pT>pT2 (p=0.08). These results are consistent with those of previous studies that demonstrated an association between high TB and prognostic factors. In a study published by O’Connor et al.,9 high-grade budding (> 10 buds in 10 HPFs) was associated with a high tumor grade, lymphovascular invasion, and perineural invasion. In our study, 53.8% of patients with lymph node invasion or advanced stage had a high TB score; likewise, 76.9% of patients with perineural invasion had a high TB score. However, these findings were not statistically significant (p=0.53, p=0.32, and p=0.53, respectively), which could be related to the small sample size in our study. Of note, regardless of the method used, most published studies on pancreatic cancer did not reveal a statistically significant association between TB and prognostic factors.8,10,13–15\n\nIn the present study, the authors described a statistically significant association between tumor budding and overall survival (p=0.016) in the multivariate analysis after adjusting for other significant variables. This finding is consistent with previous reports that support the prognostic value of the TB score in pancreatic carcinoma for better patient stratification and treatment guiding.8–11 Although these results are promising, there are still many discrepancies in the TB counting methods. First, some authors only considered TB at the tumor-host interface8; however, there is increasing evidence that intra-tumor and peri-tumor buds have comparable prognostic significance.4,6,11–17 Second, some authors suggested that tumor budding evaluation is more accurate and reproducible using immunohistochemistry with anti-CK antibody18; however, in a multicenter study, Hacking S et al.19 demonstrated that although immunohistochemical staining facilitates the detection of tumor cells, it has comparable intra- and inter-observatory reproducibility to the HE slides TB counting approach. Finally, in the era of artificial intelligence, using digital pathology for TB assessment is an interesting alternative approach that could considerably reduce the examination time and offer better accuracy and reproducibility. In this context, many studies have demonstrated a high range of diagnostic concordance (90-99%) between digital slides and conventional glass slides.20,21 Many digital pathology image software packages have been developed; however, access to these platforms remains difficult for some pathologists.22,23 Hence, QUPATH software could be an interesting alternative for integrating digital pathology in routine practice. A consensus on tumor budding counting and reporting on digitalized slides in pancreatic carcinoma is necessary to definitively integrate TB in pathology reports.\n\n\nConclusions\n\nOur results demonstrated that tumor budding either assessed manually on HE slides or semi-automated on digitalized images is a relatively constant finding in pancreatic carcinoma, with a high score in about 50% of cases. Our findings also showed a high concordance of both methods in TB assessment, supporting the benefits of integrating digital pathology in routine practice. Finally, our results provide further evidence for the potential prognostic value of TB in pancreatic carcinoma. However, our study has some limitations, such as its retrospective design and small sample size. Further studies on TB counting using QUAPATH in pancreatic carcinoma are needed to integrate this method into routine practice for better risk stratification.\n\n\nEthics approval\n\nThis research was conducted following the ethical guidelines outlined by the Ethics committee of the Internal Security Forces Hospital (Obtained on 1st December 2023, approval number 12/23). All procedures involving human tissues were approved by the committee and were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments as well as the National Medical Code of Ethics (Title VI, Article 99 to 111). Verbal informed consent was obtained at admission from all individual participants included in the study. The majority of patients were illiterate, unable to read or write, therefore verbal consent was preferred. Confidentiality and anonymity of participants were strictly maintained throughout the study. Any potential conflicts of interest have been disclosed and managed appropriately. Confidentiality and anonymity of participants were strictly maintained throughout the study. Any potential conflicts of interest have been disclosed and managed appropriately.\n\nLink to National Medical Code of Ethics: chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/http://www.atds.org.tn/Decretdeontologiemedicale93.pdf\n\n\nAuthors contribution\n\nSarra Ben Rejeb: Conceptualization Investigation; Methodology Writing Validation;\n\nJasser yaacoubi:; Data curation; Formal analysis;", "appendix": "Data availability statement\n\nFigshare: Tumor budding in pancreatic carcinoma.https://doi.org/10.6084/m9.figshare.25265755.v2\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nfigshare: STROBE Checklist for Tumor budding in pancreatic carcinoma https://doi.org/10.6084/m9.figshare.25265755.v2\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nSoftware availability statement: The statistical analyses performed in this article using SPSS21 software can be conducted using the freely accessible software Jamovi https://www.jamovi.org\n\nSource code available from: https://github.com/jamovi/jamovi/tree/v2.2.4\n\nArchived software available from: [DOI specific to version 2.2.4, typically accessible from Zenodo]\n\nLicense: OSI approved open license software is under GPL-3.0 License\n\nThe user manual is available at the following link. https://lsj.readthedocs.io/ru/latest/Ch03/Ch03_jamoviIntro_1.html\n\n\nReferences\n\nWHO Classification of Tumours Editorial Board: WHO Classification of Tumors: Digestive System Tumours. 5th ed.Lyon, France: International Agency for Research on Cancer; 2019.\n\nHase K, Shatney C, Johnson D, et al.: Prognostic Value of Tumor “Budding” in Patients With Colorectal Cancer. Dis. Colon Rectum. 1993; 36: 627–635. Publisher Full Text\n\nPark SY, Choe G, Lee HS, et al.: Tumor Budding as an Indicator of Isolated Tumor Cells in Lymph Nodes From Patients With Node-Negative Colorectal Cancer. Dis. Colon Rectum. 2005; 48: 292–302. PubMed Abstract \| Publisher Full Text\n\nLugli A, Kirsch R, Ajioka Y, et al.: Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod. Pathol. 2017; 30: 1299–1311. PubMed Abstract \| Publisher Full Text\n\nBankhead P, et al.: QuPath: Open source software for digital pathology image analysis. Sci. Rep. 2017; 7: 16878. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBudau KL, Sigel CS, Bergmann L, et al.: Prognostic Impact of Tumor Budding in Intrahepatic Cholangiocellular Carcinoma. J. Cancer. 2022 May 6; 13(8): 2457–2471. 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PubMed Abstract \| Publisher Full Text\n\nLugli A, Vlajnic T, Giger O, et al.: Intratumoral budding as a potential parameter of tumor progression in mismatch repair-proficient and mismatch repair-deficient colorectal cancer patients. Hum. Pathol. 2011; 42(12): 1833–1840. PubMed Abstract \| Publisher Full Text\n\nGrigore AD, Jolly MK, Jia D, et al.: Tumor Budding: The Name is EMT. Partial EMT. J. Clin. Med. 2016; 5(5): 51. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nChen S, Zhang N, Jiang L, et al.: Clinical use of a machine learning histopathological image signature in diagnosis and survival prediction of clear cell renal cell carcinoma. Int. J. Cancer. 1 févr 2021; 148(3): 780–790. PubMed Abstract \| Publisher Full Text\n\nHacking S, Nasim R, Lee L, et al.: Whole slide imaging and colorectal carcinoma: A validation study for tumor budding and stromal differentiation. Pathol. Res. Pract. nov 2020; 216(11): 153233. 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PubMed Abstract \| Publisher Full Text \| Free Full Text" }	[ { "id": "305079", "date": "09 Aug 2024", "name": "Ozden Oz", "expertise": [ "Reviewer Expertise clinic pathology" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nFirst of all, it is a well-designed study and seems applicable.\n\nMajor 1. The criteria by which patients were selected should be written in more detail. None of the patients appear to have metastases (table 1). Was a selection made in this regard? 2. It should be discussed why tumor budding could not be found in 16% of the patients with QUPATH method.\n3. It should be discussed why a higher TB degree 3 was found with the morphological method.\n5. Figure 3.4.5 Univariate analysis (Kaplan-Meier) ? or multivariate Cox? It must be clear\n\nMinor 1. Details of tumor budding in pancreatic cancer should be more supported by literature. Such as: DOI: 10.4103/ijpm.ijpm_905_21 etc.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "12788", "date": "11 Nov 2024", "name": "Sarra Ben Rejeb", "role": "Author Response", "response": "Response to Reviewer 1: Dear Reviewer, thank you for your valuable comments. 1- Regarding our inclusion criteria: we included all cases of primary pancreatic adenocarcinoma diagnosed on surgical specimens or biopsies in the pathology departments of the security forces hospital and Charles Nicolles Hospital, regardless of the stage of the disease, whether metastatic or localized. However, at the time of data collection, none of our patients had known metastases at diagnosis by mere coincidence. This was not a selection criterion. It is worth noting, however, that during follow-up, 20% of the patients developed metastases . 2- To further clarify our inclusion criteria: 2.1. Inclusion Criteria: We included in this study all patients with primary pancreatic adenocarcinoma diagnosed on surgical specimens or pancreatic biopsies in the Department of Pathology and Cytology at FSI Hospital and HCN during the study period. 2.2. Non-inclusion Criteria: The following cases were not included in this study: Patients with intraductal papillary mucinous tumors without invasive foci. Other histological types (neuroendocrine or mesenchymal tumors). Patients with ampullary, gallbladder, or bile duct adenocarcinoma. 2.3. Exclusion Criteria: We excluded from our study: Patients with unusable clinical records. Small and non-representative biopsy samples. Biopsy samples of suboptimal technical quality that created artifacts during image digitization 3- Regarding tumor budding using QUPATH: Through our study, tumor budding was observed in 100% of cases by morphological analysis and in 84% with the QUPATH software. This suggests that using a semi-automated approach may offer greater analytical precision by reducing false positives. These cases likely corresponded to atypical mesenchymal fibroblastic or myofibroblastic cells or poorly differentiated tumor glands that were mistaken for isolated tumor cells 4- High TB on morphological method : Similarly, using the QUPATH software reduced the number of cases classified as high BUDD3 with the morphological approach. This is due to the software's precision in distinguishing between isolated tumor cells or clusters of fewer than 5 cells, which meet the definition of tumor budding, as opposed to poorly differentiated carcinoma clusters or remnants of neuroendocrine islets that were misdiagnosed as TB on HE slides examination and were sofalse positives. Indeed, with its annotation features, the QUPATH software allows for the identification and deselection of false positives 5- Survival curves : Survival data were analyzed by generating survival curves using the Kaplan-Meier method and compared using the Log-rank test in univariate analysis Minor Revisions: 1- This publication was not found during the literature search and manuscript writing, but it is highly relevant to our research topic." } ] } ]	1	https://f1000research.com/articles/13-282
https://f1000research.com/articles/11-1405/v1	30 Nov 22	{ "type": "Research Article", "title": "Differential gene expression during recall of behaviorally conditioned immune enhancement in rats: a pilot study", "authors": [ "Markus Rueckels", "Marcus Picard-Maureau", "Marcus Picard-Maureau" ], "abstract": "Background: Behaviorally conditioned immune functions are suggested to be regulated by bidirectional interactions between CNS and peripheral immune system via the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system (SNS), and the parasympathetic nervous system (PNS). Since the current knowledge about biochemical pathways triggering conditioned immune enhancement is limited, the aim of this pilot study was gaining more insights into that. Methods: Rats were conditioned with camphor smell and poly I:C injection, mimicking a viral infection. Following stimulus re-exposure, animals were sacrificed at different time points, and neural tissues along the HPA axis was analyzed with a rat genome array together with plasma protein using Luminex analysis. Results: In the hypothalamus, we observed a strong upregulation of genes related to Wnt/β-catenin signaling (Otx2, Spp1, Fzd6, Zic1), monoaminergic transporter Slc18a2 and opioid-inhibitory G-protein Gpr88 as well as downregulation of dopaminergic receptors, vasoactive intestinal peptide Vip, and pro-melanin-concentrating hormone Pmch. In the pituitary, we recognized mostly upregulation of steroid synthesis in combination with GABAergic, cholinergic and opioid related neurotransmission, in adrenal glands, altered genes showed a pattern of activated metabolism plus upregulation of adrenoceptors Adrb3 and Adra1a. Data obtained from spleen showed a strong upregulation of immunomodulatory genes, chemo-/cytokines and glutamatergic/cholinergic neurotransmission related genes, as also confirmed by increased chemokine and ACTH levels in plasma. Conclusions: Our data indicate that in addition to the classic HPA axis, there could be additional pathways as e.g. the cholinergic anti-inflammatory pathway (CAIP), connecting brain and immune system, modulating and finetuning communication between brain and immune system.", "keywords": [ "Behavioral conditioning", "NK cells", "gene expression analysis", "HPA axis", "poly I:C", "campher smell", "Otx2", "Sox11", "Wnt/β-catenin pathway", "Slc18a2", "VMAT2", "Spp1", "OPN", "Osteopontin", "Gpr88", "Fzd6", "Zic1", "Pmch", "Npy", "Nps", "Chrna3", "CAIP", "ACTH", "IFN-α" ], "content": "Introduction\n\nPavlovian or classical conditioning is a phenomenon of associative learning, in which a behavioral response is induced by establishing a temporal pairing between a conditioned stimulus (CS) and unconditioned stimulus (US).1 In addition to the well-known phenomenon of classic conditioning of physiological reflexes, immune responses can also be memorized and recalled using Pavlovian conditioning, based on a reciprocal communication between the central nervous system (CNS) and the peripheral immune system.2\n\nThis concept of behaviorally conditioned immune modulation was rediscovered by Ader and Cohen3 in the 1970s, who used cyclophosphamide as an immunosuppressive agent (US) and illness-induced taste aversion by lithium chloride (LiCl) solution as CS and then measured the changes in immune responsiveness by a specific antibody reaction, using sheep erythrocytes as antigen. Since the study was published, this phenomenon of conditioned immunosuppression has been replicated in a multitude of studies4–7 by different researchers all over the world and current knowledge about this phenomenon including potential pathways at work and experimental paradigms employed have been comprehensively summarized in a recent review by Hadamitzky et al.8\n\nWhile most of our knowledge on conditioning of immunological functions is derived from immunosuppression paradigms, relatively few studies have been focusing on immune enhancement. A series of these studies targeted the conditioned enhancement of both CTLs and natural killer (NK) cells in rodents, identifying multiple possible signaling molecules and pathways driving these effects.9–12\n\nHistorically, behaviorally conditioned immune functions are suggested to be regulated by bidirectional interaction between CNS and peripheral immune system via the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system (SNS), and the parasympathetic nervous system (PNS).13 In addition to the HPA axis, the brain limbic system (cortex, hippocampus, amygdala) has also been associated with behaviorally conditioned immune responses.13 In a previous study,11 both adrenocorticotropic hormone (ACTH) and interferon-alpha (IFN-α) were shown to be involved in the efferent signaling pathways during recall of the conditioned enhancement of NK cell activity.11 However, the exact biological basis (biochemical, neuroanatomical, genetic) and the underlying molecular mechanisms driving these processes are still unclear.\n\nTo shed more light on these pathways, we conducted a pilot study, using the formerly published 3-day conditioning paradigm originally developed by Hsueh et al..11 Following that paradigm, animals were first exposed to camphor smell and then injected with polyinosinic:polycytidylic acid (poly I:C), simulating a viral infection and also inducing so-called sickness behavior, an animal model for depression-like behavior in rodents.14,15 48h later, animals in the test group were re-exposed to camphor smell, only, to recall a behaviorally conditioned immune response in rats while animals in a positive control group receive a re-injection of poly I:C and animals in a negative control group receive smell conditioning, only, but no poly I:C re-injection.\n\nWe then used a gene-agnostic expression analysis approach to identify first gene candidates along the 4 major tissues – hypothalamus, pituitary gland, adrenal glands, and spleen - of the HPA axis while in parallel looking at cytokine/chemokine protein levels in the plasma of the conditioned animals. Results from both approaches were combined and aligned with the existing literature to provide a list of candidate genes and proteins for future studies.\n\n\nMethods\n\nMale, Sprague Dawley (SD) rats (5-7 weeks, 160-250 g) were obtained from InVivos Pte Ltd, Singapore. Male animals were chosen to minimize the impact of hormonal cyclical changes on gene expression and behavioral readouts. Animals were housed at the Biological Resource Centre (BRC) in groups of 2 in individually ventilated cages and maintained on a 12h light/dark cycle with food and water ad libitum in accordance with the Agency for Science, Technology and Research (ASTAR) Animal Care and Use Committee. All efforts were made to ameliorate any suffering of animals; animals were provided with Nylabones (hard non-toxic nylon), nestlets and/or domes for environmental enrichment to ensure adequate welfare and psychological well-being. In accordance with IACUC guidelines, animals were allowed to acclimatize for a minimum of 3 days prior to study commencement and examined to confirm their health status.\n\nAnimals (N=30) were randomly allocated into two series (a and b) of 15 animals, each, and divided into three experimental groups as shown in Table 1. A 3-day conditioning paradigm was used in the study as described previously11 where camphor smell was used as conditioned stimulus (CS) and poly I:C injection (ip) as unconditioned stimulus (US). In the present study, camphor smell exposure was performed in a separate procedure room for 1h using a 10 cm petri dishes filled with 5 g of camphor powder (Sigma #21310) placed above the cage (on top of the metal grid) and warmed up with a heat lamp. On day D0, animals from all the three groups were exposed to camphor smell for 1h following exposure to saline (ip; 10 ml/kg; negative control group) and poly I:C (Sigma #P1530; ip; 1 mg/kg; test and positive control group). On day D2, animals from test and negative control groups received saline injections (ip), following exposure to camphor smell for 1h whereas animals from positive control group were exposed to poly I:C only. After the last injection on day D2, animals from each group were sacrificed at 0h (n=2), +3h (n=2), +6h (n=2), +24h (n=2) and +48h (n=2) post injection, and tissues were collected (adrenal gland, hypothalamus, pituitary gland, and spleen) and stored snap frozen in RNAlater (MilliporeSigma, Burlington, U.S.A) for further analysis. Blood was collected for the isolation of peripheral blood mononuclear cells (PBMCs) and serum to perform cytokine/chemokine array analysis. Animal experiments were conducted at Biological Resource Centre (BRC), Biomedical Sciences Institutes, Agency for Science, Technology and Research (ASTAR), 20 Biopolis Way, #07-01 Centros Building, Singapore 138668.\n\nThe SPT is a standard behavioral test to assess depression-like behavior in rodents during the development of anti-depressive treatments. The SPT is based on anhedonia (lack of interest in rewarding stimuli), which is present in some forms of affective disorders including depression. In this test, the interest of animals in seeking out a sweet rewarding drink relative to plain drinking water is used and a bias toward the sweetened drink is typical, failure to do so is an indication of anhedonia/depression.16 The SPT was carried out on days -7 to - 1 (run-in phase for baseline data) as well as days D0 - D3. Rats were presented with two drinking bottles, one for each plain drinking water and 2% (w/v) sucrose solution for 24 h. The ratio of the sweetened and plain water consumed was calculated, and results were expressed as %sucrose preference.\n\nAt the end of the study, mRNA from all tissues harvested at different time points was isolated by using a RNeasy Plus minikit (QIAGEN, Hilden, Germany). RNA quality was assessed by using a Bioanalyzer 2100 (Agilent Technologies, Santa Clara, U.S.A.). Highly purified RNA was subjected to microarray analysis with a GeneChipTM Rat Gene 2.0 ST Array (Affymetrix, Inc, Santa Clara, U.S.A.) to identify differential gene expression during the recall of behaviorally conditioned immune responses. RNA labelling, hybridization, staining, and scanning were performed according to the manufacturer’s instructions. Briefly, 100 ng of total RNA from each sample was reverse transcribed to cDNA, followed by overnight in vitro transcription to generate cRNA which was further fragmented and labeled. The quality of cDNA and fragmented cRNA was assessed with an Agilent bioanalyzer. We used the Robust Multichip Average (RMA) model for array background correction and quantile normalization as described previously.17–19 Probes were mapped to the Rattus norvegicus genome chip (RGSC 5.0/rn5) and results from all tissues were normalized using beta-Actin.\n\nAll gene expression results of samples in test and positive control were matched by tissue and time point with their respective counterpart in negative control and subtracted to derive single point gene expression differences (all data expressed as 2^x). Due to insufficient RNA quality after extended storage, we could not analyze all tissue samples by microarray and had to discard multiple samples (hypothalamus negative control +24h, pituitary test and positive control 0h and +3h, adrenal test +6h and +24h and positive control 0h and +3h, spleen +24h and +48h all samples); accordingly, we first limited the analysis to the average across all available time points and then looked at single point regulations with focus on neurotransmitter-related genes in more detail; in each sample, a minimum of three individual time points were available. Following gene enrichment and comparison of test vs. negative and positive vs. negative control selection, all differentially expressed genes per tissue were then further analyzed by Reactome pathway analysis.20 As we hypothesized the origin of the message post recall was from hypothalamus, we additionally leveraged QIAGEN Ingenuity Pathway Analysis (QIAGEN IPA) for a more detailed analysis of hypothalamic genes. All genes identified with avg. regulation >2fold in the hypothalamus of test animals were selected and subcellular network analysis was derived using IPA graphic interface.\n\nThe same RNA of all samples as used in the microarray analysis was also subjected to quantitative reverse transcription PCR (qRT-PCR) to confirm the observed differential gene expression. The qPCR laboratory work was conducted as a fee-for-service by the Qiagen service laboratory (Qiagen Life Science Service & Support, Hilden, Germany), using the RT2 ProfilerTM PCR custom Array RAT (CLAR27943). Briefly, RNA was isolated, and cDNA was synthesized with Qiagen RT2 First Strand Kit using 500 ng of RNA, 1 μl RT primer mix (oligo-dT and random hexamer primers), 4 μl Quantscript RT buffer (5X) and 1 μl Quantiscript Reverse Transcriptase (QuantiTect kit, Cat. No. /ID: 205311, Qiagen). qPCR reactions were then assembled using synthesized cDNA (1μl), 5 μl RT2 Profiler PCR Array SYBR Green master mix (Qiagen, Germany), 1μl of each primer diluted to a 5 μM working solution and 1μl sterile water and processed in 96-well format including housekeeping genes, RNA and DNA controls, using Qiagen’s proprietary primer panel. The mRNA expression was determined using the 2−ΔΔCT method.21 All gene expression values were normalized using Hypoxanthine phosphoribosyl transferase (HPRT), glyceraldehyde phosphate dehydrogenase (GAPDH) and β-Actin as references for expression analysis of genes of interest.\n\nPlasma protein levels for all animals and time points were evaluated as a fee-for-service by Singapore Immunology Network (SIgN), coordinated by Biomedical Research Council (#04-06 Immunos, Singapore), using the MILLIPLEX® MAP rat pituitary endocrine multiplex assay (RPTMAG-86K) for ACTH and BDNF and MILLIPLEX® MAP Cytokine/Chemokine Panel (RECYMAG65K27PMX, both MerckMillipore, Darmstadt, Germany) to simultaneously analyze the levels of 27 further cytokines/chemokines. Plasma samples were diluted to 2 mg/ml protein concentration, then analyzed on a MAGPIX system (Luminex, Austin, U.S.A.) and quantified using MILLIPLEX® Analyst 5.1 software. Cytokines/chemokine measured included RANTES, GRO KC CINC-1, VEGF, Fraktalkine, LIX, MIP-2, G-CSF, Eotaxin/CCL11, GM-CSF, IL-1α, Leptin, MIP-1α, IL-4, IL-5, IL-1β, IL-2, IL-6, EGF, IL-13, IL-10, IL-12p70, IL-5, IL-17A, IL-18, MCP-1, IP-10, KC, VEGF, Fractalkine, LIX, MIP-2 and TNF-α.\n\nAll statistical analysis was conducted using RMA gene expression data for all available time points for test, positive and negative control, respectively, and applying a two-tailed, unpaired, homoscedastic Student t-test (Microsoft® Excel® for Microsoft 365 MSO, version 2202). A p-value of <0.05 was considered significant.\n\nThis study was approved under the Institutional Animal Care and Use Committee (IACUC) protocol number BRC IACUC #151001 by the IACUC of the Biological Resource Centre (BRC, Biomedical Sciences Institutes, Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, #07-01 Centros Building, Singapore 138668) on 26 Feb 2015. A specific procedure amendment pertaining to the use of sucrose preference test was approved on 03 Feb 2016.\n\n\nResults\n\nThe present pilot study was designed to identify differentially expressed genes along the HPA-axis i.e., hypothalamus, pituitary, adrenal, and spleen during recall of the behaviorally conditioned immune response, using a conditioning paradigm to explore efferent pathways.11 As we didn’t know the exact time point of gene alteration, we first looked at genes with maximum average regulation across all time points (0h, +3h, +6h, +24h, and +48h post recall) in all three studied groups and then looked at neurotransmitter-related regulations in more detail, also considering single point regulations. Each analysis per group and tissue included a minimum of three independent timepoints (for exact samples analyzed, see Methods).\n\nLeveraging this approach to identify major upregulated genes in test vs. negative control (‘test’) across all tissues with a >2fold average regulation across all time points, we identified 12 and 10 upregulated transcripts in hypothalamus and pituitary, respectively (Figure 1). In adrenal and spleen, however, the number of genes upregulated using this approach was significantly higher. To identify meaningful candidates in these tissues, we therefore excluded transcripts with unknown identity and focused only on genes with strong upregulation during the first 6h post recall and/or p<0.05, comparing expression across all time points in test with their respective counterpart in negative control, thereby reducing the number of transcripts in adrenal glands and spleen to 18 and 20, respectively. We also excluded genes with a stronger upregulation in positive vs. negative control (‘positive’) than test except when also showing a strong regulation across multiple other tissues as e.g. Cxcl11 or Cxcl13 and applied a similar approach to focus on the most promising candidate genes for downregulation (Figure 2).\n\nIn addition to this, we focused at up- and downregulation of neurotransmitter-associated genes such as receptors, transporters, and solute carriers, potentially involved in the efferent signaling post recall such as dopaminergic, serotonergic, opioid, cholinergic, glutamatergic, and GABAergic neurotransmission, selecting for strong regulation across multiple tissues even if not crossing an average >2fold regulation across all timepoints and limiting the time frame to the first 6h post recall unless otherwise mentioned.\n\nIn the hypothalamus, a total of 11 transcripts, detected by 12 probes, were upregulated >2fold when comparing average regulation across all time points test vs. negative. Out of these, Slc18a2 coding for vesicular monoamine transporter 2 (VMAT2) was found upregulated significantly test vs. negative, while both Otx2, coding for orthodenticle homeobox 2 and detected by two independent probes, and Spp1, coding for secreted immune modulator osteopontin (OPN), despite strong regulation only showed a trend towards significance when combining all timepoint test vs. negative control (Figure 1).\n\n8 additional genes - Hapln4, Cxcl11, Fa2h, Fzd6, Zic1, Cbln1, Tspan18, and Sh2b2 - were also found upregulated >2fold in test however either were also strongly upregulated in positive or did not reach significance when comparing gene expression in test vs. negative control: while Fzd6 and Zic1 were mainly upregulated in test vs. negative, Hapln4, Cxcl11, Fa2h, Tspan18, and Sh2b2 showed a similar or even higher differential gene expression in positive vs. negative than test vs. negative.\n\nAs both Otx2 and Spp1 have been shown to interact with Sox9 (SRY box transcription factor 9)22and furthermore, like Fzd6 and Zic1, seem to be involved in Wnt/ß-catenin signaling, we also analyzed Sox-related gene expression and found that Sox7/8/9/10/11 and 13 were also upregulated in hypothalamus test vs. negative control, with Sox11 showing the strongest immediate regulation post recall (Figure 4).\n\nLooking at downregulation (Figure 2), among the genes with the strongest average regulation across all time points were dopamine receptor Drd1 and Drd2, inhibitory regulatory G-protein Rgs9, and Gpr88, involved in negative regulation of opioid signaling as well as thyroid hormone-binding protein crystallin-mu (Crym). Likewise, Gpr52, shown to have a modulatory role in dopamine receptor signaling, as well as Mlip, Tiam2, Kcnv1, Chrm1, Ephx4, Arhgap6, Tac3, Plk2, and Ano3 were strongly downregulated.\n\nLooking in more detail at neurotransmitter-related regulation (Figure 3a), we detected an upregulation of inhibitory glycine- (Glra1, Slc6a9, Slc6a5) and GABA- (Slc6a11, Gabra6) plus excitatory glutamate-related genes (Grik3, Grik4, Grm1, Grm4, Grin2d and 3b, Slc17a6 and Slc25a18). In addition, we saw an upregulation of neuropeptide S (Nps), adenylate cyclase activating polypeptide 1 (Adcyap1) plus an upregulation of nicotinic cholinergic (Chrna4, Chrna2, and Chrna6) and opioid genes (Pnoc, Pcsk1n; detected by two independent probes). Interestingly, while this upregulation was observed with multiple genes immediately post recall in positive, the same upregulation was only observed +3h post recall in test.\n\nThis pattern of +3h delayed regulation in test vs. positive was also seen with many downregulated signaling-related transcripts (Figure 3b) as enkephalin precursor proenkephalin Penk. We also observed a downregulation of Pcsk1 and prodynorphin Pdyn, opioid receptors kappa and mu (Oprk1, Oprm1), GABAergic- (Gabra4, Gabra5, Gabrad, Gabrarq), serotonergic- (Htr2a, Htr1d, and Htr6) and muscarinic cholinergic receptors (Chrm1), opioid regulators Rgs4 and 9, and neuropeptide Y (Npy; detected by two independent probes). Interestingly, two of the most pronounced regulated genes - pro-melanin-concentrating-hormone Pmch and vasoactive intestinal peptide Vip - were downregulated in the hypothalamus of test animals immediately post recall by more than 30fold.\n\nIn the pituitary samples of test and positive control, we found a heterogenous pattern of expression in steroidogenic, nuclear, and metabolism-related genes. Except Fam111a and Nt5c3b, most of the genes like Cyp11b1/2, Plk5, unknown transcript RGD1564409, and Myo15 showed an upregulation preferentially in test but not in positive; however, as we had to exclude the first two time points in pituitary, most of the upregulation of these genes was observed only +24h post recall. Contrary to this pattern in test, we detected a very strong upregulation of interferon stimulated genes (ISGs) in positive vs. negative control such as Cxcl9/10/11, Gbp5, Rsad2, Ccl2 and 12, Isg15, Oasb1a/b, Ifit2/3, in some cases exceeding regulations by factor 100.\n\nLooking at downregulation, we only observed four genes with an average gene expression downregulated >2fold: ubiquitin-conjugating enzyme Ube2U, Efcab1, Hist2h2ab and Fndc9.\n\nWith regard to neurotransmission, we detected an upregulation of ionotropic glutamate receptors like kainate receptor (Grik2) at +6h and monoamine transporter Slc18a1 (VMAT1, endocrine variant of CNS-specific and hypothalamus-upregulated VMAT2), GABA receptors (Gabbr1, Gabre) and opioid binding protein-like (Opcml) upregulation in test pituitary +24h post recall. At the same time, tryptophan hydroxylase Tph1 and GABA-related transporter Slc6a1 were downregulated at +6h post recall, while cholinergic nicotinic neurotransmission-related genes as Chrna9 and Slc44a4, neuron-derived neurotrophic factor Ndnf and proline transporter Slc6a20 were downregulated +24h post recall (Figure 9).\n\nIn the adrenal glands, 19 genes were found to be upregulated >2fold on average in test animals compared to their negative counterparts. Most of the observed upregulated genes were involved in thermogenesis and metabolic pathways like carbohydrate metabolism (Pck1), lipid metabolism (Cidec, Thrsp), triglyceride catabolism (Fabp3) and heat generation related functions (Ucp1; Thermogenin), which showed a strong and immediate upregulation in test.\n\nIn addition to above-mentioned genes, we observed an upregulation of tumor necrosis factor signaling genes (Tnfaip6, Nr4a2), stress responsive gene (Ddit4), gene encoding serine/threonine protein kinase (Sik1), thyroid hormone responsive protein (Thrsp), nuclear receptor (Nr4a2), proto-oncogene (Junb), and cell death-inducing DFFA-like effector c (Cidec).\n\nLooking at downregulation, we observed 9 genes with an average gene expression downregulated >2fold: Phosphodiesterase (Pde01a), Gdpgp1, Mgc11619, LOC31693, Rho family GTPase (Rnd3), Guanosine monophosphate receptor (Gmpr), Myosin protein (Myo16), NONMMU and Golgi vesicular membrane trafficking protein (Bet1l).\n\nRelated to neurotransmission in the adrenal glands of test animals, we found an immediate upregulation of adrenergic receptors (Adra1a, Adrb3), neuropeptide Y receptor (Npy4r), purinergic signaling receptor (P2rx5) as well as cholinergic nicotinic receptor (Chrna7). We also observed an upregulation of endorphin precursor proenkephalin (Penk), opioid receptor mu (Oprm1), neuron-derived neurotrophic factor (Ndnf) and dopamine receptor (Drd2) (Figure 10). We further saw an upregulation in the inhibitory neurotransmission associated genes like GABA receptors (Gabrg1, Gabrg2), excitatory neurotransmitter glutamate/D-serine amino acid transporter (Slc1a4) and muscarinic cholinergic receptor 1 (Chrm1). Moreover, we observed single point downregulation for opioid-related convertase (Pcsk1/2), vesicular glutamate transporter (Slc17a6), GABA transporters (Slc6a1, Slc6a11), and serotonin receptor (Htr3a).\n\nWhile analyzing the gene expression in the spleen, the expression of 15 transcripts was found to be upregulated on average >2fold across all timepoints measured in test animals as compared to negative control (Figure 1). These genes included Ig-like domain-containing protein MOR5S4 (“Hiramoto factor”), lymphocyte antigen 6 complex (Ly6al), ubiquitin-like modifier (Isg15), similar to paired-Ig-like receptor A1 LOC690948, signal regulatory protein delta (Sirpd), chemokines Cxcl10 and Ccl12, oligoadenylate synthetase (Oasl), interferon signaling molecules as Ifitm3 and Ifit3, oxidized low density lipoprotein (Olr1), B-cell receptor Cd72, folate receptor 2, RT-1BP, and erythrocyte protein band Ebp4.1. Most of the upregulated genes identified in spleen were either involved in immune activation or in immune function regulation.\n\nLikewise, also many genes downregulated in spleen across all time points measured were related to immune regulatory functions such as G protein signaling regulator (Rgs13) and Killer cell lectin receptor (Klrd1). In addition, we observed a strong downregulation of olfactory receptor Olr1516, detected by two probes, Smarce1l, UDP-Gal:betaGlcNAc beta 1,4-galactosyltransferase polypeptide 4 (B4galt4) and two further uncharacterized transcripts (LOC10254, LOC10091).\n\nLooking at gene expression regarding neuronal and endocrine signaling (Figure 11), we detected an upregulation of opioid signaling (Pcsk2 and Pcsk1; detected by two independent probes and opioid receptor Sigmar1), nicotinic acetylcholine receptor alpha 3 (Chrna3), ionotropic glutamate receptor delta 2 (Grid2), DNA directed RNA polymerase II (Polr2m), NMDA glutamate receptor ionotropic 1A (Grin1a), D-serine transporter (Slc1a4) and glutamate decarboxylase 2 (Gad2). We also observed a downregulation opioid receptor delta 1 (Oprd1), adrenomedullin 2 (Adm2), cholinergic receptor muscarinic 2 and both glutamatergic (Grik1, Gad2, Grm4), GABAergic (Gabbr1, Gabrp) and serotonergic receptors (Htr1d). Interestingly, exactly opposite as in hypothalamus, we observed an upregulation of neuropeptide Y (Npy) and a downregulation of neuropeptide S (Nps) in spleen.\n\nTaken together, gene expression data obtained from spleen were summarized by a strong upregulation of immunomodulatory genes, chemo-/cytokines and glutamatergic as cholinergic neurotransmission related genes. And similar to hypothalamus, also in spleen we saw a pattern of immediate regulation in positive e.g. of opioid-related transcripts as Pcsk1 or Gpr88, while the same upregulation in test was only observed +3h later.\n\nTo validate the gene expression results obtained by rat full genome microarray analysis, we picked a representative subset of 32 genes including housekeeping genes, interleukins, ISGs, and chemokines, preferably regulated across multiple tissues (Table 2).23 The mRNA quantity of those genes was analyzed by qRT-PCR and correlation with the corresponding microarray results was assessed. While not all genes correlated perfectly, a strong overall correlation across multiple tissues and expression levels (r2 = 0.8377) was detected (Figure 5).\n\nPlasma levels of ACTH were found to be increased during the first 6h post recall in both in test and positive control animals, with a peak at +6h in positive. Similar, we observed an increased plasma level of IFN-γ immediately post recall in test and 0h to +3h in positive control. IL-1α showed a similar yet less pronounced response in the plasma of both test and positive control animals, peaking at 0h and +6h post recall while IL-1β showed a similar profile to IFN-γ, peaking 0h to +3h in test and 3h later in positive control. The most pronounced changes were observed for the plasma levels of chemokines GRO/KC/Cinc-1 (Cxcl1), IP-10 (Cxcl10), MCP-1 (Ccl2), MIP-1α (Ccl3), Rantes (Ccl5), and TNF-α, with a strong peak at +6h post recall, both in test and in positive control animals (Figure 6).\n\nWith regard to future studies, we also assessed behavioral data during recall of the conditioned immune response employing the sucrose preference test to evaluate potentially conditioned depression-like anhedonia. During the run-in phase from day -7 to -1, a constant and strong preference for the sucrose solution >90% was observed in all study groups. On D0 (day of 1st camphor exposure/poly I:C treatment), a drop in sucrose preference both in test and positive control was observed after poly I:C injection, indicating anhedonia, while there was a less pronounced reduction of sucrose preference in negative control with saline injection, only. Following a return to normal, these effects were further exacerbated on D2 (post recall) with further reduction in sucrose in all animal groups (Figure 12).\n\n\n\nWater and 2% sucrose solution was presented to all animals, and the relative consumption of sucrose solution is shown as % (100% = exclusively sucrose solution). The consumption over 24h was measured and analyzed for each day.\n\n\nDiscussion\n\nIn the present pilot study, we tried to shed preliminary light on the underlying molecular mechanisms, driving behaviorally conditioned immune enhancement. For that purpose, we employed a conditioning paradigm using camphor smell as conditioned stimulus and an i.p. injection of poly I:C as unconditioned stimulus and hypothesized that the efferent signals for the recall of immune response originate from the hypothalamus. To test our hypothesis, we analyzed differential gene expression in the organs along the HPA axis in test (smell re-exposure and sham injection on D2), positive (poly I:C injection on D0 and D2, only) and negative control (smell re-exposure however sham injection both on day 0 and day +2, respectively) animals along with plasma levels of cytokines/chemokines.\n\nAs opposed to our initial hypotheses, it seems there could not only be one but multiple signaling pathways post recall along the HPA axis. Analyzing gene expression patterns in hypothalamus, pituitary, adrenal glands, and spleen, we found evidence for the involvement of WNT/β-catenin pathways, including genes as Otx2, Fzd6, Zic1, and Sox7/8/9/10/11 and 13 in the hypothalamus during the early phases of the recall, corroborating earlier studies and recent studies.24,25 These findings are complemented by the elevated expression of secreted immunomodulators (osteopontin, OPN) in the hypothalamus and dopaminergic as well as opioid signaling. In the pituitary of test animals, we observed a strong upregulation of steroid synthesis related genes, while gene expression of interferon stimulated genes (ISGs) as Cxcl11, Cxcl10, Cxcl9, Ccl2, Ccl7, Ccl12, Gbp5, Rsad2, Oasb1a/b, and Ch25h seemed mostly confined to positive control. We also identified a strong and immediate upregulation of thermogenesis and prostaglandin synthase associated genes in the adrenal glands and strong upregulation of immunoregulatory molecules in the spleen. Overall, the molecular signaling post recall seems to travel from hypothalamus to pituitary and then onwards to adrenal and spleen, both via neuronal pathways as blood borne messengers and then reach back to the hypothalamus via feedback loops. The same expression pattern can also be observed in positive control; however, here the reaction seems to occur much faster, especially regarding downregulated genes, which show up 3h earlier with poly I:C re-injection compared to re-exposure to the conditioned stimulus.\n\nLooking at the cascade in more detail, one of the key players in the hypothalamus seems to be Otx2, with its immediate and strong upregulation in the test arm, detected by two independent array probes. The upregulation of frizzled receptor Fzd6 and transcription factor Zic1 in test further point towards an involvement of the WNT/β-catenin pathway. While Wnt1 upregulation in the test arm did not reach the >2fold threshold, we observed an immediate upregulation of Wnt5a and Wnt7b in the hypothalamus of test animals. This observation of Wnt regulation in association with genes involved in dopaminergic signal transmission (Slc18a2) links to a recent study by Zhang & Yang, 2021,26 which found two other Wnt genes, Wnt1 and Wnt3a play a critical role in the differentiation of neural stem cells into dopaminergic neurons using tetrahydroxy stilbene glycoside and Wnt-signaling specific inhibitor (IWR1).\n\nDownstream of Otx2, we saw an upregulation in neural transcription factors Sox8, 9, 10, 11 and 13, with Sox11 being upregulated immediately post recall in test and Sox10 showing the strongest upregulation at +3h post recall. Of note, Sox9, 10, and 11 have previously been shown to interact with Otx2 during the neural development27 and regulation of visual cycle gene expression in the retinal pigment epithelium.22 In addition, we also observed a single point upregulation of the homeobox transcription factor Engrailed 1 (En1) +3h post recall in test and immediately in positive. Engrailed 1 has been shown to interact with Otx2, repressing canonical Wnt-signaling during murine embryonic development of the mid and hindbrain and its expression seems to be an important survival factor both for serotonergic and dopaminergic neurons.28\n\nBeside Otx2, two further genes were found strongly upregulated in hypothalamus post recall in test: Spp1, coding for immune regulator osteopontin (OPN) and Slc18a2, coding for vesicle transporter VMAT2. OPN, beside its historical role in biomineralization, has been shown to hold a central role in immune activation and regulation e.g. by interacting with leukocyte integrin receptors (α4β1, α9β1, and α9β4)29,30 and cell-surface marker (CD44),31 involved in lymphocyte activation, recirculation, and homing. OPN is also a chemoattractant for neutrophils, expressed by wide range of immune cells and has been shown to play a role in immunomodulation by blocking IL-10 in Th2 type cytokine responses and promoting inflammatory IL-12 and Th1 type expansion.32,33 Considering its pronounced upregulation during the first 6h post recall in test and its humoral immunomodulatory functions, we postulate a central role for OPN in the recall of conditioned immune enhancement, either directly or working in concert with release of CRH and/or other soluble factors into the median eminence, triggering the release of ACTH and further immunomodulatory molecules from the pituitary gland. While this hypothesis is in line with earlier findings by Hsueh et al.,11 which demonstrated the involvement of plasma ACTH in the recall of the behaviorally conditioned immune enhancement, except a short peak +3h in positive, we did not detect any upregulation of Pomc, precursor of ACTH and multiple other peptide hormones, on mRNA level in any of the tissues. We did, however, detect an immediate, single point upregulation of IFN-γ gene expression in the hypothalamus of test and a similar upregulation of IFN-α in the spleen +6h post recall of positive control animals.\n\nAnother - not necessarily mutually exclusive - option of how OPN might be involved in the signaling cascade during recall of the conditioned immune reaction, could be the HPA feedback loop. As shown by Wang et al.,34 OPN -/- mice show reduced levels of ACTH and elevated levels of cortisol during chronic restraint stress and as speculated, same could be due to a negative feedback loop involving OPN. Interestingly, we also detected decreased levels of Cxcl10 and Ccl2, both in hypothalamus of test +6h post recall and immediately post recall in the pituitary of positive control animals. Further to this hypothesis, Trinh et al. in 202035 further demonstrated that stress, induced by systemic poly I:C injection, can increase plasma OPN, triggering the release of ACTH. This is in line with the Wang’s observation that OPN injection results in partial restoration of the ACTH response to stress in OPN -/- mice, while an anti-OPN antibody was shown to partially inhibit the stress response in OPN WT mice.34\n\nThe third strongly upregulated gene in hypothalamus in test post recall was Slc18a2, encoding vesicular monoamine transporter (VMAT2). VMAT2 is responsible for the transport of cholinergic neurotransmitters norepinephrine and dopamine into synaptic vesicles. Interestingly, both Reserpine, which irreversibly inhibits VMAT2, and 6-Hydroxydopamine (6-OHDA), a neurotoxin inhibiting dopamine signaling, have been shown to downregulate Slc18a2 transcription, blocking both the conditioned recall of an enhanced NK reaction36 and the conditioned recall of the enhanced neutrophil reaction.12 As further shown by Hsueh et al.,11,12,37 both cholinergic and serotonergic pathways in the CNS seem to be involved during acquisition as well as recall of the conditioned NK cell response and same has been shown to involve both muscarinic and nicotinic receptors. In line with these data, we saw a downregulation of both dopamine receptors (Drd1, Drd2) and serotonergic receptors (Htr1f, Htr2a) in the hypothalamus of test animals +3h post recall, further pointing towards an involvement of dopaminergic and/or noradrenergic signaling pathways during the recall of the conditioned response. Figure 7 shows the putative interaction between the upregulated genes and potential interactors.\n\nAdditional genes strongly downregulated in hypothalamus included pro-melanin-concentrating hormone gene (Pmch), precursor of the orexigenic peptide MCH, vasoactive intestinal peptide (Vip) as well as neuropeptide Y (Npy), together with an upregulation of neuropeptide S (Nps). MCH, in addition to its role in appetite stimulation, has been shown to play a critical role in regulating dopamine signaling by suppressing DA release in the nucleus accumbens while NPY seems to play a similar role by directly inhibiting dopaminergic neurons in the ventral tegmental area (VTA).38 Neuropeptide S has the exact opposite effect as neuropeptide Y, acting anxiolytic and anorectic, which adds to the pattern of appetite-reduction and energy conversation by immediate and strong downregulation of Pmch and Vip, further augmented by downregulation of Npy and upregulation of Nps, observed immediately in positive and +3h post recall in test.\n\nWe also observed a strong downregulation of opioid inhibitory G-protein coupled receptor 88 (Gpr88) and regulator of G-protein signaling 9 (Rsg9) in concert with an upregulation of prepronociceptin (Pnoc) and proprotein convertase subtilisin/kexin type 1 inhibitor (Pck1n), detected by two independent probes; like with Npy and Nps, regulation was observed +3h in test and immediate in positive. Again, these observations are in line with former studies by Hsueh et al.,39 which have demonstrated the involvement of opioid pathways during the recall of behavioral conditioned immune enhancement.\n\nFinally, we also identified RT-1A upregulated in both hypothalamus and adrenal of test animals. RT-1A is a classical rat MHC class Ia gene, involved in the presentation of peptides to cytotoxic T lymphocytes and has been shown to interact with the Ly-49 family of receptor on NK cells as “self-identifier”, thereby providing protection against NK cell lysis.40\n\nMost of the other genes we observed regulated in hypothalamus shortly post recall such as cilia and flagella associated protein Cfap43, involved in olfactory detection, Npas4, key regulator of GABAergic synapse development, stabilizing the activity of neurons during glutamatergic input, or dynein subunits Dnah12 and Dnah1, point towards a heavy involvement of microtubular transport processes during the recall of the conditioned immune reaction.\n\nPituitary onwards, we observed an upregulation of steroidogenic, nuclear, and metabolism-related genes like Fam111, Star or Rgs1 in test animals post recall as opposed to a strong upregulation of ISGs in positive. Same view, however, might be distorted as we were not able to analyze time points +0h and +3h in pituitary, and hence might have missed upregulation during first 3h.\n\nIndependently of this, we did observe an upregulation of orphan nuclear receptors Nr4a2 and Nr4a3 in test - while the exact function of both receptors has not been fully elucidated, recent studies point towards a role in antigen presentation and viral response.41 Downregulation did not yield a consistent pattern and beside few, single point downregulations as observed with Tetraspanin (Tspan8) and Claudin (Cldn1), only serotonin-related tryptophan hydroxylase Tph1 showed a clear pattern. This rather mixed expression pattern in test is in strong contrast to the clear and strongly ISG-dominated expression pattern in positive control, showing more than 50x upregulation for genes like Cxcl9, 10, 11 or Gbp5, Rsad2, and Ccl2, which points to a different mechanism when comparing poly I:C re-injection to the recall of the conditioned immune reaction.\n\nFurther along the HPA axis, the strong immediate upregulation of Ucp1 (>300fold) in the adrenal glands of test animals point towards a dramatic shift in metabolism towards heat generation as e.g. required for fever induction. Likewise, strongly upregulated Thrsp has also been shown to play a role in thermogenesis of brown adipocytes,42 which was recently confirmed in fed and refed hatchling chicks. This metabolic shift towards heat generation is also in line with the upregulation of fatty acid binding protein Fabp3, involved in the regulation of mitochondrial thermogenesis and temperature homeostasis. At the same time, we saw the upregulation of both adrenergic receptors Adr1a and Adr3b. Both receptors have been shown to be involved in metabolic abnormalities and associated diseases and mutations in these receptors have been speculated to be associated with weight gain in association with anti-psychotic drugs, further corroborating a role of gene expression towards metabolic adaptation to sickness-related conditions.\n\nIn the spleen, we saw a strong upregulation of known and partially unknown immunomodulatory genes. The highest upregulation was observed for a 354bp uncharacterized transcript, coding for a 118aa Ig-like domain containing protein (M0R5S4; “Hiramoto factor”). Reactome analysis suggests the involvement of this protein in immunoregulatory interaction between lymphoid and non-lymphoid cells involving lymphoid expressed Fc-gamma receptors and/or in signaling of the B cell receptor. The second upregulated gene, Ly6aI, also known as stem cell antigen 1 (SCA-1), has recently attracted attention after it was identified as key gene in the transport of neurotropic vector adeno-associated virus serotype 9 across the blood-brain barrier in C57BL/6J mice.43 Its classic function, however, is more known in hematopoiesis; in fact, Sca1 is one of the most common cell surface marker used to enrich adult hematopoietic stem cells. Furthermore, a regulatory role of Ly6 proteins in nicotinic acetylcholine receptors (nAChRs) has been suggested.44\n\nIn addition to M0R5S4 and Ly6aI, many other genes upregulated in spleen fall into the category of immunomodulation and -regulation. RT1-Bb is a member of the MHC class II family interacting with CD4 receptors on helper T cells. SIRPδ (Sirpd) is a member of the signal regulatory protein family, involved in signal transduction and cell adhesion and more researched member SIRPα acts as inhibitory receptor by interacting with transmembrane protein CD47, controlling effector functions of the innate immune response.45 Loc690948, predicted to code for Lilrb3a, is an inhibitory member of the leukocyte immunoglobulin-like receptor family and LILRBs have been documented on a broad range of immune cells including NK cells, where they can modulate immune cell functions as cytokine release, antibody production and -presentation46 as well as Toll-like receptor signaling.47 Apol11a, coding for a Apolipoprotein L, a Bcl-2 like protein, has been proposed to have cell death related function due to their pore-forming domain, inflicted by dendritic cells after viral stimulation and also gets strongly expressed splenic DCs post stimulation with poly I:C, dependent on TLR3/TRIF, a reaction mimicked by IFN-ß.48 CD72 is an inhibitory co-receptor on B cells, that recognizes the RNA-containing Sm/RNP (Smith/Ribonucleoproteins as resulting from cell death) by an extracellular C-type lectin domain (CTLD) while inhibiting the corresponding B cell response through it intracellular immunoreceptor tyrosine-based inhibition motif (ITIM), thereby blocking the TLR7-mediated activation of antibody production.49 Finally, RT1-N2 belongs to the family of rat MHC class Ib molecules. This class has recently been shown to interact with both inhibitory and activating Ly49 receptors, resulting in the specific expansion of allospecific NK cells.50 All these findings point towards a central role for spleen in the modulation of the behavioral conditioned immune enhancement.\n\nWith reference to Hsueh et al.11 original study in mice, we also looked at IFN-related gene expression in spleen and while we couldn’t find an upregulation of Ifn-α or -β in spleen of test, we did observe an upregulation of Ifn-α2 gene expression in positive +6h post recall. More importantly, we also saw an immediate peak of Ifn-γ expression in hypothalamus of test, also reflected by elevated IFN-gamma levels in plasma. Likewise in line with Hsueh et al., we did observe elevated ACTH plasma levels in test and positive during the first 6h post recall but not in negative control animals (Figure 6).\n\nFor other chemokines, we saw a rather mixed pattern when comparing plasma levels and gene expression: while we did see a peak of GRO/KC/Cinc-1, MIP-1α, and Rantes +6h in plasma of both test and positive control, a corresponding upregulation of Cxcl1, Ccl3 and Ccl5 on gene level could only be observed in pituitary and adrenal of positive. Likewise, a plasma peak of TNF-α did show a corresponding upregulation of Tnf gene expression. For plasma MCP-1, we observed immediate upregulation of Ccl2 in the spleen of positive and 3h later in spleen of test. This pattern resembles very much the expression of Cxcl10 and corresponding plasma levels of IP-10, where we first saw an upregulation of Cxcl10 in spleen of positive and 3h later in test plus a similar, 3h delayed pattern in hypothalamus. This pattern, an upregulation in spleen, first, and 3h later in hypothalamus, starting in positive, immediately and 3h delayed in test, was also observed for other ISGs as Cxcl11, Gbp5, and Rsad2, and might suggest that the upregulation of ISGs in hypothalamus is rather a secondary effect, triggered by an upregulation of ISGs in spleen.\n\nIn this context, it might be interesting to mention that we also observed a short but clear upregulation of acetylcholine receptor Chrna3 in the spleen of test animals immediately post recall. Most of the available literature suggest Chrna7 as the main receptor for acetylcholine51 in the spleen, involved in the relay of vagus nerve signals to cytokine-producing macrophages via acetylcholine-synthesizing T cells in the spleen52 and as recently discovered, this Chrna7-based activation of macrophages seems to be mediated by a downregulation of α1,3-Fucosyltransferase Fut7.53 We could not see any upregulation of Chrna7 in spleen, however we did see a downregulation in Fut7 +3h post recall in both test and positive, hinting towards a potential involvement of the vagal system in modulating the recall of the conditioned immune reaction. And while a recent paper by Verlinden et al. 201954 demonstrated catecholaminergic but no direct cholinergic innervation of the spleen, this finding does not rule out the possibility of an indirect vagal innervation via postganglionic non-cholinergic fibers, further supported by a recent study by Zhang et al.55 that has shown that CRH neurons originating from the CeA of the amygdala and PVN of the hypothalamus can stimulate splenic plasma cells formation via direct splenic innervation, potentially via intermediate T cells, translating the noradrenalinergic signal into an acetylcholinergic message.\n\nIn summary, our data indicate that in addition to the classic HPA axis involving CRH, ACTH and cortisol release, there could be additional pathways connecting brain and immune system during the recall of behavioral conditioned immune enhancement e.g. by direct splenic innervation, modulating and finetuning the message via cholinergic signaling from the PVN. We further postulate that recall of the conditioned immune response starts in the hypothalamus via a Wnt/β-catenin related pathway, involving Otx2, Sox7/8/9/10/11, Zic1, and Fzd6 as well as monoaminergic (Slc18a2) and opioid messaging (Gpr88). While still to be analyzed in more detail, both osteopontin as strongly upregulated, potentially in concert with Pmch and Vip as strongly downregulated immediately post recall, seem to play an important role during the early phases - either in the communication between hypothalamus and pituitary and/or as blood borne immune modulators themselves. While pituitary onwards, it is hard to identify one specific pathway, we observe the upregulation of steroidogenic and thermogenic genes in pituitary and adrenal, respectively, pointing towards an early hormonal activation in parallel to a strong immunomodulation observed in spleen, from where the feedback loop involving strongly upregulated ISGs as Cxcl9/10/11 reaches back to the brain.\n\n\nData availability\n\nUnderlying data deposited in Zenodo.org: https://doi.org/10.5281/zenodo.7086375.56\n\n• 20220902 Affymetrix all tissues all timepoints red green incl p v2.xlsb (Affymetrix raw data and analysis across all tissues and time points)\n\n• 20220803 Ct values and Affymetrix correlation v2.xlsx\n\n(qRT-PCR Ct values and corresponding Affymetrix data for 32 genes)\n\nZenodo: ARRIVE checklist for “Differential gene expression during recall of behaviorally conditioned immune enhancement in rats: a pilot study”, https://doi.org/10.5281/zenodo.7086375.56\n\nData are available under the terms of the Creative Commons Attribution 4.0 International “No rights reserved” data waiver (https://creativecommons.org/share-your-work/public-domain/cc0/)", "appendix": "Acknowledgements\n\nWe thank Hannes Martin Hentze, Mukta Pathak, and Parul Saxena for helpful comments to adjust the study design and their contribution to the animal, tissue isolation, and gene expression experiments. 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Publisher Full Text" }	[ { "id": "173302", "date": "15 Jun 2023", "name": "Manfred Schedlowski", "expertise": [ "Reviewer Expertise Behavioral Immunobiology" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe present approach taken by Rueckels et al. investigates in biochemical pathways generating conditioned immune enhancement. The authors showed, upregulation of genes related to Wnt/β-catenin signaling (Otx2, Spp1, Fzd6, Zic1), monoaminergic transporter Slc18a2, and opioid-inhibitory G-protein Gpr88 in the hypothalamus as well as downregulation of dopaminergic receptors, vasoactive intestinal peptide (Vip), and pro-melanin-concentrating hormone (Pmch). In the pituitary, they report upregulation of steroid synthesis and neurotransmission genes (GABAergic, cholinergic, opioid). Peripheral data from spleen showed upregulation of immunomodulatory genes, chemo-/cytokines, and neurotransmission genes (glutamatergic/cholinergic). Plasma analyses confirmed increased chemokine and ACTH levels. Based on their results the authors suggest the possibility of additional pathways, such as the cholinergic anti-inflammatory pathway (CAIP), which could serve as a connection between the brain and immune system. This pathway may play a role in regulating and finely adjusting the communication between these two systems.\nThe authors have taken an interesting approach, revealing the hypothesis of an alternative pathways in addition to the classic HPA axis. However, there are a number of issues which have to be addressed before the manuscript can be indexed.\n\nThe overall poor quality of language (huge amount of typos and grammar errors) makes the manuscript difficult to read and unfortunately suggests sloppiness in terms of preparation. The manuscript needs to be carefully checked for grammar and typos (by a native English speaker).\n\nThere is some inconsistency between the abstract and the discussion section. Quality of language changed throughout the manuscript. Please comment on this.\n\nEven though the methodologies used in these studies appear to be appropriate, there are some issues that need discussion. All experiments are missing a “negative control group”, in order to exclude possible residual effects of PolyI:C in which animals are injected with Poly I:C during the learning phase and receive no treatment during recall D2. These results would confirm that the measured ”conditioning effects” are not only “residual effects” of Poly I:C treatment, since the experimental design allows only one day retention interval between the learning and testing phases.\n\nPage 1: ”connecting brain and immune system, modulating and finetuning communication between brain and immune system” redundant; please rephrase.\n\nPage 3: line 1-5 “Pavlovian or classical conditioning is a phenomenon of associative learning”, it is not clear why you make a difference between both conditioning paradigms. The reader might get confused, because both expressions describe the same paradigm.\n\nPage 3 line 30-31: “48h later, animals in the test group were re-exposed to camphor smell, only, to recall a behaviorally conditioned immune response in rats while animals in a positive control group receive a re-injection of poly I:C and animals in a negative control group receive smell conditioning, only, but no poly I:C re-injection”. This sentence does not make sense. Please rephrase.\n\nMethodology/terminology - animals in the negative control group did not receive smell conditioning (neither in the learning phase (saline injection) nor in the recall phase (re-exposure to camphor smell)).\n\nPage 3, line 11: terminology - what does \"work paradigms“ mean?\n\nPage 3 Table 1: An additional timeline would be very helpful for the reader to understand the complex experiments.\n\nPage 4 line 1: Please provide literature for this poly I:C dose (Sigma #P1530; ip; 1 mg/kg)\n\nPage 4 , line 8-9: Consistent terminology – \"for the isolation of […] serum to perform cytokine/chemokine array analysis“ throughout the rest of the paper, the term \"plasma“ is used.\n\nPage 4 line 16: Consistent terminology – \"days D-7 to D-1 […] as well as days D0 – D3.“\n\nPage 4, line 18: Comprehensibility - \"Rats were presented with two drinking bottles for 24 h. One filled with plain drinking water and one filled with 2% (w/v) sucrose solution.“\n\nPage 4 line 18: Methodology – \"rats were housed in groups of two“. How was the SPT conducted to assess individual fluid consumption?\n\nPage 4, line 38-39: Poor and vague language – \"Since we hypothesized that the conditioned response evoked during recall was mediated by the hypothalamus, […]“.\n\nPage 5, line 8: blank space between number and unit of measurement – \"1 µl of each primer“ \"1 µl sterile water“.\n\nPage 5, line 22: Consistent terminology - \"All statistical analyses were conducetd“ (consistent with heading).\n\nAll figures are of poor quality/resolution; please do not use screenshots from Excel or other programs for a scientific publication. For example: Figure 1-5 : Figure legend is missing, the figure is blurry, words are cut off, no proper headings describing the columns. Does each column represent one tissue? Tables, no figures.\n\nFigure 6 & 7; the reader has to guess the numbers and Abbreviations (Poor quality) Please correct. Figure 11: poor figure – figure legend is missing, the figure is blurry, words are cut off, no proper headings describing the columns. What do the grey columns mean?\n\nPage 5, line 37: Terminology - \"test vs. negative control ('test‘) (the term \"test“ is already assigned to the conditioned experimental group. It is confusing to use this term again to describe the comparison between test vs. negative control).\n\nPage 5, line 43: Terminology - \"positive vs. negative control ('positive‘) (the term \"positive“ is already assigned to the positive group. It is confusing to use this term again to describe the comparison between positive vs. negative control)\n\nPage 6, line 1-5: Sentences throughout the paper are too long, complicated, including too many commas and are therefore incomprehensible.\n\nPage 7, line 6-8: Sentences throughout the paper are too long, complicated, including too many commas and are therefore incomprehensible – \"in test. However, they were either strongly upregulated in positive or did not reach significance when comparing gene expression in test vs. negative control. While […]“\n\nPage 8, line 2: Figures do not appear in chronological order throughout the text.\n\nPage 11, line 20: consistent terminology, poor language – \"in test was only observed +3h post recall“.\n\nPage 11, Table 2: Comprehensibility - \"including individual correlation per gene and correlation across all data points.“ Are there two different correlations? Which correlation is depicted in the table?\n\nPage 13, Figure 6: Poor figure – figure legend is missing, the figure is blurry, consistent terminology, alpha, gamma, etc. consistently depicted as symbols or written words.\n\nPage 12, line 2: Comprehensibility – \"immediately post recall“ What does immediately mean? 0h?\n\nPage 14, Figure 8: Comprehensibility – the connection between \"Viral proteins and –nucleic acids; Poly I:C“ and the rest of the figure is missing, if the figure is intended to illustrate the pathways involved during recall of behaviorally conditioned immune response, it would make more sense to depict camphor smell instead of Poly I:C, figure legend is missing\n\nPage 14, line 1: Methodology/comprehensibility – \"in negative control with saline injection only.“ (\"only“ is misleading, because animals received a saline injection and camphor smell).\n\nPage 15, Figure 10: Poor figure – figure legend is missing, the figure is blurry, words are cut off, no proper headings describing the columns. What doo the grey columns mean?\n\nPage 15, Figure 11: Poor figure – figure legend is missing, the figure is blurry, words are cut off, no proper headings describing the columns. What does the grey columns mean?\n\nPage 15, Figure 12: groups do not really differ on D0.\n\nPage 15, line 3: Consistent terminology – \"on D0 and D2, respectively)“.\n\nPage 17, line 19: Repetition/redundancy – \"further“.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "10794", "date": "20 Jan 2025", "name": "Markus Rueckels", "role": "Author Response", "response": "Response to reviewer’s comments Reviewers comments: purple Our comments: black Revised manuscript text of version 2 where applicable: blue/Italic Manfred Schedlowski University of Duisburg-Essen, Essen, Germany Laura Lückemann Institut of Medical Psychology and Behavioral Immunobiology, University of Duisburg-Essen, Essen, Germany The present approach taken by Rueckels et al. investigates in biochemical pathways generating conditioned immune enhancement. The authors showed, upregulation of genes related to Wnt/β- catenin signaling (Otx2, Spp1, Fzd6, Zic1), monoaminergic transporter Slc18a2, and opioid- inhibitory G-protein Gpr88 in the hypothalamus as well as downregulation of dopaminergic receptors, vasoactive intestinal peptide (Vip), and pro-melanin-concentrating hormone (Pmch). In the pituitary, they report upregulation of steroid synthesis and neurotransmission genes (GABAergic, cholinergic, opioid). Peripheral data from spleen showed upregulation of immunomodulatory genes, chemo-/cytokines, and neurotransmission genes (glutamatergic/cholinergic). Plasma analyses confirmed increased chemokine and ACTH levels. Based on their results the authors suggest the possibility of additional pathways, such as the cholinergic anti-inflammatory pathway (CAIP), which could serve as a connection between the brain and immune system. This pathway may play a role in regulating and finely adjusting the communication between these two systems The authors have taken an interesting approach, revealing the hypothesis of an alternative pathways in addition to the classic HPA axis. However, there are a number of issues which have to be addressed before the manuscript can be indexed. The overall poor quality of language (huge amount of typos and grammar errors) makes the manuscript difficult to read and unfortunately suggests sloppiness in terms of preparation. The manuscript needs to be carefully checked for grammar and typos (by a native English speaker) The manuscript was carefully reviewed and revised by a native English speaker improving language and expression. Typos were carefully removed. There is some inconsistency between the abstract and the discussion section. Quality of language changed throughout the manuscript. Please comment on this. The manuscript consists of parts independently written by the two authors. Language and expression were carefully revised and aligned. Even though the methodologies used in these studies appear to be appropriate, there are some issues that need discussion. All experiments are missing a “negative control group”, in order to exclude possible residual effects of PolyI:C in which animals are injected with Poly I:C during the learning phase and receive no treatment during recall D2. These results would confirm that the measured ”conditioning effects” are not only “residual effects” of Poly I:C treatment, since the experimental design allows only one day retention interval between the learning and testing phases. The experiment could have been conducted in two ways regarding the design of the negative control: first, camphor smell and poly I:C on day 0 and saline, only, but no smell on day 2. Secondly, camphor smell and saline at both day 0 and day 2. The second option was chosen to exclude a conditioning effect of the injection procedure itself, potentially recalled through saline injection on day 2. Page 1: ”connecting brain and immune system, modulating and finetuning communication between brain and immune system” redundant; please rephrase. The sentence was modified, new sentence: Our data set indicates that in addition to the classic HPA axis there could be additional pathways as e.g. the cholinergic anti-inflammatory pathway (CAIP), modulating and fine tuning communication between brain and immune system. Page 3: line 1-5 “Pavlovian or classical conditioning is a phenomenon of associative learning”, it is not clear why you make a difference between both conditioning paradigms. The reader might get confused, because both expressions describe the same paradigm. The sentence was modified, new sentence: Pavlovian, sometimes also called classical conditioning, is a phenomenon of associative learning, Page 3 line 30-31: “48h later, animals in the test group were re-exposed to camphor smell, only, to recall a behaviorally conditioned immune response in rats while animals in a positive control group receive a re-injection of poly I:C and animals in a negative control group receive smell conditioning, only, but no poly I:C re-injection”. This sentence does not make sense. Please rephrase. The sentence was modified, new sentence: Following that paradigm, all animals were first exposed to camphor smell and animals in the test and positive control group then injected with polyinosinic:polycytidylic acid (poly I:C), simulating a viral infection and inducing so-called sickness behavior, an animal model for depression-like behavior in rodents, while animals in the negative group were injected with saline. 48h later, animals in the test group were re-exposed to camphor smell, only, to recall the a behaviorally conditioned immune response in rats while animals in the positive control group receive a re-injection of poly I:C, only. Animals in the negative control group received smell re-exposure and an injection of saline. Methodology/terminology - animals in the negative control group did not receive smell conditioning (neither in the learning phase (saline injection) nor in the recall phase (re- exposure to camphor smell)). The experiment could have been conducted in two ways regarding the design of the negative control: first, camphor smell and poly I:C on day 0 and saline only day 2. Secondly, camphor smell and saline at day 0 and day 2. The second option was chosen to exclude all potential impact of the camphor smell alone. Page 3, line 11: terminology - what does \"work paradigms“ mean? The sentence was modified, new sentence: by different researchers all over the world and current knowledge about this phenomenon including potential pathways and experimental paradigms employed have been comprehensively summarized in a recent review by Hadamitzky et al Page 3 Table 1: An additional timeline would be very helpful for the reader to understand the complex experiments. A illustrative timeline was added below Table 1 Page 4 line 1: Please provide literature for this poly I:C dose (Sigma #P1530; ip; 1 mg/kg) The reference below was added: Behav Pharmacol 2010 Jul;21(4):369-73. doi: 10.1097/FBP.0b013e32833c7ce5. Synthetic double-stranded RNA polyinosinic-polycytidylic acid augments morphine-induced conditioned place preference in rats Lei Zhang1, Suqing Chen, Hongyu Liu, Lin Lu, Haifeng Zhai Page 4 , line 8-9: Consistent terminology – \"for the isolation of [...] serum to perform cytokine/chemokine array analysis“ throughout the rest of the paper, the term \"plasma“ is used. The sentence was corrected to plasma Page 4 line 16 The sentence was modified: The SPT was carried out on D-7 to D-1 (run-in phase for baseline data) as well as days D0 - D3. page 4, line 18: Comprehensibility - \"Rats were presented with two drinking bottles for 24 h. One filled with plain drinking water and one filled with 2% (w/v) sucrose solution.“ The sentence was modified accordingly: Rats were presented with two drinking bottles, one with plain drinking water and one with 2% (w/v) sucrose solution for 24 h. The ratio of sweetened vs. plain water consumed during this time period was calculated, and results were expressed as %sucrose preference. Page 4 line 18: Methodology – \"rats were housed in groups of two“. How was the SPT conducted to assess individual fluid consumption? Average values per cage were assessed. The assessment of individual values was not conducted. Page 4, line 38-39: Poor and vague language – \"Since we hypothesized that the conditioned response evoked during recall was mediated by the hypothalamus, [...]“. The sentence was modified: As we hypothesized that the message post recall originated from hypothalamus, we additionally leveraged QIAGEN Ingenuity Pathway Analysis (QIAGEN IPA) for a more detailed analysis of hypothalamic genes. All genes identified with avg. regulation >2fold in the hypothalamus of test animals were selected and subcellular network analysis was derived using IPA graphic interface. Page 5, line 8: blank space between number and unit of measurement – \"1 μl of each primer“ \"1 μl sterile water“. Corrections were made for all units of measurement accordingly throughout the manuscript. All figures are of poor quality/resolution; please do not use screenshots from Excel or other programs for a scientific publication. For example: Figure 1-5 : Figure legend is missing, the figure is blurry, words are cut off, no proper headings describing the columns. Does each column represent one tissue? Tables, no figures. All figures including headings, legend and resolution of the figures were improved. Page 5, line 22: Consistent terminology - \"All statistical analyses were conducted“ (consistent with heading). The sentence was modified accordingly: All statistical analyses were conducted using RMA gene expression data for all available time points for test, positive and negative control, respectively, applying a two-tailed, unpaired, homoscedastic Student t-test (Microsoft® Excel® for Microsoft 365 MSO, version 2022) Figure 6 & 7; the reader has to guess the numbers and Abbreviations (Poor quality) Please correct. Figure 11: poor figure – figure legend is missing, the figure is blurry, words are cut off, no proper headings describing the columns. What do the grey columns mean? We sent high resolution graphics to the editorial office to improve the quality of the figure resolution. The grey columns represent samples which could not be analyzed due to insufficient RNA quality. Page 5, line 37: Terminology - \"test vs. negative control ('test‘) (the term \"test“ is already assigned to the conditioned experimental group. It is confusing to use this term again to describe the comparison between test vs. negative control). The text was modified accordingly: Leveraging this approach to identify major upregulated genes in test vs. negative control across all tissues with a >2-fold average regulation across all time points, we identified 12 and 10 upregulated transcripts in hypothalamus and pituitary, respectively (Figure 1). Page 5, line 43: Terminology - \"positive vs. negative control ('positive‘) (the term \"positive“ is already assigned to the positive group. It is confusing to use this term again to describe the comparison between positive vs. negative control) The text was modified accordingly: We also excluded genes with a stronger upregulation in positive vs. negative control than test except when also showing a strong regulation across multiple other tissues as e.g. Cxcl11 or Cxcl13 and applied a similar approach to focus on the most promising candidate genes for downregulation (Figure 2). Page 6, line 1-5: Sentences throughout the paper are too long, complicated, including too many commas and are therefore incomprehensible. The manuscript was reviewed and revised accordingly: In addition to this, we focused at up- and downregulation of neurotransmitter-associated genes such as receptors, transporters, and solute carriers, potentially involved in dopaminergic, serotonergic, opioid, cholinergic, glutamatergic, or GABAergic neurotransmission. We then selected for strong regulation across multiple tissues, even if not crossing an average >2fold regulation across all timepoints analyzed and limited the time frame for this analysis to the first 6h post recall unless otherwise mentioned. Page 7, line 6-8: Sentences throughout the paper are too long, complicated, including too many commas and are therefore incomprehensible – \"in test. However, they were either strongly upregulated in positive or did not reach significance when comparing gene expression in test vs. negative control. While [...]“ The manuscript was reviewed and revised accordingly. In addition to Slc18a2, Otx2 and Spp1, 8 additional genes were found upregulated >2fold in hypothalamus. Of these, only Fzd6 and Zic1 showed a strong predominant upregulation in test vs. negative control, while Hapln4, Cxcl11, Fa2h, Tspan18, and Sh2b2 either showed a less strong regulation or were equally or even stronger regulated in positive vs. negative control. Page 8, line 2: Figures do not appear in chronological order throughout the text. Figures are inserted in the text by the editorial office Page 11, line 20: consistent terminology, poor language – \"in test was only observed +3h post recall“. The text was modified accordingly And similar to hypothalamus, also in spleen we saw a pattern of immediate regulation in positive vs. negative control of e.g. opioid-related transcripts as Pcsk1 or Gpr88, while the same upregulation in test vs. negative control was only observed 3h later. ○ Page 11, Table 2: Comprehensibility - \"including individual correlation per gene and correlation across all data points.“ Are there two different correlations? Which correlation is depicted in the table? The text was modified accordingly Table 2. List of 32 genes used for validation of Affymetrix rat genome chip data by qRT-PCR including individual correlation per gene and total correlation across all genes. Page 13, Figure 6: Poor figure – figure legend is missing, the figure is blurry, consistent terminology, alpha, gamma, etc. consistently depicted as symbols or written words. Graphics resolution was improved. The use of abbreviations was changed to a uniform expression. The text in figure 6 was modified accordingly: Figure 6. Heat map showing levels of IFN-γ, ACTH, GRO/KC/CINC-1, MIP-1α, RANTES, TNFα, MCP-1 and IP-10 in the plasma of test, positive and negative control animals. Page 12, line 2: Comprehensibility – \"immediately post recall“ What does immediately mean? 0h? Yes, immediately means 0 h. ○ Page 14, Figure 8: Comprehensibility – the connection between \"Viral proteins and –nucleic acids; Poly I:C“ and the rest of the figure is missing, if the figure is intended to illustrate the pathways involved during recall of behaviorally conditioned immune response, it would make more sense to depict camphor smell instead of Poly I:C, figure legend is missing Text for figure 8 was modified: Figure 8. Illustration showing the possible afferent (poly I:C, mimicking a viral infection) and efferent (gene regulation in hypothalamus, pituitary, adrenal and spleen) pathways involved in the immune regulation during recall of the behaviorally conditioned immune response. Page 14, line 1: Methodology/comprehensibility – \"in negative control with saline injection only.“ (\"only“ is misleading, because animals received a saline injection and camphor smell). “, only” was removed Page 15, Figure 10: Poor figure – figure legend is missing, the figure is blurry, words are cut off, no proper headings describing the columns. What do the grey columns mean? All figures including headings, description of columns and resolution of the figures were improved. Page 15, Figure 11: Poor figure – figure legend is missing, the figure is blurry, words are cut off, no proper headings describing the columns. What does the grey columns mean? All figures including headings, description of columns and resolution of the figures were improved. Page 15, Figure 12: groups do not really differ on D0. Test and positive control showed an average reduction of 10.6% and 13.5% sucrose preference, respectively, versus 2.5% reduction in negative control on DO compared to D-1. As none of the groups reached significance (p < 0.05), we didn’t show any data Page 15, line 3: Consistent terminology – \"on D0 and D2, respectively)“. All figures including headings, legends, description of columns and resolution of the figures were improved. Page 17, line 19: Repetition/redundancy – \"further“. The sentence was modified accordingly: Further to this hypothesis, Trinh et al. in 2020 demonstrated that stress, induced by systemic poly I:C injection, can increase plasma OPN, triggering the release of ACTH. 4, line 38-39: Poor and vague language – \"Since we hypothesized that the conditioned response evoked during recall was mediated by the hypothalamus, […]“. Page 5, line 8: blank space between number and unit of measurement – \"1 µl of each primer“ \"1 µl sterile water“. Page 5, line 22: Consistent terminology - \"All statistical analyses were conducetd“ (consistent with heading). All figures are of poor quality/resolution; please do not use screenshots from Excel or other programs for a scientific publication. For example: Figure 1-5 : Figure legend is missing, the figure is blurry, words are cut off, no proper headings describing the columns. Does each column represent one tissue? Tables, no figures. Figure 6 & 7; the reader has to guess the numbers and Abbreviations (Poor quality) Please correct. Figure 11: poor figure – figure legend is missing, the figure is blurry, words are cut off, no proper headings describing the columns. What do the grey columns mean? Page 5, line 37: Terminology - \"test vs. negative control ('test‘) (the term \"test“ is already assigned to the conditioned experimental group. It is confusing to use this term again to describe the comparison between test vs. negative control). Page 5, line 43: Terminology - \"positive vs. negative control ('positive‘) (the term \"positive“ is already assigned to the positive group. It is confusing to use this term again to describe the comparison between positive vs. negative control) Page 6, line 1-5: Sentences throughout the paper are too long, complicated, including too many commas and are therefore incomprehensible. Page 7, line 6-8: Sentences throughout the paper are too long, complicated, including too many commas and are therefore incomprehensible – \"in test. However, they were either strongly upregulated in positive or did not reach significance when comparing gene expression in test vs. negative control. While […]“ Page 8, line 2: Figures do not appear in chronological order throughout the text. Page 11, line 20: consistent terminology, poor language – \"in test was only observed +3h post recall“. Page 11, Table 2: Comprehensibility - \"including individual correlation per gene and correlation across all data points.“ Are there two different correlations? Which correlation is depicted in the table? Page 13, Figure 6: Poor figure – figure legend is missing, the figure is blurry, consistent terminology, alpha, gamma, etc. consistently depicted as symbols or written words. Page 12, line 2: Comprehensibility – \"immediately post recall“ What does immediately mean? 0h? Page 14, Figure 8: Comprehensibility – the connection between \"Viral proteins and –nucleic acids; Poly I:C“ and the rest of the figure is missing, if the figure is intended to illustrate the pathways involved during recall of behaviorally conditioned immune response, it would make more sense to depict camphor smell instead of Poly I:C, figure legend is missing Page 14, line 1: Methodology/comprehensibility – \"in negative control with saline injection only.“ (\"only“ is misleading, because animals received a saline injection and camphor smell). Page 15, Figure 10: Poor figure – figure legend is missing, the figure is blurry, words are cut off, no proper headings describing the columns. What doo the grey columns mean? Page 15, Figure 11: Poor figure – figure legend is missing, the figure is blurry, words are cut off, no proper headings describing the columns. What does the grey columns mean? Page 15, Figure 12: groups do not really differ on D0. Page 15, line 3: Consistent terminology – \"on D0 and D2, respectively)“. Page 17, line 19: Repetition/redundancy – \"further“. Is the work clearly and accurately presented and does it cite the current literature? No Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly" } ] }, { "id": "174282", "date": "20 Jun 2023", "name": "Daniele Suzete Persike de Oliveira", "expertise": [ "Reviewer Expertise Neuroscience." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReading this article was very useful for me, since it addresses a very interesting and still not well understood topic. I understand that the article was well written and presented in a clear manner. I would only have two comments:\nDespite being a pilot study, the total number of animals used per group seems to be quite small (n=5). A clarification on that would be appreciated since the Table 1 mentions 5 animals/group, but the descriptive text below it explains that the animals from each group were later divided into 0h (n=2), +3h (n=2), +6h (n=2), +24h (n=2) and +48h (n=2) making a total of 10 animals/group. I believe it would be interesting if the author addressed the \"placebo response\" in the discussion. Current placebo research postulates that conditioning processes are one of the major mechanisms of the placebo response and I believe it would be something interesting to be addressed as it might be part of the results observed. See the article: Vits et al. (20111).\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] } ]	1	https://f1000research.com/articles/11-1405
https://f1000research.com/articles/13-686/v1	24 Jun 24	{ "type": "Study Protocol", "title": "Research protocol - Evaluating data quality in the Netherlands Perinatal Registry (Perined): A data comparison study using hospital records from the IUGR Risk Selection (IRIS) study", "authors": [ "Hilde Plomp", "Corine Verhoeven", "Lilian Peters", "Aimée van Dijk", "Wes Onland", "Ank de Jonge", "Jens Henrichs", "Hilde Plomp", "Corine Verhoeven", "Lilian Peters", "Aimée van Dijk", "Wes Onland", "Ank de Jonge" ], "abstract": "Background The quality of registry based studies depends largely on the data accuracy of the registries. The Dutch Perinatal Registry (Perined) is a nationwide database comprising perinatal data digitally provided by different healthcare providers. Perined data are used for comparing outcomes across regions and healthcare institutions as well as for quality analyses and research purposes. However, little is known about the data quality of the Perined database. Therefore, the aim of this study is to assess the quality of Perined data compared to hospital records and case report forms (CRFs) that were part of the IUGR Risk Selection (IRIS) study.\n\nMethods In this comparison study data from Perined and the IRIS Study will be used. The IRIS study was a large cluster-randomized trial investigating the effectiveness of routine third trimester ultrasonography in reducing severe adverse perinatal outcomes among Dutch low-risk pregnant women. A subsample of the IRIS study of neonates being at risk of severe adverse perinatal outcomes and their mothers will be used. Baseline demographic data were collected by midwives from participating women at inclusion (around 22 weeks’ gestation) using CRFs, and in-depth neonatal and maternal clinical data were retrieved from hospital records by trained research assistants. These latter IRIS study data were linked and compared to Perined data. Completeness of Perined data will be calculated for every variable. The reliability will be assessed as the percent of agreement between Perined and hospital record data or the CRF-based data. Additionally, intra-class correlation coefficients will be calculated for continuous variables, and Kappa and ‘Prevalence-and-Bias-Adjusted Kappa’ will be calculated for categorical variables.\n\nDiscussion The results of the proposed comparison study will provide users of Perined data insight in its data quality. This will serve as an example of the accuracy of registry based data used in maternal and neonatal care research.", "keywords": [ "Perined", "perinatal database", "data quality", "completeness", "reliability", "agreement" ], "content": "Introduction\n\nMany countries have a nationwide perinatal database containing data on maternal and neonatal outcomes, such as mode of birth and birth weight.1–3 Countries use national perinatal data for monitoring outcomes, quality analyses and research. The data can also be used for comparing results between hospitals, midwifery practices and regions within the country and between countries.2,4–6 For example, EURO-PERISTAT merges aggregated data of all EU members states, Norway, Iceland, Switzerland and the United Kingdom for comparing maternal and neonatal outcomes between the countries.2 For these purposes, high quality of the data included in these national databases is essential. Nevertheless, there is a lack of research and insufficient insight into the data quality of these databases.\n\nIn 2018, a study was published about the completeness of birth registries worldwide. Phillips et al. concluded that in 2011 only 40% of the total births in the world were registered in a public database, although registration was better in high income countries.1 In 2019, two Canadian studies were published on the data accuracy of the Ontario Birth Registry (BORN).7,8 Miao et al. compared the BORN birth registry with the general Canadian clinical hospital database (n = 404,439) by evaluating data on key maternal and neonatal outcomes.7 Dunn et al. compared data from BORN with data extracted from hospital records (n = 927), and focussed on key outcomes, e.g. labour type and gestational age at birth, but also considered more specific maternal and neonatal outcomes, e.g. ‘pain relief measures during newborn screening’ or ‘serum bilirubin’.8 Both studies found an overall good agreement for most key maternal and neonatal outcomes, e.g. almost perfect agreement for gestational age at birth and date of birth.7,8 Remarkably, in the study of Miao et al. the lowest Kappa was found for stillbirth or live birth (Kappa 0.74), because of discrepancies in the coding of stillbirths between the data sources.7 The study by Dunn et al. using hospital records as comparison found lower agreement for more specific outcomes, e.g. intention to breastfeed and maternal smoking, than for key outcomes.8 Another study conducted in Finland in 2002 on the Finnish medical birth registry showed that check-box questions improved data quality, compared to open-ended questions.9 In addition to research on the accuracy of birth registry databases, studies concerning the data quality of non-perinatal databases showed that the overall completeness, validity, and reliability of national medical databases in high income countries was good and has improved over the years.10–14\n\nThe current study focuses on the evaluation of the quality of data obtained from the Netherlands Perinatal Registry (Perined).15 Such an evaluation is crucial as Perined serves important healthcare-related and scientific purposes. The aim of Perined is to improve the quality of Dutch perinatal care.15 The database is used for comparing outcomes between regions, midwifery practices and hospitals, for quality analyses to improve perinatal care and research.4 The database contains data on pregnancy, birth and neonatal outcomes.4 The data are collected by midwives, obstetricians and paediatricians as part of their regular practice, and a selection of items is shared with Perined.15 In 2020 97% of all Dutch births were registered in Perined.4\n\nSeveral large-scale Dutch studies used Perined data, for example the DELIVER (Data EersteLIjns VERloskunde) study, ABCD (Amsterdam Born Children and their Development) study and the IRIS (IUGR RIsk Selection) study.16–18 These studies all had more than 5000 participants. Data in these studies were collected in different ways and Perined data were used for key maternal and neonatal outcomes. Other studies are completely based on Perined data, e.g. the development of the latest Dutch birthweight charts.19\n\nThis illustrates that Perined data are regularly used for research purposes. However, to the best of our knowledge, the data quality of the Perined database has never been assessed in a study. Therefore, the aim of the current study is to assess the data quality of the Perined database, by assessing the completeness and agreement of the data as compared to perinatal and maternal peripartum variables based on the original hospital records and baseline demographic data from the IUGR Risk Selection (IRIS) study.\n\n\nMethods\n\nThis study is a data comparison study concerning a subsample of data based on the IRIS study.18,20 To assess agreement, data from Perined will be compared with data extracted from hospital records from the participating mothers and/or neonates or with demographic baseline data collected via Case Report Forms (CRFs) at enrolment of participating women (around 22 weeks’ gestation) completed by the midwives together with the participants.18,20 The data extracted from the hospital records and CRF-based demographics of the IRIS study are used as reference standards. In short, the IRIS study was a multi-centre nationwide stepped wedge cluster randomized trial investigating the effectiveness of routine ultrasound screening in the third trimester of pregnancy in reducing severe adverse perinatal outcomes in low risk pregnancies.18 Routine third trimester ultrasound screening was compared with standard care. Sixty primary care midwifery practices in the Netherlands and a total of 13,520 women with a low risk singleton pregnancy participated in the IRIS study. The women were enrolled between February 2015 and February 2016. Data of 13,024 (96.3% of 13,520) participating mothers and neonates were linked to Perined data.18 Data extracted from the hospital records (n=2884) were collected for neonates at risk for severe adverse perinatal outcomes and for mothers with an at risk neonate and/or with indications of peripartum pathology or hospitalization (see section data collection and selection for more details and variable operationalization).\n\nData for this study were collected in 2015 and 2016. In 2016 98% of the Dutch births were registered in Perined.21 Each profession registers a set of variables.22 Perined links the datasets of each profession and creates one record for all neonates and their mothers (Figure 1).23 Some variables are uniquely registered by the respective healthcare providers of one profession, whereas others (e.g. type of birth) are registered by healthcare providers of multiple professions. For every variable that is registered by more than one profession, Perined uses a decision tree to determine which value is leading in the Perined record.23 The records used in this study are all records with information from more than one healthcare profession, thus having a complex data structure. In 2015 and 2016 Perined started with a new registration approach for hospitals. Some hospitals used the new approach, while others still used the old approach. For the complete IRIS study, most data was provided using the old approach. The data provided according to the new approach has been recoded by Perined according to the specifications of the old approach.\n\nPerined data and extracted hospital record data for the current comparison study are selected using a subsample of the IRIS study. Figure 2 shows the used data sources for this study. For the IRIS study hospital records were selected for in-depth data collection based on certain criteria for the Perined or survey data. If the Perined record suggested a case of perinatal death (between 28 weeks pregnancy and 7 days postpartum), a low Apgar score (<4) at five minutes, a birth weight between percentile 2.3 and 5 and neonatal hospitalization for more than three days, or a birth weight < percentile 2.3, data from hospital records were extracted. Hospital records were also selected based on a longitudinal survey; a subsample of women in the IRIS study (n= 1949) took part in this survey.20 The survey data were used to identify cases at risk for a severe adverse perinatal outcome. When mothers indicated in the survey that they had a consultation or referral of care to obstetrician-led care, or that their baby visited a paediatrician or neonatologist, they were included for the in-depth data collection from hospital records if they met certain criteria. Maternal indications to be included in the in-depth data collection included maternal hospitalization during pregnancy and/or postpartum or maternal hospitalization for more than 48 hours after birth without medical intervention or an hospitalization of more than 72 hours related to a caesarean section.24 Trained research assistants performed the data extraction. After data extraction from the hospital records, the amount of error in data entry was analysed. Double entry analyses were performed on hospital records of 111 women. The incidence of data entry error was 3.2% overall, 3.7% for maternal data and 2.6% for neonatal data.18\n\nExtracted data from the selected hospital records and CRF’s will be linked to those of Perined records of the same mothers and neonates to be able to compare these two types of records. Variables will be included in the current study if they are available in both Perined and either the extracted hospital record data or the CRFs. Table 1 and Table 2 show which variables will be compared.\n\n1 Final choices for the categorization per variable will be made when doing the analysis. An attempt will be made to stay as close as possible to the Perined categories as used in the Perined data.\n\n2 As discussed in the methods section Perined variables can be registered by one healthcare profession, but also by more than one. This column will show the data source(s) of the variable.\n\nRecords with missing data for some of the selected variables will be included in this study, to assess the degree of completeness of the different variables in Perined.\n\nThe data in the IRIS study are not always coded in the same way as those in Perined. Recoding of the variables will be necessary to make comparisons possible, this will be done in Rstudio 4.2.1 and IBM SPSS statistics 28. We will stay as close as possible to the Perined categories. If too much recoding is required to compare the variables, no comparison will be considered. All statistical analyses will be performed in Rstudio 4.2.1. PABAK will be calculated in Rstudio 4.2.1 with the formula 2*((a+d)/(a+b+c+d))-1, based on a 2x2 table.25 For ordinal scales, PABAK will be calculated using the PABAK-OS calculator.26\n\nBy using descriptive statistics, frequencies and percentages will be presented for all categorical variables. For continuous variables (e.g. birthweight, Apgar score) with a normal distribution, means and standard deviations (SD) will be calculated. Medians and interquartile ranges (IQR) will be reported for continuous variables not normally distributed.\n\nThe completeness of the selected variables in Perined will be calculated as the number of patients with information recorded in Perined divided by the total number of patients in the hospital records dataset or CRF based dataset.\n\nThe agreement of the categorical variables will be assessed as the percent agreement and Cohen’s Kappa with 95% confidence interval (CI). Cohen’s Kappa is a statistical measure for dichotomous, categorical and nominal variables to examine the proportion of agreement corrected for the proportion of agreement that could be expected by chance.8,27 The following criteria to assess the strength of agreement will be used: Kappa coefficient ≤ 0 poor, 0.01-0.20 slight, 0.21-0.40 fair, 0.41-0.60 moderate, 0.61-0.8 substantial, 0.81-0.99 almost perfect.28,29 The advantage of using Kappa as a measure of agreement is the correction for chance. The disadvantage of using Kappa is the extreme sensitivity for unequal distributions. When one of the values is very common and the other very rare, Kappa is drastically lowered, even when the agreement is high, this is defined as the Kappa’s paradox.30 Therefore, the ‘Prevalence-Adjusted-Bias-Adjusted-Kappa’ (PABAK) will also be calculated for all categorical variables as this measure can account for unequal distributions of the test variables.25 For PABAK, the same strength of agreement criteria as for KAPPA will be used.\n\nFor continuous variables, the agreement between Perined and the extracted hospital record data will be assessed using the percent agreement and intra-class correlation coefficient (ICC) with 95% CI. The ICC is a correlation coefficient which tests whether there is agreement between two continuous variables measuring the same outcomes in two different data sources. The ICC is an appropriate statistical measure of reliability for continuous data.31 ICC values range between 0 (no agreement) and 1 (total agreement). The following criteria to assess the level of agreement will be used: < 0.5 poor, 0.5-0.75 moderate, 0.75-0.9 good, > 0.90 excellent.31\n\n\nConclusion and discussion\n\nThe data of the IRIS study provide a unique opportunity to validate the Perined dataset on a large scale. In recent years the Dutch Perined database has been increasingly used for various purposes, e.g. benchmarking between Dutch regions, benchmarking between nations, and various types of research. However, so far, little is known about the data quality of Perined despite its importance for healthcare evaluation and research purposes.\n\nThis study will have some strengths and limitations. The greatest strength of this study is that using a large-scale nationally representative low risk pregnancy population in the Netherlands provides the rare opportunity to validate the quality of Perined data. A potential limitation is that the data collection for the IRIS study was conducted in the years 2015 and 2016. These years were so-called ‘transition years’ for the Dutch perinatal registration during which Perined implemented a new dataset system. For the IRIS study the ‘old’ way of data registration and coding were used. Data from participating care institutions that already used the new approach were recoded to fit in the old dataset format as depicted above. A priori one might assume that this may have influenced the degree of missingness in some perinatal variables. The linkage rate between Perined and the complete IRIS study data was very high (96.3%) as compared to a recent study with a much lower linkage rate (78.5%) using the ‘new data registration approach’ only.18,32 Data used for this study were mostly based on complex records reported by different healthcare professionals, see Figure 1. In several instances, information on a certain variable, e.g. birth weight, was entered by several healthcare professionals so that a decision rule was used by Perined determining from which healthcare profession data should be used for a specific variable. One might assume that the accuracy of variables registered by only one healthcare profession may be more accurate than for those variables entered by multiple professions. However, this is unavoidable as for a large group of women and their offspring in ante- and postnatal care referred from midwifery-led care to obstetrician-led care data is generally entered into the Perined database by multiple healthcare professions.4\n\nBy investigating the data quality of Perined using data from the IRIS study we can inform researchers about the reliability and usefulness of the Perined-based neonatal and maternal variables addressed in this study. This information will help researchers to make adequate choices for Perined derived outcome variables to be used in future studies. Next to this the results of the current study will help medical software developers to improve data-extraction procedures, and Perined to improve data-collection procedures. In addition, the results of this study can illustrate how national birth registries can be improved to enhance quality improvement activities in perinatal care research.\n\nThis study is a secondary analysis of the IRIS study which was approved by the Dutch Institutional Review Board of the VU Medical University Centre Amsterdam on the 17th of December 2013 (reference number 2013.409). This study was performed in line with the ethical principles established by the World Medical Association in the Declaration of Helsinki of Ethical Principles for Medical Research Involving Human Subjects.33 Analyses for the current study will be done with a completely anonymous data source, without patient names and study ID.\n\nBetween February 2015 and February 2016, pregnant women in participating midwifery practices who fulfilled the inclusion criteria were informed about the study and received an information leaflet from their midwife during the first consultation. All participants gave written informed consent for data usage.\n\n\nAuthor contributions\n\nPlomp H: Methodology, Writing – Original Draft Preparation, Writing – Review & Editing; Verhoeven CJM, de Jonge A, Henrichs J: Conceptualization, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing. Peters L, van Dijk AE, Onland W: Writing – Review & Editing", "appendix": "Supplementary material\n\nNot applicable.\n\n\nAcknowledgements\n\nWe thank the participating women, midwives, obstetricians, sonographers, IRIS study data management and research assistants team, and staff at participating midwifery practices and hospitals in the Netherlands and the Perinatal Registry of the Netherlands (Perined) for the use of their database.\n\n\nReferences\n\nPhillips DE, Adair T, Lopez AD: How useful are registered birth statistics for health and social policy? A global systematic assessment of the availability and quality of birth registration data. Popul. 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Leicester: MBRRACE-UK collaboration; 2019.\n\nMiao Q, Fell DB, Dunn S, et al.: Agreement assessment of key maternal and newborn data elements between birth registry and Clinical Administrative Hospital Databases in Ontario, Canada. Arch. Gynecol. Obstet. 2019; 300(1): 135–143. PubMed Abstract \| Publisher Full Text\n\nDunn SLA, Sprague AE, Fell DB, et al.: Data accuracy in the Ontario birth Registry: a chart re-abstraction study. BMC Health Serv. Res. 2019; 19: 1001–1011. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nGissler M, Shelley J: Quality of data on subsequent events in a routine Medical Birth Register. Med. Inform. Internet Med. 2002; 27(1): 33–38. PubMed Abstract \| Publisher Full Text\n\nBallantine KR, Hanna S, Macfarlane S, et al.: Childhood cancer registration in New Zealand: A registry collaboration to assess and improve data quality. Cancer Epidemiol. 2018; 55: 104–109. 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Utrecht: 2020.\n\nHenrichs J, De Jonge A, Westerneng M, et al.: Cost-Effectiveness of Routine Third Trimester Ultrasound Screening for Fetal Growth Restriction Compared to Care as Usual in Low-Risk Pregnancies: A Pragmatic Nationwide Stepped-Wedge Cluster-Randomized Trial in The Netherlands (the IRIS Study). Int. J. Environ. Res. Public Health. 2022; 19(3312). PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nByrt T, Bishop J, Carlin JB: Bias, prevalence and kappa. J. Clin. Epidemiol. 1993; 46(5): 423–429. Publisher Full Text\n\nVannest KJ, Parker RI, Gonen O, et al.: Single Case Research: web based calculators for SCR analysis. (Version 2.0) [Web-based application]. Accessed February 7, 2024. Reference Source\n\nTwisk J: Inleiding in de toegepaste biostatistiek [Introduction in applied biostatistics]. Houten: Bohn Stafleu van Loghum; 2017.\n\nLandis JR, Koch GG: The measurement of observer agreement for categorical data. Biometrics. 1977; 33(1): 159–174. Publisher Full Text\n\nViera AJ, Garrett JM: Understanding interobserver agreement: the kappa statistic. Fam. Med. 2005; 37(5): 360–363. PubMed Abstract\n\nFeinstein AR, Cicchetti DV: High agreement but low kappa: I. The problems of two paradoxes. J. Clin. Epidemiol. 1990; 43(6): 543–549. PubMed Abstract \| Publisher Full Text\n\nKoo TK, Li MY: A Guideline of Selecting and Reporting Intraclass Correlation Coefficients for Reliability Research. J. Chiropr. Med. 2016; 15(2): 155–163. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBecking EC, Scheffer PG, Henrichs J, et al.: Fetal fraction of cell-free DNA in noninvasive prenatal testing and adverse pregnancy outcomes: a nationwide retrospective cohort study of 56,110 pregnant women. Am. J. Obstet. Gynecol. 2023. PubMed Abstract \| Publisher Full Text\n\nThe Helsinki Declaration of the World Medical Association (WMA): Ethical principles of medical research involving human subjects. Pol Merkur Lekarski. 2014; 36: 301. Publisher Full Text\n\nRStudio Team: RStudio: Integrated Development for R. Boston, MA: RStudio; 2020.\n\nIBM Corp: IBM SPSS Statistics for Windows, Version 28.0. Armonk, NY: IBM Corp; 2021.\n\nPfaff B, Darrington J, Stover J, et al.: GNU PSPP Statistical Analysis Software: Release 0.9. Boston, MA: Free Software Foundation; 2007." }	[ { "id": "295927", "date": "13 Jul 2024", "name": "Patricia Lee King", "expertise": [ "Reviewer Expertise quality improvement", "perinatal health" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article describes a research protocol for a planned evaluation of data quality of the Netherlands Perinatal Registry (Perined) comparing it to the IRIS study database. Intra-class correlation and Kappa will be calculated to determine accuracy. This research protocol will assess the accuracy of Perined which is widely used for research and public health decision making by comparing it to clinical data.\n\nThis is a detailed description of a study protocol of great importance to public health and research 9- the clinical accuracy of a large data set used for national decision making. It could be strengthened by clarifying in the article that this is a planned study/ study protocol being described. The structure of the article leaves the reader looking for results until they reach the conclusion section. The reference to \"study protocol\" article category at the title is probably not enough for clarity. The Tables, instead of example, could be labeled data collection forms/templates for further clarity.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable", "responses": [ { "c_id": "12875", "date": "09 Jan 2025", "name": "Hilde Plomp", "role": "Author Response", "response": "Dear Patricia Lee King, We would like to thank you for the positive evaluation and compliments concerning our article and for your thoughtful comments. We agree with your suggestion to better clarify that the current paper concerns a study protocol, this was made clear in the title, but possibly insufficiently in the rest of the article. Therefore, we now explicitly state in several relevant places in the text and in the tables that the current paper concerns a study protocol (see the manuscript). Moreover, we have made some additional changes to the text by for example by using the term “planned study” to indicate that the current work only concerns a study protocol. We hope that our changes are satisfactory. We look forward to your evaluation. Kind regards, on behalf of all authors, Hilde Plomp" } ] }, { "id": "295929", "date": "16 Jul 2024", "name": "Elizabeth Kathleen Darling", "expertise": [ "Reviewer Expertise midwifery services", "large database research", "access to care", "health equity" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript presents a study protocol for a data quality study that will compare data collected in the Netherlands Perinatal Registry (Perined) with data collected via hospital records and case report forms for participants in a large cluster-randomized trial (the IRIS study). The authors make a strong case for the importance of high-quality national perinatal registry data to support quality improvement and research, and they successfully argue that the use of high-quality data collected as part of an RCT presents a unique opportunity to assess the quality of Perined data.\nThe objectives of the study are clearly stated and the study design is appropriate to address the objectives. The data sources and the methods originally used to collect the data are adequately described. The plans for statistical analysis are appropriate and are well described. The dummy tables that are provided (Tables 1 & 2) are appropriate to present the planned analyses. (Revising the titles of these tables might help to make their purpose more clear to the reader.)\nThe protocol could be strengthened by the addition of some key information. First, no details are provided regarding how the data sources will be linked. The authors cite a prior study that linked Perined and IRIS data, implicitly demonstrating feasibility, but do not explain what variable(s) will be used for linkage. Furthermore, under 'Ethical considerations', the authors state that the analyses will be done using an anonymous data source, without patient names and study ID, which again raises the question of how the data will be linked. If a previously linked data set is being used, this should be explained. Second, the protocol for the study should include the algorithms that will be used to recode some variables to allow for comparison between two sources. This could be presented as the first table (or a supplementary table if it is very lengthy), and should ideally include the name of the variable in each source and the rules that will be applied to to recode the comparator variables to align them with Perined variables when applicable. This level of detail is necessary to permit replication of the study. Finally, it would be helpful for the reader if you could add another sentence or two to explain the difference between the old and new registration approaches for hospitals that are/were used for Perined. This additional contextual detail would help the reader understand the potential implications of the change in approach.\nGiven the citation of two similar studies in the introduction, the authors may be interested in this recent publication that also examines data accuracy of the Ontario Birth Registry (BORN) -Ref [1]\nI look forward to reading the findings from this study once it is completed.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable", "responses": [ { "c_id": "12876", "date": "09 Jan 2025", "name": "Hilde Plomp", "role": "Author Response", "response": "Dear Elizabeth K. Darling, We would like to thank you for reading and reviewing the article, for the positive evaluation and compliments concerning our article, and for the additional thoughtful comments and suggestions. Below is a point-by-point reply to your comments. We indicated the start of your comments by using your initials (EKD) and our respective reply starts with HP (i.e. Hilde Plomp the first author answering on behalf of all the authors). Changed text passages, which are presented below, are indicated by using quotation marks, and for the convenience of the reviewer, we also refer to the respective pages and lines in the manuscript where these passages can be found. Reviewer: Revising the titles of these tables might help to make their purpose more clear to the reader. Author Response: We have changed the titles of the tables to make it more clear to the reader that these are example tables and what they contain. For example, the title of Table 1 now reads: “Table 1. Example\|Descriptive statistics of the variables to be studied based on Perined and the hospital records/CRFs.” Reviewer: First, no details are provided regarding how the data sources will be linked. The authors cite a prior study that linked Perined and IRIS data, implicitly demonstrating feasibility, but do not explain what variable(s) will be used for linkage.” Author Response: We have added some additional information about the data linkage procedure in the Methods section, as shown below (see also page 6 of the manuscript): “Extracted data from the selected hospital records and CRFs were linked to those from the Perined records of the same mothers and neonates in order to compare these two types of records. Data managers linked the records by matching several demographic variables (e.g. date of birth of the mother and postal code). Variables chosen for analysis will be included in the planned study if they are available in both Perined and either the extracted hospital record data or the CRFs.” Reviewer: Furthermore, under 'Ethical considerations', the authors state that the analyses will be done using an anonymous data source, without patient names and study ID, which again raises the question of how the data will be linked. If a previously linked data set is being used, this should be explained. Author Response: We have added some extra information in the ‘Ethical considerations’ section. It is important to note that the datasets were not completely anonymous to the data managers involved in our study. However, researchers receive anonymized datasets for data-analysis purposes. Our additions to the ‘Ethical considerations’ section are shown below (see also page 14): “Women gave permission to link their records, the linking was performed by data managers of the IRIS study with the support of Perined. After linking the data all identifiable patient information about patients was removed. Analyses for the planned study will be done with a completely anonymous data set, without any identifying variables (e.g. patient names, date of births and study ID).” Reviewer: Second, the protocol for the study should include the algorithms that will be used to recode some variables to allow for comparison between two sources. This could be presented as the first table (or a supplementary table if it is very lengthy), and should ideally include the name of the variable in each source and the rules that will be applied to recode the comparator variables to align them with Perined variables when applicable. This level of detail is necessary to permit replication of the study. Author Response: We cannot include the requested syntax in the current article as the stage of our planned work does not allow this. The syntax of the recoding will be published as a supplementary file included in the subsequent scientific article reporting our final results. Until we have completed the variable coding and data-analysis, we cannot guarantee full precision regarding the best recoding method for each variable (see also page 6): “The categories of the variables will be created with data driven approaches. We expect that the data for these variables as derived from the respective source can be coded into the categories as shown in Tables 1 and 2, or are already available in this way. The syntax comprising the respective coding steps will be published, after publication of the final results as planned in the current study. In case a good comparison between certain variables is not possible, they will be removed and not included in the comparative analyses.” Reviewer: Finally, it would be helpful for the reader if you could add another sentence or two to explain the difference between the old and new registration approaches for hospitals that are/were used for Perined. This additional contextual detail would help the reader understand the potential implications of the change in approach. Author Response: We have added some additional information on this aspect in the Methods section (see also page 5): “In 2015 and 2016 Perined started with a new registration approach for hospitals in the Netherlands. Some hospitals used the new approach, while others still used the old approach. The old and the new approach differ in the variables that are recorded, some variables have been added in the new approach, while others have been removed. Also, for some variables answer options have been changed. For the IRIS study, most of the data were provided according to the old approach. The data provided according to the new approach have been recoded by Perined according to the specifications of the old approach.” Reviewer: Given the citation of two similar studies in the introduction, the authors may be interested in this recent publication that also examines data accuracy of the Ontario Birth Registry (BORN) -Ref [1]. Author Response: thank you for the suggestion. We have added your recent publication in the Introduction (see also page 4). “The BORN birth registry has also been compared to another Canadian birth registry: CIHI-DAD (Canadian Institute for Health Information Discharge Abstract Database) [Darlings et al., 2024]. When lower agreement between variables was found, disagreement could often be explained by differences in coding or differences in definitions of the compared variables [bron: Darlings, 2024].” We hope that our changes are satisfactory. We are looking forward to your evaluation. Kind regards, on behalf of all authors, Hilde Plomp" } ] } ]	1	https://f1000research.com/articles/13-686
https://f1000research.com/articles/14-54/v1	09 Jan 25	{ "type": "Systematic Review", "title": "Applications of MR Finger printing derived T1 and T2 values in Adult brain: A Systematic review", "authors": [ "Riyan Mohamed Sajer", "Saikiran Pendem", "Rajagopal Kadavigere", "Priyanka -", "Shailesh Nayak S", "Kaushik Nayak", "Tancia Pires", "Obhuli Chandran M", "Abhijith S", "Varsha Raghu", "Riyan Mohamed Sajer", "Tancia Pires", "Obhuli Chandran M", "Abhijith S", "Varsha Raghu" ], "abstract": "Introduction Magnetic resonance imaging (MRI) is essential for brain imaging, but conventional methods rely on qualitative contrast, are time-intensive, and prone to variability. Magnetic resonance finger printing (MRF) addresses these limitations by enabling fast, simultaneous mapping of multiple tissue properties like T1, T2. Using dynamic acquisition parameters and a precomputed signal dictionary, MRF provides robust, qualitative maps, improving diagnostic precision and expanding clinical and research applications in brain imaging.\n\nMethods Database searches were performed through PubMed, Embase, Scopus, Web of science to identify relevant articles focusing on the application of MR finger printing in the adult brain. We utilized the preferred reporting items for systematic reviews and meta-analysis guidelines to extract data from the selected studies.\n\nResults Nine articles were included in the final review, with a total sample size of 332 participants. In healthy brains, notable regional, sex, age, and hemispheric variations were identified, particularly in the corpus callosum and thalamus. MRF effectively differentiated meningioma subtypes, glioma grades, and IDH mutation status, with T2 values providing particularly predictive for glioma classification. In brain metastases, significant relaxometry differences were noted between normal and lesional tissues. For multiple sclerosis, MRF values correlated with clinical and disability measures, distinguishing relapsing-remitting secondary progressive forms. In traumatic brain injury, longitudinal T1 changes strongly correlated with clinical recovery, surpassing T2 values.\n\nConclusions The systematic review highlighted MRD as a groundbreaking technique that enhances neurological diagnosis by simultaneously quantifying T1 and T2 relaxation times. With reduced acquisition times, MRF outperforms conventional MRI in detecting subtle pathologies, distinguishing properties, and providing reliable biomarkers.", "keywords": [ "MR Finger printing", "Glioma grades", "Meningioma", "Multiple sclerosis", "Brain trauma", "IDH mutation" ], "content": "Introduction\n\nMRI is crucial for brain imaging offering high-resolution, non-invasive visualization that supports the diagnosis and monitoring of diverse neurological conditions.1 In adults, MRI is widely used to assess neurodegenerative diseases, brain tumors, stroke and psychiatry disorders, with advanced techniques like functional MRI (fMRI) and diffusion tensor imaging (DTI) allowing for in detail evaluation of brain functional and connectivity.2–8\n\nConventional MRI methods have limitations in providing consistent quantitative data, it depends on qualitative image contrast which may vary between the scanner and MR operator. The conventional MRI requires multiple sequences to gather diverse tissue information increasing scan time and motion artifacts- especially in pediatric and uncooperative patients. The lack of quantification limit’s objective evaluation leads to variability in interpretation and potentially limits the utility of MRI in some clinical scenarios.9–12\n\nTo overcome this limitation significant effort has been put into developing quantitative approaches. Quantitative imaging helps to better distinguish the physicians to better distinguish between healthy and pathological tissues. Earlier methods measured one parameter at a time, requiring multiple images with specific acquisition parameters held constant, followed by mathematical modelling to estimate relaxation times like T1 and T2. This process was time-consuming, impractical for clinical use due to long scan times and susceptible to motion artifacts. Recent approaches have been proposed to shorten the acquisition time to provide combined T1 and T2 measurements. However, challenges remain in achieving both speed and accuracy.13–17\n\nMR finger printing (MRF) is an innovative MRI technique that quantitatively captures multiple tissue properties. MRF transforms qualitative MRI to quantitative MRI. It is designed for fast and simultaneous mapping of multiple tissue properties, such as T1, T2 and proton density. MRF varies acquisition parameters including flip angle and repetition time, in a dynamic and a pseudo manner to generate unique signal evolutions or finger prints for different tissues. A precomputed dictionary of simulated signal patterns, based on anticipated combinations of tissue properties, is then used for pattern recognition. Each voxels acquired signal is compared with a dictionary to find the best match, with the associated properties assigned to the voxel to produce quantitative maps. This method improves scan efficiency, reduces susceptibility artifacts, and offers robust, comprehensive tissue characterization, paving the way for enhanced diagnostic and research applications in clinical imaging.18–21\n\nThere are limited studies which investigated the applications of MRF in adult brain. Hence the aim of the study is to assess the application of MRF and investigate the T1 and T2 map values for adult brain studies.\n\n\nMethods\n\nThe literature review was conducted using the guidelines proposed by Preferred Reporting items for Systematic Reviews and Meta-analysis (PRISMA)22 (PRISMA checklist – underlying data).\n\nThe literature search was conducted across databases such as Scopus, Web of Science, PubMed, Embase to find the relevant original articles ( Table 1). MesH terms such as “MR Finger printing”, “Magnetic Resonance Finger Printing”, “Adult brain”, “Brain Tumors”, “Multiple sclerosis”,“Meningioma”, “Gliomas”, “T1 and T2 relaxometry using MR Finger printing”, “Brain metastases” “Brain trauma” “Healthy Volunteers” with Boolean operators such as “AND” “OR” was utilized (underlying data). Only English-language research involving adult individuals receiving MRI exams were included in the search parameters.\n\nInclusion criteria: The screening process followed the Participant’s Intervention Comparison and Outcome (PICO) methodology ( Table 2). The final review included articles that mentioned T1 and T2 relaxometry values of adult brain using MR finger printing technique.\n\nExclusion criteria: Articles such as case studies and reports, conference abstracts, letters, editorial reviews, meta-analyses, or surveys, animal studies, MR finger printing used for non-neuro examinations, T1 and T2 relaxometry values measured used synthetic MR technique were excluded.\n\nThe extracted date includes author and year, parameters assessed, model and vendor, sample size, design, pathology studied, outcome of the study. Two researchers independently assessed data from each article, and any discrepancies were resolved by a third researcher.\n\nThe quality of the studies was assessed using the NIH quality assessment tool for cohort and cross-sectional studies developed by the National Heart, Lung, and Blood Institute in 2013.23 This tool assesses studies based on criteria with 14 questions focusing on the key research concepts (Underlying data)\n\nA total of nine articles were included in the study ( Figure 1).\n\nThe initial search across databases resulted in 252 studies. 97 duplicate entries were removed. The title and abstract of 150 studies were evaluated leading to exclusion of 135 studies as they did not meet the inclusion criteria. A total of 14 articles were retrieved. The full text of 14 articles were assessed for eligibility in total. Five articles were excluded (articles with insufficient data such as not reporting the relaxometry values in detailed table). A total of nine articles were included in the final review.\n\nThe review includes studies conducted across three countries, including United states of America (n=6), China (n=2), Austria (n=1). Seven studies have used Siemens Healthcare MRI scanner (Skyra, Verio, Prisma, Trio, 3.0T) and two studies have used GE Healthcare MRI scanner (Discovery 750 W and Discovery 750, 3.0 T). The total sample size across the studies was 332. All nine studies used prospective data collection methods. A summary of the study characteristics and outcomes can be found in Table 3.\n\nFigure 2 presents a summary of the quality assessment findings. A total of four studies24,25,27,29 was rated as high and five studies26,28,30,31,32 as moderate quality.\n\nSummary of “T1 and T2 relaxometry” values for all studies were provided in Table 4.\n\nA study in healthy volunteer24 identified notable differences in brain tissue relaxometry metrics, particularly in the corpus callosum (CC) and thalamus. Within the CC, the splenium showed significantly higher T1 values but lower T2 values compared to the genu (p<0.0001). In thalamus, the medial components exhibited higher T1 and T2 values than the lateral components (p<0.001). T1 relaxometry showed significant increase with age observed in the genu of the CC, in three frontal white matter (WM) regions (p<0.05) and decrease trends were identified in the left substantia nigra (SN) (p=0.0004; R2=0.24) T2 showed significant increase with age in the left frontal WM and the medial left thalamus (p<0.05) and decrease trends were identified in the bilateral SN. Men showed significantly higher T1 values in the left temporal WM, bilateral cerebellar hemispheres, and pons compared to women (p<0.05). For T2 relaxometry, a significant difference was found in the right lentiform nucleus between sexes (p<0.05). Data from right-handed individuals revealed differences between hemispheres. Significant asymmetries were noted in frontal WM (p=0.02), parietal WM (p<0.0001) and other regions.\n\nThree studies evaluated the usefulness of MRF in meningioma classification. A study by Mostarderio et al.26 revealed that meningiomas had significantly longer T1 relaxation times compared to the thalamus (p=0.001), corpus striatum (CS; p<0.001), and cerebral white matter (CWM; p<0.001). Similarly, T2 relaxation times of meningiomas were significantly longer than those of the thalamus, CS, and CWM (p<0.001). Pairwise comparison showed that deep gray matter structures such as the thalamus and corpus striatum, had longer relaxation times than white matter (p<0.001). Another study by Zhang et al.27 studied MRF-derived T1 and T2 relaxation times to distinguish meningioma subtypes and compared them to normal brain tissue. Meningothelial meningiomas had significantly higher T1 and T2 values than translational (p=0.002) and fibrous (p=0.002) for T1, p=0.001 for T2) subtypes. No significant differences were found between transitional and fibrous meningiomas (p=0.936 for T1, p=0.617 for T2). The ROC analysis demonstrated the diagnostic efficacy of T1 and T2 relaxation times in differentiating meningioma subtypes. For distinguishing meningothelial and transitional meningiomas, the AUCS were 0.819 for T1, 0.822 for T2, and 0.826 for the combined T1 and T2 values, with optimal thresholds of 1564 ms (T1) and 72 ms (T2), both achieving 80% sensitivity and 83.3 specificity. In differentiating meningothelial from fibrous meningiomas, the AUCs were higher;0.841 for T1, 0.874 for T2, and 0.903 for the combined T1 and T2 values. The optimal thresholds were 1563 ms for T1 and 71 ms for T2, with T2 providing a sensitivity of 86.67% and specificity 84.62%, while the combined values achieved a sensitivity of 80% and specificity of 92.31%.\n\nStudy by Bai et al.28 reported that MRF derived T1 and T2 values showed significant differences between the three consistencies (p<0.05), with combined T1 and T2 values achieving the highest diagnostic performance (AUC up to 0.994 for soft vs hard meningiomas) and 100% sensitivity and specificity. T2-weighted signal intensities distinguished soft meningiomas from moderate and hard subtypes (p<0.05) but could not differentiate moderate from hard ones. ADC values and T1-weighted signal intensities were not significantly different across consistencies (p=0.085 and p>0.05, respectively). A multi-class model combining T1, T2 and ADC values achieved 100% prediction efficiency for all subtypes.\n\nA study by Badve et al.25 2017 reported MRF-derived T1 and T2 relaxometry to differentiate glioblastomas (GBMs), lower-grade gliomas (LGGs), and metastases (METs). Patients with LGGs were younger than those with GBMs or METs, with no significant differences in steroid usage or contralateral white matter (CW) metrics. Mean and standard deviation (SD) of T1 and T2 values in solid/enhancing tumor regions (ST) regions were significantly difference from CW across all types of tumor types (p<0.0001). Significant differences were also observed in peritumoral white matter (PW) between GBMs and METs, with mean T1 remaining significant. LGGs and METs differed significantly in ST and PW parameters, with mean T2 in ST regions remaining significant (p<0.05). IDH1 mutation was present in 4 of 6 LGGs but absent in all GBMS. ROC analysis identified the mean T2 of ST regions as the best single predictor for distinguishing GBMs from METs (AUC=0.86, p<0.0001).\n\nSpringer et al.31 reported MRF derived T1 and T2 relaxometry values, ADC values, and rCBV values across IDH-mutant and IDH-wildtype gliomas, as well as between tumor components:solid tumor, peritumoral edema, and normal-appearing white matter (NAWM). T1 and T2 values, along with ADC values, were significantly higher in IDH-mutant gliomas compared to IDH-wildtype gliomas in the solid tumor region (p=0.024, p=0.041, and p<0.001, respectively), while rCBV values were higher in IDH-wildtype gliomas but not statistically significant (p=0.252). In perilesional edema, IDH-wild type gliomas exhibited significantly higher T1 and T2 values than IDH mutants (p=0.038 and p=0.010), but differences in ADC values were not significant (p=0.409).\n\nROC analysis demonstrated that mean T2 values (AUC=0.754) and ADC values (AUC=0.875) were effective for distinguishing IDH-mutant gliomas without 1p/19q codeletion from IDH-wildtype gliomas. Combining T1 and T2 values improved classification, with sensitivity and specificity reaching 0.773 and 0.321 for T1 thresholds (>1670.9) and 0.727 and 0.286 for T2 thresholds (>84.55). Additionally, MRF T1 and T2 values were significantly higher in LGGs compared to HGGs (p=0.017, p=0.002) and were strongly correlated with conventionally measured T1 and T2 values (r=0.913 and r=0.775, p<0.001). rCBV was significantly higher in HGGs than LGGs (p<0.001).\n\nA study by Konar et al.30 observed that in normal-appearing tissues, mean T1 and T2 values were gray matter (GM) 1205 ms and 108 ms, white matter (WM) 840 ms and 78 ms, and cerebrospinal fluid (CSF) 4233 ms and 442 ms. Significant differences in T1 and T2 values were observed between normal WM and brain metastases (BM) lesions (p<0.05). untreated BM lesions had mean T1 and T2 values of 2035 ms and 168 ms, while treated lesions had mean values of 2163 ms and 141 ms. However, the differences between treated and untreated lesions were not statistically significant (p>0.05). Heat maps revealed heterogeneity in T1 and T2 values among BM lesions, with T1 values more generally consistent across patients than T2. Slightly lower T1 values were observed in untreated BMs and in one patient with a history of primary lung cancer who had undergone stereotactic radiosurgery (SRS).\n\nOntaneda et al.32 studied demographic, clinical, conventional, MRI and magnetic resonance finger printing (MRF) characteristics among healthy controls (HC), relapsing-remitting multiple sclerosis (RRMS), and second progressive multiple sclerosis (SPMS) patients. Significant differences were observed between MS and HC across all clinical and MRI measures. RRMS and SPMS groups differed in disease duration, Expanded disability status score (EDSS), Timed 25-foot walk (T2FSW), Nine-hole peg test (9HPT), thalamic and caudate volumes, but not in Brain parenchymal fraction (BPF), les T2w correlated strongly with clinical measures like EDSS, T2SFW, 9HPT and Paced auditory serial addition test (PASAT), while Magnetization transfer ratio (MTR) showed no consistent decline with disease progression.\n\nGerhalter et al.29 analyzed twenty-two patients with mild traumatic brain injury (mTBI) using quantitative MRI (qMRI) measures at two time points: 24±10 days (range:8-53) and 90±17 days (range: 82-142) post injury. Clinical outcomes improved significantly over time, with reductions in concussion symptoms measured by the Rivermead Post-concussion questionnaire (RPQ) across all subscales (p<0.05) and higher scores on the Glasgow outcome scale-Extended (GOSE, p=0.005). cognitive improvements were reflected in better performance on Brief Test of Adult Cognition by Telephone (BTACT) subsets, including word list recall (p=0.005) and number series (p=0.005), and over all z-score increase (p=0.001). MRI analyses revealed that T1 and ADC values in the caudate and global cortical gray matter (GM) significantly lower in mTBI patients than controls at time point 2 (p<0.05). Longitudinally T1 values demonstrated six times more significant correlations with clinical outcomes at time point 2 compared to T2 values, with strong associations (r>0.7) between genu T1 and RPQ scores. FA decreased significantly in regions such as the corpus callosum and thalamus, while T2 values in the palladium increased (p<0.05). Predictive analysis revealed that T1 values in the corona radiata, posterior white matter (WM), and splenium at time point 1, and their longitudinal changes, were strong predictors of recovery (AUC >0.80. These results emphasize the importance of T1 relaxation times as robust markers for mTBI progression and outcome prediction.\n\n\nDiscussion\n\nMRF represents a transformative advancement in MRI technology, addressing many limitations of conventional imaging methods. While traditional MRI provides high-resolution anatomical details, it relies on qualitative image contrasts that can vary between scanners and operators, introducing subjectivity and limiting reproducibility.9–12,33 MRF overcomes these challenges by enabling fast, simultaneous, and quantitative mapping of multiple tissue properties, including T1 and T2 and proton density. In the current study, the utility of MRF-derived T1 and T2 maps in providing quantitative insights into brain tissues and lesions for adult studies were assessed.\n\nFor MRF derived T1 and T2 values of brain regions in healthy adults, aging effects on white matter (WM) were significant, with increased T1 and T2 values linked to microstructural changes such as demyelination, gliosis and increase free water content. Frontal and parietal WM showed dynamic age-related changes quadratically, while deep gray matter regions like the substantia nigra (SN) exhibited age-related decreases in T2 due to iron deposition. Sex differences revealed higher relaxation times in men for frontal and parietal WM, reflecting potential neurodegenerative susceptibility, while relaxometry of temporal regions, cerebellum, and pons were influenced by sex dimorphism. Hemispheric asymmetry in relaxation metrics was noted in moto-related regions, and the genu and splenium of the corpus callosum (CC) demonstrated distinct relaxometry profiles tied to microstructural differences. This T1 and T2 normative database serves as a valuable reference for future MRF studies across various disease states. Ongoing efforts aim to enhance in-plane resolution, enable comprehensive 3D coverage, and minimize inhomogeneity artifacts, with the goal of advancing MRF into a more efficient and robust quantitative tool for neuro imaging and broader clinical applications.24\n\nFor MRF derived T1 and T2 values in meningioma, Mostarderio et al.26 reported that MRF-based T1 and T2 values of the normal structures of the brain were consistent with previously reported 2D acquisitions and demonstrated strong correlations with reference standards.24 The findings align with prior study by Komiyama et al.34 showing higher T1 and T2 values in meningiomas and other intracranial tumors compared to normal tissues, attributed to increased water content. Zhang et al.27 highlighted the potential of MRF in differentiation WHO grade I meningioma subtypes, specifically transitional and fibrous types, from meningothelial meningiomas, which conventional MRI techniques, including T1WI, T2WI, contrast enhanced T1WI, and ADC values, fail to achieve. MRF generated T1 and T2 values correlate with histological differences, with lower values in transitional and fibrous types due to their dense cellularity and collagen content compared to the higher water content in meningothelial types. This differentiation is clinically significant as transitional and fibrous meningiomas have a higher risk of intraoperative hemorrhage and aggressive behaviors linked to 22q chromosomal abnormalities.34 Another study by Bai et al.28 reported the effectiveness of MRF in predicting meningioma consistency, classifying tumors into soft, moderate and hard categories based on quantitative T1 and T2 values. MRF offers precise measurements reflecting tissue composition such as water, collagen and calcium content. Soft meningiomas with higher water content show elevated T1 and T2 values, while harder tumors rich in collagen and calcium, exhibited lower T2 values. These findings underline MRF’s utility in surgical planning by providing accurate, reproducible information that can aid in neurosurgical instrument selection and improve operative outcomes. They also noticed no significant difference in ADC values among soft, moderate and hard meningiomas, consistent with previous research.35–37 ADC values, influenced by extracellular water fraction and tumor cellularity, are not effective for predicting meningioma consistency, as soft meningiomas primarily contain intracellular water and benign tumors across consistencies exhibit similar cellularity. Thus, ADC lack discriminatory power in differentiating meningioma consistencies.\n\nA study by Badve et al.25 reported that MRF successfully identified differences in solid tumor regions of LGGs and METs, as well as in the peritumoral regions of glioblastomas (GBMs) and LGGs. It faced challenges in differentiating between solid tumor (ST) regions of LGGs and GBMs, likely due to their shared glial origin and similar cellular characteristics.38,39 The study revealed that T1 and T2 relaxation times are influenced by factors such as cellularity, water content, and molecular composition. In LGGs, distinct tissue origins contribute to significant differences in relaxometry values compared to METs. The subtle differences in T2 skewness between GBMs and LGGs suggest higher cellular density and microvascular proliferation in GBMs. Conversely, the lack of significant T1 and T2 differences between LGGs and GBMs highlights the challenge of differentiating glioma grades using relaxometry alone. Analysis of peritumoral regions showed that GBMs exhibit infiltrative cells mixed with vasogenic edema, whereas METs are surrounded primarily by vasogenic edema with little histological invasion. This cellular and molecular heterogeneity contributes to measurable relaxometry differences in peritumoral white matter, offering a potential diagnostic marker.40– 43 Another study by springer et al.31 reported that MRF demonstrated significant differences in MRF derived T1 and T2 values were observed between IDH-mutant and IDH-wild type gliomas, particularly in solid tumor regions. IDH-wild type gliomas exhibited lower ADC values and higher MRF T1 and T2 values in peritumoral edema, suggesting increased cellularity and greater infiltration compared to IDH-mutant gliomas. MRF provides quantitative results with higher accuracy, repeatability and efficiency than conventional MRI.\n\nMRF derived T1 and T2 values for characterizing brain metastases (BMs) and differentiating between untreated BMs, treated BMs, and normal-appearing brain tissue. MRF-derived metrics revealed significant differences in T1 and T2 values, highlighting tumor heterogeneity and treatment related changes such as microvascular alterations and radiation necrosis. Untreated BMs exhibited higher T1 and T2 values compared to treated BMs, likely reflecting microvascular alterations and radiation effects such as necrosis or increased iron concentration from blood leakage. The study also identified slight discrepancies between MRF and synthetic MRI (MAGiC) values due to methodological differences, with MRF providing consistent results.30\n\nOntaneda et al.32 explored the use of magnetic resonance finger printing (MRF) in multiple sclerosis (MS) and demonstrated a stepwise increase in T1 and T2 relaxation times in RRMS and secondary progressive MS (SPMS) compared to healthy controls (HC) in both normal appearing and lesional brain tissue. Significant differences in normalappearing brain regions emphasize the widespread effects of MS, while T1 and T2 relaxation times in focal normal-appearing white matter (FNAWM) and lesional tissue differentiated between RRMS and SPMS, suggesting these regions are particularly informative. By providing normalized, multiparametric imaging, MRF holds promise for distinguishing demyelination from other pathological processes, particularly in cortical lesions, which remain challenging with traditional methods.\n\nStudy by Gerhalter et al.29 evaluated the potential of T1 and T2 relaxation times, derived using magnetic resonance finger printing (MRF), to predict clinical outcomes following mild traumatic brain injury (mTBI). Key findings include the predictive strength of T1 relaxation times for global functional (Glasgow outcome scale – extended GOSE), symptomatology (Rivermead post-concussion symptoms Questionnaire- RPQ), and neuropsychological (Brief Test of Adult Cognition by Telephone-BTACT) outcomes surpassing T2 and Diffusion tensor imaging (DTI) metrics like fractional anisotropy and ADC. Higher rates of increasing T1 values were consistently associated with worse clinical outcomes, particularly in white matter regions such as the genu, while T2 performed comparably with DTI metrics without yielding significant predictive associations. The predictive utility of T1 values likely reflects underlying pathologies such as cytoskeletal damage, inflammation, and edema, with higher values potentially indicating progressive neuronal loss.\n\nFirstly, the review primarily focused on applications of MRF in adult, future studies can be done in pediatric population. Secondly, the focus on specific conditions, such as brain tumors and multiple sclerosis, overlooks potential applications in the other neurological and psychiatric disorders. Thirdly, many studies included are pilot investigations with small sample sizes, reducing the generalizability of findings and limiting the exploration of MRFs longitudinal and prognostic capabilities. Additionally, the studies often lack direct correlations with molecular or histopathological data, which constrains the understanding of the biological foundations of MRF derived T1 and T2 values.\n\n\nConclusion\n\nThe systematic review on the applications of MRF in the adult brain concludes that MRF is a transformative imaging technique with significant potential to enhance the characterization and diagnosis of various neurological conditions. Its ability to simultaneously quantify T1 and T2 relaxation times with reduced acquisition times offers a promising alternative to conventional MRI techniques, particularly for diseases like brain tumors, multiple sclerosis, and traumatic brain injury. MRF demonstrates strengths in detecting subtle pathological changes, differentiating tissue properties, and providing reproducible quantitative biomarkers.\n\nThe study did not involve any human participants, and only systematic review was conducted, hence the written informed consent and institutional ethical committee approval (IEC) was not taken.", "appendix": "Data availability\n\nNo data associated with this article.\n\nFigshare: MRF Systematic Review. https://doi.org/10.6084/m9.figshare.28009427.v244\n\nThis project contains the following underlying data:\n\n• PRISMA check list\n\n• MeSH terms\n\n• PRISMA Flow chart\n\n• Quality assessment questions\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0)\n\n\nAcknowledgements\n\nThe authors have no acknowledgements to declare.\n\n\nReferences\n\nRunge VM, Aoki S, Bradley WG Jr, et al.: Magnetic Resonance Imaging and Computed Tomography of the Brain-50 Years of Innovation, With a Focus on the Future. 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Imaging Med. Surg. 2021; 11(4): 1447–1457. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBai Y, Zhang R, Zhang X, et al.: Magnetic Resonance Fingerprinting for Preoperative Meningioma Consistency Prediction. Acad. Radiol. 2022; 29(8): e157–e165. PubMed Abstract \| Publisher Full Text\n\nGerhalter T, Cloos M, Chen AM, et al.: T1 and T2 quantification using magnetic resonance fingerprinting in mild traumatic brain injury. Eur. Radiol. 2022; 32(2): 1308–1319. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKonar AS, Shah AD, Paudyal R, et al.: Quantitative Relaxometry Metrics for Brain Metastases Compared to Normal Tissues: A Pilot MR Fingerprinting Study. Cancers (Basel). 2022; 14(22): 5606. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSpringer E, Cardoso PL, Strasser B: i MR Fingerprinting-A Radiogenomic Marker for Diffuse Gliomas. Cancers (Basel). 2022; 14(3): 723. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nOntaneda D, Gulani V, Deshmane A, et al.: Magnetic resonance fingerprinting in multiple sclerosis. Mult. Scler. Relat. Disord. 2023; 79: 105024. PubMed Abstract \| Publisher Full Text\n\nNayak SS, Pendem S, Menon GR, et al.: Quality Assessment of MRI-Radiomics-Based Machine Learning Methods in Classification of Brain Tumors: Systematic Review. Diagnostics. 2024; 14(23): 2741. Publisher Full Text\n\nKomiyama M, Yagura H, Baba M, et al.: MR imaging: possibility of tissue characterization of brain tumors using T1 and T2 values. AJNR Am. J. Neuroradiol. 1987; 8(1): 65–70. PubMed Abstract\n\nZikou A, Alexiou GA, Goussia A, et al.: The role of diffusion tensor imaging and dynamic susceptibility perfusion MRI in the evaluation of meningioma grade and subtype. Clin. Neurol. Neurosurg. 2016; 146: 109–115. PubMed Abstract \| Publisher Full Text\n\nWatanabe K, Kakeda S, Yamamoto J, et al.: Prediction of hard meningiomas: quantitative evaluation based on the magnetic resonance signal intensity. Acta Radiol. 2016; 57: 333–340. PubMed Abstract \| Publisher Full Text\n\nHoover JM, Morris JM, Meyer FB: Use of preoperative magnetic resonance imaging T1 and T2 sequences to determine intraoperative meningioma consistency. Surg. Neurol. Int. 2011; 2: 142.\n\nMaher EA, Furnari FB, Bachoo RM, et al.: Malignant glioma: genetics and biology of a grave matter. Genes Dev. 2001; 15: 1311–1333. PubMed Abstract \| Publisher Full Text\n\nLouis DN, Ohgaki H, Wiestler OD, et al.: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007; 114: 97–109. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMa L, Song ZJ: Differentiation between low-grade and high-grade glioma using combined diffusion tensor imaging metrics. Clin. Neurol. Neurosurg. 2013; 115: 2489–2495. PubMed Abstract \| Publisher Full Text\n\nMin ZG, Niu C, Rana N, et al.: Differentiation of pure vasogenic edema and tumor-infiltrated edema in patients with peritumoral edema by analyzing the relationship of axial and radial diffusivitieson3.0TMRI. Clin. Neurol. Neurosurg. 2013; 115: 1366–1370. PubMed Abstract \| Publisher Full Text\n\nKelly PJ, Daumas-Duport C, Kispert DB, et al.: Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J. Neurosurg. 1987; 66: 865–874. PubMed Abstract \| Publisher Full Text\n\nPalfi S, Swanson KR, De Bouard S, et al.: Correlation of in vitro infiltration with glioma histological type in organotypic brain slices. Br. J. Cancer. 2004; 91: 745–752. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPendem S: MRF Systematic review. Dataset. figshare. 2024. Publisher Full Text" }	[ { "id": "358478", "date": "17 Jan 2025", "name": "Shashi Kumar Shetty", "expertise": [ "Reviewer Expertise Radiology" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe review emphasizes MR Finger printing as a groundbreaking technique for adult brain imaging, offering shift from qualitative to quantitative MRI.\nMajor comments: The use of the PRISMA framework and NIH quality assessment tool ensures a methodologically sound review.\nIn abstract the phrase “robust, qualitative maps” should be corrected to “robust, quantitative maps”. In conclusion, “MRD” should be corrected to “MRF”\nIntroduction provides an overview of the limitations of conventional MRI techniques and effectively sets the stage for the discussion on MR Fingerprinting (MRF).\nMethodology is well written\nResults section presents a detailed summary of the findings from the included studies, focusing on various applications of MR Fingerprinting (MRF) in the adult brain\nDiscussion consolidates the key results from the study, including the diagnostic advantages of MRF in conditions such as gliomas, meningiomas and traumatic brain injuries.\nConclusion succinctly reiterates the diagnostic and clinical advantages of MRF, particularly in providing quantitative metrics like T1 and T2 values that enhance diagnostic precision and reduce acquisition times.\nMinor comments: In introduction, “Conventional MRI methods have limitations in providing consistent quantitative data, it depends on qualitative image contrast which may vary between the scanner and MR operator” to be corrected as “Conventional MRI methods have limitations in providing consistent quantitative data. They depend on qualitative image contrast, which may vary between the scanner and MR operators”\nTerms like “MR Finger printing” and its abbreviation are used inconsistently. Use the abbreviation after the first mention for consistency.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable", "responses": [] }, { "id": "358477", "date": "20 Jan 2025", "name": "Manna Debnath", "expertise": [ "Reviewer Expertise Magnetic Resonance Imaging (MRI)" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nComments\nIn the conclusion of the abstract, I noticed that \"MRD\" has been used, which I believe should be corrected to \"MRF.\" Kindly correct it. The introduction is well-written, highlighting the limitations of conventional MRI and the advantages of Quantitative MRI. It provides a solid foundation for the study and conveys the significance of the topic. The study follows the well-established PRISMA guidelines, which enhances its methodological clarity. In Table 1 (Page 4), you have mentioned that the total number of studies is 252, including those from PubMed, Scopus, Web of Science, and Embase. However, in Figure 1 (Page 6), the total number of studies identified is listed as 256 including Database 4, if so, which Databases? Please clarify. On Page 5, under the \"Study Selection\" section (2nd line), please mention that 5 studies were removed for other reasons, as indicated in the flowchart (Figure 1). The rest of the Results, Discussion, and Conclusion sections are well-written. They provide a clear and comprehensive interpretation of the findings and study outcomes.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes", "responses": [] } ]	1	https://f1000research.com/articles/14-54
https://f1000research.com/articles/13-1088/v1	24 Sep 24	{ "type": "Research Article", "title": "Morphological and Molecular Characterization of Trichoderma Isolates from Vegetable Crop Rhizospheres in Nepal", "authors": [ "Puja Jaiswal", "Ram B. Khadka", "Aashaq Hussain Bhat", "Suraj Baidya", "Arvind Kumar Keshari", "Aashaq Hussain Bhat", "Suraj Baidya", "Arvind Kumar Keshari" ], "abstract": "Background\nTrichoderma spp. hold significant potential as biocontrol agents in agriculture due to their antagonistic properties against plant pathogens. The study aimed to characterize and identify Trichoderma isolates from rhizospheric regions of vegetable crops.\n\nMethods In this study, Trichoderma isolates were collected from rhizospheric soil samples of vegetable crops from different ecological zones and were selected for comprehensive morphological and molecular characterization. The isolates were visually assessed for colony color, growth pattern, aerial mycelium presence, phialide and conidial morphology, and chlamydospore presence. Molecular analysis was employed based on ITS and tef-1α sequences. Diversity indices were also computed for different ecological zones.\n\nResults The morphological characteristics and phylogenetic trees for both regions provided a clear species resolution, with four main clades: Harzianum, Viride, Brevicompactum and Longibrachiatum with 12 species T. harzinaum, T. afroharzianum, T. lentiforme, T. inhamatum, T. camerunense, T. azevedoi, T. atroviride, T. asperellum, T. asperelloides, T. koningii, T. longibrachiatum and T. brevicompactum and nine species as a new country record. Diversity indices indicated that high mountain regions displayed the highest species diversity and evenness (H = 1.724 [0.28], J = 0.84, D = 0.28), followed by hilly regions (H = 1.563 [0.28], J = 0.72, D = 0.28). Plains, on the other hand, exhibited lower species diversity (H = 1.515, J = 0.66, D = 0.33). The calculated species abundance values showed that plains (E = 2.11), mid-hills (E = 1.95), and high mountains (E = 1.99) each had their unique diversity profiles. Notably, T. afroharzianum and T. asperellum were predominant.\n\nConclusions Overall, the study unveiled a rich diversity of Trichoderma species in different agricultural zones of Nepal. These findings shed light on the ecological distribution and diversity of Trichoderma spp., which could have significant implications for sustainable agriculture and biological control strategies.", "keywords": [ "Biocontrol agent", "phylogenetic analysis", "Rhizospheric region", "Species diversity", "Nepal" ], "content": "Introduction\n\nThe genus Trichoderma comprises a highly diverse group of soil dwelling fungi, demonstrating remarkable versatility. Within this genus, a wide array of strains exhibits significant potential for various applications, including biological control as biopesticides, biofertilizers, soil enhancers and promoters of crop growth.1,2 Furthermore, Trichoderma isolates have the capacity to stimulate plant defense mechanisms, a phenomenon extensively documented in studies conducted by various researchers.3–6\n\nThe Trichoderma genus was originally proposed by Persoon in Germany in 1794, more than two centuries ago, and their potential as bioagents was first documented by Weindling in 1932.7 To date, over 250 Trichoderma species have been identified worldwide.8 Trichoderma species can be readily isolated from soil using various conventional methods, thanks to their adaptability to diverse conditions, ranging from deserts and wetlands to the Himalayan regions. However, the most effective method for isolating Trichoderma spp. is from rhizospheric soil samples.9 A comprehensive understanding of Trichoderma biodiversity is crucial for harnessing the full potential of this genus in various biological applications. Previous surveys that investigated Trichoderma diversity in specific geographical regions have primarily focused on isolates obtained from soil samples. These surveys have been conducted in various locations, including Russia and the Siberian Himalayas,10,11 China,12,13 South-East Asia,14 India,15 Egypt,16 Iran,17 Philippines,18 Europe,19 Canary Islands,20 Sardinia21and South America.22 The potential of Trichoderma species as biological control agents (BCAs) has been under investigation for over 70 years, and more recently, these species have become commercially available.23,24 Certain Trichoderma species have been successfully utilized as BCAs, showcasing their antagonistic mechanisms to mitigate damage caused by soil-borne pathogens, both in greenhouse and open field conditions.25–27 Trichoderma deploys diverse mechanisms, including antibiosis, competition, mycoparasitism, and enzymatic hydrolysis, to manifest its biocontrol activity.28 However, it is important to note that not all Trichoderma species yield the same effects on crops or pathogens. Therefore, the characterization and precise identification of isolates at the species level are pivotal for their effective application as BCAs and the preservation of isolates as viable commercial products.24\n\nTraditional methods for identifying Trichoderma species have conventionally relied on morphological characteristics and culture-based approaches. However, owing to the limited and often indistinguishable morphological features shared among Trichoderma species, alongside the increasing recognition of morphologically cryptic species, accurate identification through these methods becomes challenging and can potentially lead to misidentification.10,29 As a result, molecular techniques such as amplification of important taxonomic markers, and sequencing have emerged as indispensable tools for achieving precise species identification.29–32 In the present study, the identification of Trichoderma species at the species level was accomplished by focusing on two key genetic markers: the Internal Transcribed Spacer (ITS) region of rDNA and a partial sequence of the translation elongation factor 1-alpha gene (tef-1α) in addition to classical taxonomy.33 Recent researches have evaluated the ecological specialization of diversity. Numerous studies have documented the discovery of new isolates and phylogenetic species across various natural ecosystems.20,34 While some studies have been conducted in Nepal, they all have focused on different ecological zones.35 In contrast, limited attention has been given to studying Trichoderma in agricultural environments. Importantly, such investigations have practical implications, as they highlight the potential of agricultural soil rhizosphere as a rich source of beneficial strains with biocontrol capabilities. Building upon these findings, we propose that the composition, distribution, and genetic structure of Trichoderma spp. in the rhizosphere of vegetable crops along with ecological domains and altitudinal gradients may exhibit significant differences. Confirming these differences will enhance our understanding of Trichoderma’s biodiversity across distinct biological niches and various altitudinal gradients across the country.\n\n\nMethods\n\nTo isolate Trichoderma, soil samples were collected from different agricultural regions spanning three ecological zones in Nepal: the plain region (80-141 m above sea level), the mid-hill region (1284-1650 m above sea level), and the high mountain region (1800-2500 m above sea level). These regions exhibited variations in altitude and ecological traits, and were recognized for cultivating a range of agricultural crops. The soil samples were collected from vegetable-growing areas within each region, covering eight districts in Nepal, including Sindhupalchok and Solukhumbu districts in the high mountains; Kathmandu, Lalitpur, Bhaktapur and Kavrepalanchok districts in the mid-hills, and Sunsari and Morang in the plains (Figure 1).\n\nUsing a sterile spatula, approximately 200 grams of soil were collected from the rhizospheric zone of crops such as cauliflower, leaf mustard, cabbage, asparagus bean, tomato, cucumber, brinjal, chilly, pumpkin, and okra. These soil samples were carefully placed in clean polythene bags and appropriately labelled. Subsequently, the soil samples were transported to the National Plant Pathology Research Center, Khumaltar, Nepal and stored at 4°C until isolation.\n\nFor isolation, 10 grams soil samples were suspended in 90 ml of sterile distilled water and mixed using a rotary shaking machine set at 260 × g for 30 minutes to ensure thorough homogenization.36 To facilitate the isolation, 1 mL aliquots of the soil suspensions were diluted from 10−1 to 10−5 onto Trichoderma Selective Media (TSM) using the spread plate technique as described by Askew and Laing.37 After inoculation, Trichoderma colonies were sub-cultured onto potato dextrose agar (PDA) plates and incubated at 28±2°C for seven days to allow for development and growth. Colonies have key characteristics that can be used to identify them as Trichoderma including growth pattern, growth speed, odour and colour. Depending on the diversity of colony characteristics, one to two colonies were selected from each sample for pure culture preparation. Each individual isolate was assigned a unique code and stored in a PDA slant for further study. Isolates were then grown on PDA plates for 3-5 days for sporulation. Different dilutions (10−1 to 10−3) of spore suspension for each isolate were spread on 10% water agar plates and incubated at 28±2°C for 24 hours in the dark to prepare monoconidial cultures. A germinating, isolated single spore was picked up using a sterile needle from the water agar plates and placed on PDA plates to prepare monoconidial culture for each isolate. Spore suspensions were prepared as mentioned earlier and preserved in silica gel for long term storage at -40°C.38\n\nA total of 167 Trichoderma isolates were isolated from various soil samples and preserved using silica gel and were subsequently cultured on PDA plates at 28±2°C for three days. Following the incubation period, cultures with similar morphological characteristics, including growth pattern, diffusible pigments and odor, were observed and sorted into 25 different groups (T1-T25). While most groups consisted of 4 to 5 isolates, T11 and T22 (two larger groups) comprised 20 to 25 isolates each. Within each group, one representative isolate was selected for further study, except for the larger groups where 3 to 5 isolates were chosen for the study. Morphological characteristics such as the aspects of phialides, conidia and chlamydospores were scrutinized under a light microscope (Optika Microscope Italy, B-383PLi) equipped with a camera. To achieve this, Trichoderma isolates were grown on corn meal agar plate for 2-3 days, after which mycelial tips from the colony margin were transferred onto microscope slide and mounted with 3% KOH using sterile glass needles. Subsequently, these specimens were subjected to observation following the flattening and stretching of hyphae with a pair of glass needles. Once suitably prepared, a coverslip was placed over the samples, and any excess liquid was removed using tissue paper. Microscopical measurements and analyses were conducted using the ImageJ software (https://imagej.en.download.it, LOCI, University of Wisconsin). A total of 30 individual phialides and conidia from each specimen were measured and analyzed.\n\nThe colony characteristics of Trichoderma isolates were investigated on PDA plates that were incubated at 28°C under dark conditions. Notably, all Trichoderma isolates developed conidia within 4-5 days. Various diffusible pigments were observed, manifesting as distinct colors, which were then compared with the Audrey & Bear Color Chart (https://www.audrey and bear.com). Additionally, the presence or absence of a coconut odor was noted following 48 hours of culturing on PDA plates.39\n\nGenomic DNA was extracted from thirty-three isolates, which morphologically represented different Trichoderma species from various ecological regions (Figure 2). Approximately, 30-40 mg of mycelium was scraped off from 3–5-day-old colonies cultured on potato dextrose agar (PDA) using sterilized glass slides prior to sporulation. The obtained mycelia were then ground in liquid nitrogen and DNA extraction was carried out using the Promega Wizard genomic DNA extraction kit following the manufacturer’s instructions (Promega Corporation, Madison, WI).\n\nA fragment of rRNA containing the internal transcribed spacer regions was amplified using the primers ITS4 (TCCTCCGCTTATTGATATGC) and ITS5 (GGAAGTAAAAGTCGTAACAAGG).40 The translation elongation factor 1-alpha gene (tef-1α) was amplified using the primers EF1-728F (CATCGAGAAGTTCGAGAAGG)41 and TEF1R (GCCATCCTTGGGAGATACCAGC).10,42,43 Each PCR reaction (25 μL) comprised 12.5 μL of GoTaq® Green Master Mix (Promega), 9.5 μL of nuclease-free water, 1 μL of each forward and reverse primer (10 mM), and 1 μL of gDNA. The PCR reactions were performed using a thermocycler (LifeEco Thermal Cycler (BIOER)) with the following settings: For ITS: 1 cycle of 2 minutes at 95°C followed by 34 cycles of 30 seconds at 95°C, 30 seconds at 57°C, 1 minute at 72°C, followed by a final elongation step at 72°C for 5 minutes. For tef-1α: 1 cycle of 5 minutes at 95°C followed by 35 cycles of 45 seconds at 95°C, 45 seconds at 63°C, 1 minute at 72°C, followed by a final elongation step at 72°C for 10 minutes. Amplified PCR products (3 μL) were subjected to electrophoresis (45 minutes, 100 volts) in a 1.0% agarose gel stained with GelGreen® Nucleic Acid Gel Stain (Biotium, Fremont, CA, USA) alongside a 1 kb DNA ladder (Promega) for size estimation of the amplified bands. The PCR products were purified using the Wizard SV gel and PCR cleanup system (Promega) following the manufacturer’s instructions and were subsequently sequenced using both reverse and forward primers by Sanger sequencing (BGI Solutions Co., Ltd. Tai Po, Hong Kong, China).\n\nSequences were manually edited using Finch TV 1.4.0 for Windows (Geospiza, https://digitalworldbiology.com/FinchTV). Consensus sequences of forward and reverse amplicons were created using BioEdit software44 and deposited in the NCBI under accession numbers (OR140790- OR140818) for ITS rRNA and (OR567133-OR567158) for tef-1α. The BLASTn similarity search program was employed to identify homologous sequences in the NCBI nucleotide database, confirming species-level similarity with the sequence of the isolates. The ITS and tef-1α gene sequences were concatenated using Mesquite software version 2.75.45 Final alignments were done using Clustal W 2.0 in MEGA X version 10.1 and were used to construct phylogenetic trees using the Maximum Likelihood method with the Tamura-Nei evolution model.46 The choice of the Tamura-Nei evolution model was made after evaluating individual alignments through a model test (MEGAX software). Bootstrap values were computed with 1,000 replications to assess the statistical support for each branch. Graphical representation and editing of the phylogenetic trees were carried out using the Interactive Tree of Life (v3.5.1).47,48\n\nAnalysis of the diversity among Trichoderma species\n\nThe degree of dominance index, also known as the McNaughton dominance index (Y), was used to quantitatively assess the habitat preference of Trichoderma isolates in different agricultural fields. The dominance values were calculated using the equation:\n\nSpecies richness (the total number of species), abundance (the total number of isolates of each species), and diversity were calculated using several ecological indices: the Simpson biodiversity index (D),50 Shannon’s biodiversity index (H),51 Pielou species evenness index (J),52 and Margalef’s abundance index (E).53 These indices were applied to quantitatively describe the diversity and habitat preferences of Trichoderma species in various agricultural fields across different ecological zones of Nepal.\n\nThe biological diversity indices were calculated using the following equations:\n\nWhere Hmax = InS\n\nIn these equations, ‘S’ is the total number of Trichoderma species, ‘N’ is the total number of Trichoderma species isolates, ‘Pi’ is the relative quantity of Trichoderma species ‘i’, and ‘ni’ is the number of isolates of Trichoderma species ‘i’.\n\n\nResults\n\nA total of 167 Trichoderma isolates were isolated from soil samples collected from rhizospheric regions of various vegetable crops. Among this collection, 33 Trichoderma isolates were selected based on morphological and microscopic characteristics. The isolates were visually characterized based on phenotypic traits such as colony color (ranging from dark green to cottony whitish green, Plate 1), growth pattern, presence or absence of aerial mycelium (Figure 3a, b), as well as the shape and size of phialides (Figure 3c–f) and conidia (Figure 3g–i). Additionally, the presence (Figure 3j) or absence of chlamydospores was observed microscopically (Table 1). Isolates from the groups T2, T3, T6, T7, T8, T9, T11, T14, T18, T19, T24 were morphologically and microscopically identified as belonging to the Harzianum clade. Meanwhile, isolates from groups T1, T4, T10, T12, T13, T15, T16, T21, T22, T23, T25 were identified as members of the Viride clade. Isolates from groups T5 and T17 were grouped within Longibrachiatum clade, corresponding to T. longibrachiatum species, while isolates from T20 group were classified within Brevicompactum clade, associated with T. brevicompactum species.\n\na, b: with and without aerial mycelium. c–f: different types of phialides. g–i: different types of spores. j: presence of chlamydospores in Trichoderma asperellum.\n\nMorphological variations were observed among different groups of Trichoderma isolates (Table 1). Illustrations of colonies grown in PDA Petri plates are shown in Plate 1.70 Various diffusible pigments were observed, displaying different colors, which were compared to the Audrey & Bear Color Chart (https://www.audreyandbear.com). In the Harzianum clade, which includes species such as T. afroharzianum, T. lentiforme, T. camerunense, T. inhamatum and T. azevedoi colonies exhibited 1-2 concentric rings with the production of green-colored conidia. No diffusible pigments were detected in PDA medium, and a coconut odor was also not noticeable. The conidia were oval to oblong and ranged from 0.6-4.1μm. Within the Viride clade, comprising species like T. asperellum, T. asperelloides, T. koningii and T. atroviride colonies on PDA displayed a somewhat granular appearance with green and white regions distributed throughout the plate. No diffusible pigments were detected in the PDA medium, but coconut odor was found in some groups and absent in others (Table 1). The conidia were generally round and ranged from 1-4 μm. The T5 and T17 groups of isolates displayed white mycelium with green pustules and produced yellow diffusible pigments, classifying them within the Longibrachiatum clade. Conidia in this group were oblong and ranged from 2-3.9 μm. Isolates from T20 group were challenging to differentiate and were grouped together, with conidia measuring 1.2-2.2μm. Phialides were flask-shaped in both the Harzianum and Viride clades and were present in whorls in almost all species, except in ST3 (T. afroharzianum) and ToT11(T. longibrachiatum), where they were solitary.\n\nThe Harzianum clade was found within an altitudinal range of 80-1800 masl, spanning from lowland plains to hilly regions, and was common in both tropical and temperate regions (Table 2). Similarly, the Viride clade were also identified in both tropical and temperate regions, with altitudes ranging from between 90-1475 masl, which was generally lower than that of the Harzianum clade. Isolates of the T20 group (T. brevicompactum) were primarily located in lowland plains (at 80 masl), rather than in higher mountain region, whereas T. longibrachiatum was primarily found in mid-hill regions, with altitudes ranging from 1300-1500 masl (Table 2). However, morphological characteristics alone proved insufficient for distinguishing between the various Trichoderma isolates. Therefore, molecular identification was required to differentiate among complex and overlapping Trichoderma isolates.\n\nTrichoderma isolates were further identified using molecular sequencing data of ITS rRNA and tef-1α genes. Out of 33 strains, PCR and bidirectional sequencing were successfully completed for 29 presumptive isolates by ITS oligonucleotide barcode identification (OR140790-OR140818) and for only of 26 isolates using tef-1α (OR567133-OR567158). The average consensus sequence length for tef-1α was 663 bp, while for the ITS rRNA, it was 646 bp. Nucleotide BLAST analysis and pairwise alignments of the ITS rRNA and tef-1α sequences identified the Trichoderma isolates as belonging to T. harzianum, T. afroharzianum, T. lentiforme, T. inhamatum, T. camerunense, T. azevedoi, T. atroviride, T. asperellum, T. asperelloides, T. brevicompactum, T. koningii and T. longibrachiatum which shared 97-100% identity match with published sequences in the NCBI database.\n\nThe phylogenetic tree (Figure 4) based on ITS rRNA unambiguously identified 11 species among the 29 isolates, based on their clustering with reference taxa. The isolates identified in the analysis included T. harzianum, T. afroharzianum, T. lentiforme, T. inhamatum, T. camerunense, T. azevedoi, T. asperellum, T. asperelloides, T. brevicompactum, T. koningii and T. longibrachiatum. Although the ITS rRNA tree could not clearly delimit the species resolution of the isolates MT8, ST49, MT5, and PanT1, however there were clear and distinct resolution of other isolates (Figure 4). The phylogenetic tree (Figure 5) obtained from the tef-1α region identified 10 species among the 26 isolates, which included T. afroharzianum, T. lentiforme, T. inhamatum, T. camerunense, T. azevedoi, T. atroviride, T. asperellum, T. asperelloides, T. longibrachiatum and T. brevicompactum. The maximum likelihood phylogenetic tree, based on the concatenated dataset ITS and tef-1α (1352 bp), produced four distinct, well supported clades with bootstrap values higher than 70%: Harzianum, Viride, Longibrachiatum and Brevicompactum clades (Figure 6).\n\nThus, based on above three phylogenetic trees, four clades were identified: Harzianum, Viride, Brevicompactum and Longibrachiatum clades. Eighty-five isolates belonged to the Harzianum clade, consisting of T. afroharzianum (64 isolates), T. harzianum (3 isolates), T. lentiforme (1 isolate), T. camerunense (11 isolates T. inhamatum (5 isolates), and T. azevedoi (1 isolate). The Viride clade included 67 isolates, comprising species such as T. asperellum (57 isolates), T. asperelloides (6 isolates), T. atroviride (1 isolate), and T. koningii (3 isolates). The Longibrachiatum clade comprised 11 isolates, all belonging to the T. longibrachiatum. The Brevicompactum clade consisted of 4 isolates, all of which were identified as T. brevicompactum (Table 3). Among these, T. afroharzianum was the most abundant species in this study, followed by T. asperellum.\n\nAnalysis of the diversity among Trichoderma species\n\nTable 4 shows Simpson’s biodiversity index (D), Shannon’s biodiversity index (H), evenness (J), and the abundance index (E) for various agricultural fields in different ecological zones. The highest species diversity and evennesswere recorded in the high mountain region, with Shannon’s index (H) of 1.724, evenness (J) of 0.84 and Simpson’s index (D) of 0.28). Following this the hilly region which exhibited the Shannon’s index of 1.563, eveness of 0.7 and Simpson’s index of of 0.28. In contrast, the plain region had the lowest species diversity with Shannon and Simpson diversity indices and evenness estimatedto be H = 1.515, J=0.66, D = 0.33. The species abundance values were E = 2.11 for the plain, E = 1.95 for mid-hill and E = 1.99 for the high mountain region. The dominance values (Y) of T. arfoharzianum T. asperellum, T. camerunense and T. longibrachiatum were 0.04, 0.03, 0.01, and 0.01 respectively and they were classified as the principal species. On average, the diversity values for Trichoderma species were H = 1.61, D = 0.29, J = 0.74, and E= 2.02 (Table 4). Simpson’s index (1-D) and the evenness index were close to 1 in all regions except for the plain region, indicating a very high diversity of Trichoderma species in the major agricultural areas of Nepal. The number of species and isolates, as well as the dominant species of Trichoderma, varied geographically (Table 5) revealing that the mid hill and high mountain regions have a high diversity of Trichoderma species.\n\n\nDiscussion\n\nThe remarkable biodiversity found in Nepal can be attributed directly to its unique geographical position, which spans a broad spectrum of altitudinal variances and a wide array of climatic conditions. Consequently, Nepal holds a significant position as one of the world’s important biodiversity hotspots. The fungal genus Trichoderma has been extensively studied for its diverse metabolites and their applications in agriculture, industry and health.6 Its ability to establish beneficial interactions with plants and produce bioactive compounds makes it a valuable resource for sustainable and eco-friendly solutions in multiple sectors.26,27,54 However, there have been very few studies on the diversity of Trichoderma species in Nepal compared to other parts of the world.10,15,35\n\nIn the present study, the isolates of Trichoderma (n = 167) isolated from soils of different ecological zones were categorized into three clades based on their morphological characterization: Harzianum, Viride and Longibrachiatum. However, some isolates were challenging to differentiate and were not assigned to any specific clade (T20). Our observations in terms of morphological characterization align with the previous studies on these species.38,55 The use of a single method for identifying Trichoderma species can present challenges and potential issues. To address this concern, Bissett proposed integration of both morphological and molecular studies.56 This combined approach allows for a more comprehensive and accurate species-level classification within Trichoderma spp. In our study, species were identified following previous studies that utilized ITS and tef-1α sequencing.57 Using molecular approaches, we were able to clearly identify some cryptic species, and we also distinguished isolates that could not be identified solely based on morphological features.\n\nTrichoderma species are typically identified through DNA gene sequence analysis, with the generally accepted practice being the use of two gene sequences. However, recent studies suggest that the identification of new Trichoderma species may require the analysis of at least three DNA gene sequences.58,59 In this particular study, 33 Trichoderma isolates were selected from a pool of 167 isolates isolated from soil samples that were collected from various regions of Nepal (Figures 1 and 2). To identify these isolates, we analyzed two DNA gene sequences: the ITS rRNA and the tef-1α genes. This analysis involved comparing the obtained sequences with those available in the NCBI database using BLASTn analysis. It has been observed that relying solely on individual gene sequences, such as ITS rRNA or tef-1α , is insufficient for accurately distinguishing all Trichoderma species. As a result, we used a combination of ITS rRNA and tef-1α gene sequences, for a more comprehensive understanding of Trichoderma species distribution. In BLASTn searches, ITS sequences did not provide sufficient resolution of Trichoderma phylogeny for some species, such as the T. harzianum complex. However, the concatenated dataset (ITS-tef-1α ) produced four well-supported clades. The resulting tree grouped together the same or closely related species into distinct clades (Figure 2). The comparison of test and conference taxa aligned with earlier reports.12,60,61 The findings revealed similarities among Trichoderma species, with the out-group sequence of Fusarium oxysporum forming dissimilar clusters. Although tef-1α sequencing provided a clear picture of Trichoderma phylogeny, the predominant species complex (T. harzianum complex) comprises multiple cryptic species.62,63 The T. harzianum complex has undergone significant revision in recent times, resulting in the classification of T. harzianum into 14 distinct species.64,65\n\nIn this research, we conducted a comprehensive examination of the diversity of indigenous Trichoderma species found in the rhizospheric soil across different districts of Nepal, taking into account variations in altitude. We assessed Trichoderma species diversity, which is defined as the product of the evenness and the number of species, using the Shannon biodiversity index -H.51 To evaluate the dominance of individual species, we calculated Simpson’s diversity index,50 which indicates the probability that two randomly selected species from a given ecosystem will belong to different categories. We also used Margalef’s abundance index to assess species richness and the Pielou index to determine the evenness of the Trichoderma population. The diversity and occurrence of Trichoderma species reported from different agroclimatic zones of Nepal, namely, the plain (80-141 masl), mid-hill (1284-1650 masl), and high mountain (1800-2500 masl) regions, clearly indicate that climatic topography and soil type are major factors influencing the distribution of Trichoderma species.\n\nThe present study aimed to assess the suitably of several widely used diversity indices for various types of statistical analyses. We conducted both simple and multifaceted statistical analyses to determine if certain indices were better suited for specific types of analyses. Notably, Simpson’s index(1-D) and the evenness index approached 1 in the mid-hill and high mountain regions, except in the plain region. This observation suggests a remarkably high diversity of Trichoderma species in the major agricultural areas of Nepal, particularly in the mid-hill and high mountain regions. This is obvious that mountains and hills have high climatic diversity due to latitudinal variation compared to plain and harbor higher diversity of Trichoderma species compared to plain.\n\nThese findings underscore the substantial diversity of Trichoderma species in these specific regions. Interestingly, Shannon’s index yielded quite similar values (~1.5) in the plain and mid-hill regions, which could be attributed to the extensive disturbance caused by human activities in both regions. The results of this study indicate that Trichoderma spp. diversity and habitat preference can serve as natural indicators of rhizosphere soil health. Moreover, our findings align with the research conducted by Ma49 in Chinese grasslands of China and Mulatu66 in Ethiopian coffee ecosystems. This diversity analysis of Trichoderma strains will facilitate the improved identification of Trichoderma species with biocontrol mechanisms, which can, in turn, contribute to the development of suitable bioformulations in sustainable agriculture.\n\nThe number of Trichoderma species and isolates, as well as the dominant species, varied significantly across different geographical regions. The plain region (80-141 masl) encompasses two districts, Sunsari and Morang. In this region, we identified a total of six different species of Trichoderma: T. afroharzianum, T. lentiforme, T. inhamatum, T. asperellum, T. brevicompactum and T. azevedoi. We found a total of 72 isolates in the plain region, with T. afroharzianum (38 isolates) being the dominant species. The mid-hill region (1284-1650 masl) includes four main districts: Kathmandu, Lalitpur, Bhaktapur, and Kavrepalnchok. Here we identified six different types of Trichoderma species: T. afroharzianum, T. camerunense, T. longibrachiatum, T. asperellum, T. asperelloides and T. atroviride with total of 61 isolates. In the mid-hill region, T. asperellum (26 isolates) was the dominant species. The high mountain region (1800-2500 masl) comprises two districts, Solukhumbu and Sindhupalchok. In this region, we found only four Trichoderma species: T. harzianum, T. afroharzianum, T. asperellum and T. koningii, with a total of 34 isolates. In this region, T. asperellum (16 isolates) was the dominant species. The presence of these Trichoderma species in the rhizospheric soils of vegetables in Nepal can be attributed to the diverse ecological substrates and climate conditions in the country’s vegetable crop growing areas. Our results suggest that these areas provide an optimal environment for the survival and colonization of a diverse group of Trichoderma species. Trichoderma afroharzianum (39.0%) was found to be the most widely distributed and abundant species in our study. The occurrence of Trichoderma species is influenced by various factors, including metabolic diversity, reproductive capabilities, substrate availability and the competitive abilities of Trichoderma isolates in natural ecosystems.\n\nIn the present, we identified nine new country record of Trichoderma species: T. afroharzianum T. harzianum, T. lentiforme, T. inhamatum, T. camerunense, T. atroviride, T. brevicompactum, T. longibrachiatum and T. azevedoi. However, these species have previously been described in regions across the world, including America,63,67,68Asia,10,15,16Africa9,31,66and European Mediterranean countries.23,42 During this study, we reisolated some species, including T. asperellum, T. asperelloides and T. koningii, along with nine additional species. However, two previously reported species, T. rugulosum and T. lixii were not found in this study.10,35 The Harzianum clade contained economically important species such as T. harzianum, T. afroharzianum, T. camerenunse, T. lentiforme and T. inhamatum, which are used in agriculture as biological control agents. The Viride clade included T. asperellum, T. asperelloides, T. koningii and T. atroviride. The Longibrachiatum clade consisted of T. longibrachiatum, while the Brevicompactum clade with T. brevicompactum. T. longibrachiatum has high optimal and maximum growth temperatures and exhibits yellow reverse pigmentation due to the production of secondary metabolites such as pyrone. T. brevicompactum is utilized in the production of various antimicrobial substances, offering significant agricultural, health, and environmental benefits.\n\nIn this study, we obtained isolates of T. harzianum, T. afroharzianum, T. inhamatum, T. lentiforme, T. azevedoi, T. camerunense, T. asperellum, T. asperelloides, T. atroviride, T. koningii, T. longibrachiatum, and T. brevicompactum from various crop ecosystems. Notably, T. afroharzianum and T. asperellum were most widely distributed species in our study. However, previous studies in crop ecosystems in Nepal have reported T. asperellum and T. asperelloides as the most widely distributed species of this genus.35 It is worth noting that among these reported species, only T. asperellum, T. asperelloides and T. koningii have been previously documented in Nepal.10,35\n\n\nConclusion\n\nThis study presents novel findings regarding the presence of Trichoderma species in the Himalayan foothills of Nepal at different altitudes in previously unexplored geographic regions. However, it is important to note that our observations provide only a limited glimpse into the overall diversity of Trichoderma in Nepal. Despite being recognized as a biodiversity hotspot, fungal diversity in this region remains poorly understood. To gain a more comprehensive understanding, further investigations involving the isolation of Trichoderma from various substrates like forest areas and high-altitude areas in Nepal are highly recommended. Such endeavors are likely to unveil a multitude of additional species, some of which may be previously unknown. These new discovered taxa hold significant potential for various biotechnological applications and can contribute to further advancements in this field.\n\n\nAuthor information\n\nAuthors and Affiliations\n\nPuja Jaiswal\n\nCentral Department of Zoology, Tribhuvan University, Kirtipur, Nepal\n\nRam B. Khadka and Suraj Baidya\n\nNational Plant Pathology Research Center, Nepal Agricultural Research Council, Khumaltar, Nepal\n\nAashaq Hussain Bhat\n\nDepartment of Bioscience, University Centre for Research and Development, Chandigarh\n\nUniversity, Punjab, India\n\nArvind Kumar Keshari\n\nDepartment of Zoology, Patan Multiple Campus, Tribhuvan University, Lalitpur, Nepal\n\n\nAuthor’s contributions\n\nPuja Jaiswal conceptualized, did data curation, formal analysis, investigation, methodology, validation and writing original draft. Ram Bahadur Khadka worked on conceptualization, formal analysis, investigation, methodology, project administration, resources, supervision, and validation of the study. Suraj Baidya helped with writing, review and editing the manuscript. Aashaq Hussain Bhat did formal analysis, validation and writing, review and editing the manuscript. Arvind Kumar Keshari conceptualization, project administration, resources, supervision, validation, writing, review and editing the manuscript. All authors read and agree to the final draft of the paper.\n\n\nEthics and consent\n\nThe present study didn’t involve the use of human and animals so ethical approval and consent were not required.", "appendix": "Data availability\n\nThe sequencing data are available on the NCBI Genbank webpage\n\nMorphological and Molecular Characterization of Native Trichoderma isolates from Nepal (OR140790- OR140818; OR567133-OR567158)\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140790; https://www.ncbi.nlm.nih.gov/nuccore/OR140790 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140791; https://www.ncbi.nlm.nih.gov/nuccore/OR140791 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140792; https://www.ncbi.nlm.nih.gov/nuccore/OR140792 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140793; https://www.ncbi.nlm.nih.gov/nuccore/OR140793 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140794; https://www.ncbi.nlm.nih.gov/nuccore/OR140794 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140795; https://www.ncbi.nlm.nih.gov/nuccore/OR140795 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140796; https://www.ncbi.nlm.nih.gov/nuccore/OR140796 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140797; https://www.ncbi.nlm.nih.gov/nuccore/OR140797 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140798; https://www.ncbi.nlm.nih.gov/nuccore/OR140798 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140799; https://www.ncbi.nlm.nih.gov/nuccore/OR140799 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140800; https://www.ncbi.nlm.nih.gov/nuccore/OR140800 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR1407801; https://www.ncbi.nlm.nih.gov/nuccore/OR1407801 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR1407802; https://www.ncbi.nlm.nih.gov/nuccore/OR1407802 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR1407803; https://www.ncbi.nlm.nih.gov/nuccore/OR1407803 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR1407804; https://www.ncbi.nlm.nih.gov/nuccore/OR1407804 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR1407805; https://www.ncbi.nlm.nih.gov/nuccore/OR1407805 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR1407806;https://www.ncbi.nlm.nih.gov/nuccore/OR1407806 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR1407807; https://www.ncbi.nlm.nih.gov/nuccore/OR1407807 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR1407808; https://www.ncbi.nlm.nih.gov/nuccore/OR1407808 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140809; https://www.ncbi.nlm.nih.gov/nuccore/OR140809 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140810; https://www.ncbi.nlm.nih.gov/nuccore/OR140810 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140811; https://www.ncbi.nlm.nih.gov/nuccore/OR140811 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140812; https://www.ncbi.nlm.nih.gov/nuccore/OR140812 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140813; https://www.ncbi.nlm.nih.gov/nuccore/OR140813 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140814; https://www.ncbi.nlm.nih.gov/nuccore/OR140814 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140815; https://www.ncbi.nlm.nih.gov/nuccore/OR140815 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140816; https://www.ncbi.nlm.nih.gov/nuccore/OR140816(Jaiswal et al. 2024)\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140817; https://www.ncbi.nlm.nih.gov/nuccore/OR140817 69\n\nNCBI: Trichoderma Internal Transcribed Spacer RNA (ITS): Accession number OR140818; https://www.ncbi.nlm.nih.gov/nuccore/OR140818 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1): Accession number OR567133; https://www.ncbi.nlm.nih.gov/nuccore/OR567133 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567134; https://www.ncbi.nlm.nih.gov/nuccore/OR567134 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567135; https://www.ncbi.nlm.nih.gov/nuccore/OR567135 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567136; https://www.ncbi.nlm.nih.gov/nuccore/OR567136 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567137; https://www.ncbi.nlm.nih.gov/nuccore/OR567137 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567138; https://www.ncbi.nlm.nih.gov/nuccore/OR567138 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567139; https://www.ncbi.nlm.nih.gov/nuccore/OR567139 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567140; https://www.ncbi.nlm.nih.gov/nuccore/OR567140 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567141; https://www.ncbi.nlm.nih.gov/nuccore/OR567141(Jaiswal et al. 2024)\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567142; https://www.ncbi.nlm.nih.gov/nuccore/OR567142 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567143; https://www.ncbi.nlm.nih.gov/nuccore/OR567143 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567144; https://www.ncbi.nlm.nih.gov/nuccore/OR567144 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567145; https://www.ncbi.nlm.nih.gov/nuccore/OR567145 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567146; https://www.ncbi.nlm.nih.gov/nuccore/OR567146 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567147; https://www.ncbi.nlm.nih.gov/nuccore/OR567147 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567148; https://www.ncbi.nlm.nih.gov/nuccore/OR567148 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567149; https://www.ncbi.nlm.nih.gov/nuccore/OR567149 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567150; https://www.ncbi.nlm.nih.gov/nuccore/OR567150 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567151; https://www.ncbi.nlm.nih.gov/nuccore/OR567151 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567152;https://www.ncbi.nlm.nih.gov/nuccore/OR567152 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567153; https://www.ncbi.nlm.nih.gov/nuccore/OR567153 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567154; https://www.ncbi.nlm.nih.gov/nuccore/OR567154 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567155; https://www.ncbi.nlm.nih.gov/nuccore/OR567155 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567156;https://www.ncbi.nlm.nih.gov/nuccore/OR567156 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1v): Accession number OR567157; https://www.ncbi.nlm.nih.gov/nuccore/OR567157 69\n\nNCBI: Trichoderma DNA sequence of translation elongation factor 1α (tef-1α): Accession number OR567158; https://www.ncbi.nlm.nih.gov/nuccore/OR567158 69\n\nFigshare: Morphological and molecular characterization of Trichoderma isolates from vegetable crop rhizospheres in Nepal; https://doi.org/10.6084/m9.figshare.26380360.v1 69\n\nData are avalilable under the terms of the Creative Commons Attribution 4.0 Internasional license (CC-BY 4.0)\n\nFigshare: Morphological and molecular characterization of Trichoderma isolates from vegetable crop rhizospheres in Nepal; Plate 1. Culture of Trichoderma isolates grown in 28±2°c in potato dextrose agar medium; https://doi.org/10.6084/m9.figshare.26405059.v1 70\n\nData are avalilable under the terms of the Creative Commons Attribution 4.0 Internasional license (CC-BY 4.0)\n\n\nAcknowledgements\n\nAuthors would like to acknowledge NARC-National Plant Pathology Research Center for providing laboratory facilities, and members of NARC- Molecular Plant Pathology Lab for the support to conduct the research.\n\n\nReferences\n\nYobo KS: Biological control and plant growth promotion by selected Trichoderma and Bacillus species. Ph.D. Thesis. Discipline of Plant Pathology, School of Applied Environmental Sciences, Faculty of Science and Agriculture. University of KwaZulu-Natal, Pietermaritzburg, Republic of South Africa.2005.\n\nMukhtar T, Hussain MA, Kayani MZ: Biocontrol potential of Pasteuria penetrans, Pochonia chlamydosporia, Paecilomyces lilacinus and Trichoderma harzianum against Meloidogyne incognita in okra. 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Publisher Full Text Reference Source\n\nSebumpan R, Guiritan KR, Suan M, et al.: Morphological and molecular identification of Trichoderma asperellum isolated from a dragon fruit farm in the southern Philippines and its pathogenicity against the larvae of the super worm, Zophobas morio (Fabricius, 1776) (Coleoptera: Tenebrionidae). Egypt. J. Biol. Pest. Control. 2022; 32: 47. Publisher Full Text\n\nWuczkowski M, Druzhinina I, Gherbawy Y, et al.: Species pattern and genetic diversity of Trichoderma in a mid-European, primeval floodplain-forest. Microbiol. Res. 2003; 158: 125–133. PubMed Abstract \| Publisher Full Text\n\nZachow C, Berg C, Muller H, et al.: Fungal diversity in the rhizosphere of endemic plant species of Tenerife (Canary Islands): relationship to vegetation zones and environmental factors. ISME J. 2009; 3: 79–92. 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PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nChaverri P, Castlebury LA, Samuels GJ, et al.: Multilocus phylogenetic structure within the Trichoderma harzianum/Hypocrea lixii complex. Mol. Phylogenet. Evol. 2003; 27: 302–313. PubMed Abstract \| Publisher Full Text\n\nDruzhinina IS, Kubicek CP, Komon-Zelazowska M, et al.: The Trichoderma harzianum demon: complex speciation history resulting in coexistence of hypothetical biological species, recent agamo species and numerous relict lineages. BMC Evol. Biol. 2010; 10: 94. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLi QR, Tan P, Jiang YL, et al.: A novel Trichoderma species isolated from soil in Guizhou, T. guizhouense. Mycol. Prog. 2013; 12: 167–172. Publisher Full Text\n\nChaverri P, Branco-Rocha F, Jaklitsch W, et al.: Systematics of the Trichoderma harzianum species complex and the re-identification of commercial biocontrol strains. Mycologia. 2015; 107: 558–590.PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMulatu A, Megersa N, Abena T, et al.: Biodiversity of the genus Trichoderma in the rhizosphere of coffee (Coffea arabica) plants in Ethiopia and their potential use in biocontrol of coffee wilt disease. Crops. 2022; 2(2): 120–141. Publisher Full Text\n\nCastle A, Speranzini D, Rghei N, et al.: Morphological and molecular identification of Trichoderma isolates on North American mushroom farms. Appl. Environ. Microbiol. 1998; 64(1): 133–137. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nChaverri P, Samuels GJ: Hypocrea/Trichoderma (Ascomycota, Hypocreales, Hypocreaceae): species with green ascospores. Stud. Mycol. 2003; 48: 1–116.\n\nJaiswal P, Khadka RB, Bhat AH, et al.: Data sheet. Dataset. figshare. 2024. Publisher Full Text\n\nJaiswal P, Khadka R, Bhat AH, et al.: Plate 1. Culture of Trichoderma isolates grown in 28±2°c in potato dextrose agar medium. figshare. Figure. 2024. Publisher Full Text" }	[ { "id": "327961", "date": "04 Oct 2024", "name": "Yunus Korkom", "expertise": [ "Reviewer Expertise Trichoderma", "plant pathology", "biological control", "soil-borne diseases", "fruit diseases", "endophytic fungi", "fungal pathogens" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear Author, The article is well written. But it would be even better with some suggestions below. Best regards,\nComments Introduction “These surveys have been conducted in various locations, including Russia and the Siberian Himalayas,10,11 China,12,13 South-East Asia,14 India,15 Egypt,16 Iran,17 Philippines,18 Europe,19 Canary Islands,20 Sardinia21and South America.22” The following studies conducted in Turkey can be added here.\nKorkom, Y., & Yıldız, A. (2024). First report of Trichoderma guizhouense isolated from soil in Türkiye. Journal of Plant Diseases and Protection, 131(2), 619-625.\n\n“Certain Trichoderma species have been successfully utilized as BCAs, showcasing their antagonistic mechanisms to mitigate damage caused by soil-borne pathogens, both in greenhouse and open field conditions.25–27”\nKorkom, Y., & Yildiz, A. (2022). Evaluation of biocontrol potential of native Trichoderma isolates against charcoal rot of strawberry. Journal of Plant Pathology, 104(2), 671-682.\n\nMethods Isolation and culture of Trichoderma isolates\n“After inoculation, Trichoderma colonies were sub cultured onto potato dextrose agar (PDA) plates and incubated at 28°C for seven days to allow for development and growth.” should replaced with “After inoculation, Trichoderma colonies were sub cultured onto potato dextrose agar (PDA) plates and incubated at 28°C for seven days to allow for growth.”\n\n“Colonies have key characteristics that can be used to identify them as Trichoderma including growth pattern, growth speed, odour and colour.”\nThe odour is not a characteristic feature used to distinguish Trichoderma species and should be removed.\n\n“the Audrey & Bear Color Chart (https://www.audrey and bear.com)” When the given link is opened in the browser, an irrelevant page opens.\n\nMolecular characterization of Trichoderma isolates\n“colonies cultured on potato dextrose agar (PDA) using sterilized” should be replaced with “colonies cultured on PDA using sterilized”\n\n“Promega Wizard genomic DNA extraction kit” catalogue number should be added.\n\n“the internal transcribed spacer” should be replaced with “the internal transcribed spacer (ITS)”\n\nPhylogenetic relationships\n\n“in the NCBI” should be replaced with “in The National Center for Biotechnology Information (NCBI)”\nResults Morphological characterization of single spores of Trichoderma isolates\n“the Audrey & Bear Color Chart (https://www.audreyandbear.com)” When the given link is opened in the browser, an irrelevant page opens. “The maximum likelihood phylogenetic tree, based on the concatenated dataset ITS and tef-1α (1352 bp),” Were the concatenated dataset of 26 isolates used here or 29 isolates? (Figure 6)\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13034", "date": "09 Jan 2025", "name": "Ram Khadka", "role": "Author Response", "response": "Comments Introduction “These surveys have been conducted in various locations, including Russia and the Siberian Himalayas,10,11 China,12,13 South-East Asia,14 India,15 Egypt,16 Iran,17 Philippines,18 Europe,19 Canary Islands,20 Sardinia21and South America.22” The following studies conducted in Turkey can be added here. Korkom, Y., & Yıldız, A. (2024). First report of Trichoderma guizhouense isolated from soil in Türkiye. Journal of Plant Diseases and Protection, 131(2), 619-625. “Certain Trichoderma species have been successfully utilized as BCAs, showcasing their antagonistic mechanisms to mitigate damage caused by soil-borne pathogens, both in greenhouse and open field conditions.25–27” Korkom, Y., & Yildiz, A. (2022). Evaluation of biocontrol potential of native Trichoderma isolates against charcoal rot of strawberry. Journal of Plant Pathology, 104(2), 671-682. Response: As per the recommendation both the studies are cited as 23 ad 29 . Methods Isolation and culture of Trichoderma isolates “After inoculation, Trichoderma colonies were sub cultured onto potato dextrose agar (PDA) plates and incubated at 28°C for seven days to allow for development and growth.” should replaced with “After inoculation, Trichoderma colonies were sub cultured onto potato dextrose agar (PDA) plates and incubated at 28°C for seven days to allow for growth.” Response: As per suggestion sentence is corrected. “Colonies have key characteristics that can be used to identify them as Trichoderma including growth pattern, growth speed, odour and colour.” The odour is not a characteristic feature used to distinguish Trichoderma species and should be removed. Response: We have removed odour as suggested. “the Audrey & Bear Color Chart (https://www.audrey and bear.com)” When the given link is opened in the browser, an irrelevant page opens. Response: The link is corrected as https://audreyandbear.com/products/audrey-bear-color-chart Molecular characterization of Trichoderma isolates “colonies cultured on potato dextrose agar (PDA) using sterilized” should be replaced with “colonies cultured on PDA using sterilized” “Promega Wizard genomic DNA extraction kit” catalogue number should be added. Response: We have added catalogue number as Catalogue No. A1120. “the internal transcribed spacer” should be replaced with “the internal transcribed spacer (ITS)” Phylogenetic relationships “in the NCBI” should be replaced with “in The National Center for Biotechnology Information (NCBI)” Response: Both the above suggestions are incorporated. Results Morphological characterization of single spores of Trichoderma isolates “the Audrey & Bear Color Chart (https://www.audreyandbear.com)” When the given link is opened in the browser, an irrelevant page opens. Response: The link is corrected as https://audreyandbear.com/products/audrey-bear-color-chart “The maximum likelihood phylogenetic tree, based on the concatenated dataset ITS and tef-1α (1352 bp),” Were the concatenated dataset of 26 isolates used here or 29 isolates? (Figure 6) Response: For the concatenation dataset of 22 isolates were used." } ] }, { "id": "331288", "date": "25 Nov 2024", "name": "Raja Asad Ali Khan", "expertise": [ "Reviewer Expertise Mycology", "Biocontrol" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript provides insights into the diversity of Trichoderma species in agricultural zones across Nepal, integrating morphological and molecular approaches. The research is robust and presents significant findings with potential applications in sustainable agriculture. However, a few minor revisions are recommended to enhance clarity and overall quality. Expand briefly on the practical implications of Trichoderma spp. for small-scale farmers in Nepal, considering the local agricultural context. Clarify the criteria used for selecting representative isolates from the initial pool of 167 isolates. This will improve reproducibility. Provide more detail about the statistical analysis software and versions used for diversity index calculations. In Table 1, consider aligning the morphological features with molecular clades for easier interpretation. Expand the discussion on the discrepancies observed between ITS and tef-1α sequencing results, emphasizing their implications for species identification.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "13038", "date": "09 Jan 2025", "name": "Ram Khadka", "role": "Author Response", "response": "Expand briefly on the practical implications of Trichoderma spp. for small-scale farmers in Nepal, considering the local agricultural context. Response: We really appreciate your valuable time to read and provide highly constructive feedback to improve the manuscript. As per the suggestions, the practical implication of Trichoderma in small-scale farmers’ perspectives in Nepal has been added. Please check the fourth paragraph in the introduction section. Clarify the criteria used for selecting representative isolates from the initial pool of 167 isolates. This will improve reproducibility. Response: Thank you for the suggestion, the sentence has been added to the first paragraph of the “Method” section in the “Molecular characterization of Trichoderma isolates” subsection to clarify the selection criteria for 33 isolates for molecular characterization. Provide more detail about the statistical analysis software and versions used for diversity index calculations. Response: The biological diversity indices were computed numerically using the given equations in Microsoft Excel (Excel 2010 (v14.0)). This has been explained. In Table 1, consider aligning the morphological features with molecular clades for easier interpretation. Response: Thank you for the comments, the species indicated in Table 1 are identified through molecular characterization, and the molecular clade group has been added to the table. Please check Table 1. Expand the discussion on the discrepancies observed between ITS and tef-1α sequencing results, emphasizing their implications for species identification. Response: Thanks for the suggestions, a paragraph has been added in discussion section. Please see fourth paragraph in discussion section." } ] } ]	1	https://f1000research.com/articles/13-1088
https://f1000research.com/articles/14-45/v1	08 Jan 25	{ "type": "Research Article", "title": "Comparison of sagittal measurements of cervical spine in spondylosis patients between Magnetic Resonance Imaging and Radiograph", "authors": [ "Maria Nicolet", "Priyanka -", "Rajagopal Kadavigere", "Shailesh S Nayak", "Saikiran Pendem", "Surbhi Gupta Aggarwal", "Tancia Pires", "Varsha R", "Maria Nicolet", "Surbhi Gupta Aggarwal", "Tancia Pires", "Varsha R" ], "abstract": "Background Cervical spondylosis is the common degenerative disease of the vertebrae in adults which can lead to change in sagittal alignment of cervical spine. Radiograph and Magnetic resonance imaging (MRI) are widely used imaging modalities for measuring the sagittal parameters. However sagittal parameters measured using radiograph and MRI can be influence by patient positioning and imaging technique. The study aims to compare sagittal parameters measured using MRI (Magnetic Resonance Imaging) and radiograph in cervical spondylosis patients.\n\nMethods The study was done retrospectively. 77 patients who underwent both MRI and radiograph were included in the study. The sagittal parameters such as Neck Tilt (NT), T1 slope (T1S), thoracic inlet angle (TIA), C2-C7 angle (C2-C7A) and C2-C7 sagittal vertical axis (C2-C7 SVA) were measured on sagittal MRI and lateral cervical spine radiograph. Paired t-test was used to compare cervical sagittal measurements between MRI and radiography.\n\nResults The cervical sagittal parameters such as NT, T1S, TIA and C2-7 SVA showed significant difference between MRI and radiograph (p < 0.05). But C2-C7A did not show significant difference (p > 0.05)\n\nConclusion The study concludes that MRI cannot be used as an alternative to cervical spine radiograph in spondylosis patient for measuring the sagittal balance as there was significant difference between sagittal parameters except C2-C7 A.", "keywords": [ "Cervical spine", "Cervical spondylosis", "Sagittal parameters", "Magnetic Resonance Imaging", "Radiograph" ], "content": "Introduction\n\nThe cervical spine has the greatest range of motion in comparison to the rest of the spine and supports the weight of the head. Because of the intricacy of the cervical spine, it is prone to disease, including deformity.1 Cervical spondylosis is the common degenerative disease of the vertebrae in adults. It is predicted that more than 85% of adults over the age of 60 will exhibit some evidence of cervical spondylosis on imaging tests, however all will not develop symptoms. Common cause of cervical spondylosis is aging, as we age the vertebral disc gets dissecated which reduces the spaces between the vertebral disc. This can result in pain, difficulty in movement and nerve damage. These degenerative changes can lead to the modification of cervical spine particularly the sagittal alignment.2–4\n\nSagittal alignment refers to the shape of the spine which is the sum of the shapes in the spine, discs, and muscle. Accurate measurement of cervical sagittal parameters such as thoracic inlet angle (TIA), neck tilt (NT) and T1 slope (TS) and sagittal vertical axis (SVA) are crucial for understanding the management of cervical spondylosis, eventually leading to better clinical results and higher patient quality of life.5–7\n\nRadiographs (X-rays) and magnetic resonance imaging (MRI) are the imaging modalities used for measuring the sagittal parameters of c-spine. Radiographs are a rapid and cost-effective way to visualize bony structures and alignment, but MRI gives comprehensive details of both bony and soft tissue components, including intervertebral discs and the spinal cord. Despite their widespread usage, there may be inconsistencies in the sagittal parameters evaluated by radiography and MRI due to variances in patient posture, imaging procedures, and intrinsic modality-specific properties.4,8,9\n\nCurrently few studies focus on the use of radiography or MRI individually for measuring the cervical sagittal parameters. However, no studies have directly compared the sagittal parameters between these two imaging modalities in cervical spondylosis. Such comparisons are required to assess if measurements from radiographs, which are more easily available in many clinical situations, can consistently replace those acquired from MRI.\n\n\nMethods\n\nThis is a retrospective study. Approvals for the study was obtained from Institutional Research Committee (IRC) and Institutional Ethical Committee (IEC2-159-2022) of Kasturba Medical College and Hospital, Manipal, India on 12th May 2022. We used the STROBE reporting guidelines for our study; a completed checklist is available under Reporting Guidelines.10 As this is a retrospective study, the data was collected from the patients who had undergone lateral radiograph in standing and MRI of C-spine in supine position within a time of one week between January 2016 to September 2022.\n\nA total of 77 cervical spondylosis patients who had undergone lateral radiograph in standing and MRI of C-spine in supine position within a time of one week between January 2016 to September 2022 were included in the study. All the patients had undergone radiograph using computed radiography system (CR X-ray Wipro GE®, TM) and MRI using Philips Achieva®, TM (1.5 T MRI). The sagittal T2 weighted MRI and lateral C-spine radiographic images were retrospectively retrieved from PACS (picture-archiving and communication system). The exclusion criteria included the following: patients with cervical spine surgeries, cervical spine deformity caused by fractures, tumour, infection or congenital disorders, neuromuscular disorder, spondylolisthesis and ankylosing spondylitis.\n\nThe cervical parameters such as NT, T1S, TIA, C2-C7 angle and C2-C7 SVA were measured on cervical lateral radiograph and sagittal T2 weighted MRI using measuring tool in PACS. All the measurements were done independently by the two readers and the average value was taken as final measurement.\n\nNT is the angle formed by “vertical line passing through the upper end of the sternum and a line connecting the centre of the first thoracic upper endplate (T1UEP) and the upper end of the sternum” ( Figure 1). T1S is the “angle formed between the horizontal plane and the T1UEP” ( Figure 2). TIA is the “angle formed by a line from the centre of the T1UEP vertical to the T1UEP and a line connecting the centre of the T1UEP and the upper end of the sternum” ( Figure 3). C2-C7A is the “angle between the horizontal line of the C2 lower endplate and the horizontal line of the C7 lower endplate” ( Figure 4). C2-C7 SVA is the “horizontal offset from the centre odontoid process (dens) to the centre of the vertebral body of seventh cervical spine (C7)” ( Figure 5).11\n\nStatistical analysis of the data was performed using Jamovi-2.3.28.0 https://www.jamovi.org/. Paired t-test was used to compare cervical sagittal measurements between MRI and radiography. The ‘p’ value less than 0.05 was considered as significant (α = 0.05).\n\n\nResults\n\nThe study included a total of 77 patients out of which 39 of them were female and 38 were male who had undergone both C- spine MRI and lateral c-spine radiograph with the history of cervical spondylosis. The age was ranging from 25 to 71 years with mean age of the patient was 45 ± 11.22 years. The demographic details of the study participants are shown in Table 1.\n\nCervical sagittal parameters such as NT, T1S, TIA, C2-C7 Angle and C2-C7 SVA was measured on MRI and X-ray image. Mean, standard deviation (SD) and difference in mean value of cervical parameters measured on MRI and radiograph was calculated and is shown in Table 2.\n\nSagittal parameters such as NT (MRI: 53.91 ± 11.61; Radiograph: 49.31 ± 8.67), T1S (MRI; 23.90 ± 7.13; Radiograph: 26.23 ± 3.79), TIA (MRI: 70.55 ± 12.20; Radiograph: 74.12 ± 10.65) and C2-C7 SVA (MRI: 6.55 ± 4.01; Radiograph: 9.15 ± 6.36) showed statistically significant difference between MRI and radiograph (p < 0.05). However, C2-C7 A measurement did not show statistically significant difference between MRI (15.37 ± 5.86) and radiography (15.87 ± 7.52) ( Table 1).\n\n\nDiscussion\n\nThe MRI and X-ray are the crucial imaging modalities used for the evaluation of degenerative changes in spine. In the present study the cervical sagittal measurements were compared between MRI and X-ray in cervical spondylosis patients.12,13 The following parameters such as NT, TIA, T1S, C2-7A and C2-7SVA were measured on both X-ray and MRI. The results of our study are compared with few other studies and the mean values are shown in the Table 3.\n\nMost of studies showed significant difference in sagittal parameters measured using MRI and radiograph which was similar to the findings of our study ( Table 3). Theses difference in measurement could be due to the position of the patient as MRI examination will be done with patients in supine position and radiograph will be done with patient in standing position.\n\nIn a study done by Lee et al., the mean value of T1S and C2-C7 SVA was higher compared to current study. However, in a study by Xing et al., the mean value of TIA, T1S and NT was lower compared to our study in MRI and radiograph. The difference between the mean values of the parameters in both the studies were since the values were measured on asymptomatic and our study had symptomatic patients.14,15 Bernstein et al., all segments of the MRI had better visibility between 70 and 100%, with the upper thoracic regions having the maximum visibility at 98 to 100%. Kyphosis angles could not be assessed in X-ray images because of the structures that obscured the higher thoracic structures, but no such issues existed in MRI.16\n\nCheng et al., conducted a study in which NT, T1S, TIA, C2-C7A and C2-C7 SVA was measured both on MRI and radiograph.11 Zhang et al., conducted a study, parameters such as T1S and C2-C7 SVA was measured in straightened group and lordosis group.17 There is no disagreement on both the studies because the mean difference between their study and our study is remarkably similar. Park et al. investigated a study, the mean value of NT, T1S, TIA and C2-7A were measured. However, NT was higher in MRI in our study compared to their study. As MRI and CT are carried out in similar positions (supine), the mean of NT, T1S, TIA and C2-7A matched MRI but not radiograph.18 Xing et al., the mean value of C2-C7 SVA was higher compared to our study and the NT, T1S and TIA value was similar to our study.15 Yang et al. conducted a study on patients with neck pain, radiculopathy, and myelopathy. Measurements were done on MRI and radiograph. The mean of TIA and C2-C7 SVA were 76.07±9.54° and 21.34±11.42 mm respectively.19 The mean value of TIA was almost similar compared to our study and the C2-C7 SVA was high compared to our study because in contrast to their work, the C2-C7 SVA that was assessed in our investigation was different.\n\nThe study has few limitations. The data was collected retrospectively, and therefore only limited patient’s clinical history was available. Secondly, the difference in measurement of sagittal parameters with age was not assessed. Future prospective studies can be performed with the age group classification.\n\n\nConclusion\n\nMRI cannot be used as alternative for C-spine radiograph for measuring the sagittal balance in cervical spondylosis patient as most of the sagittal parameters shows significant difference except for C2-C7 Angle. Therefore, standing C-spine lateral radiograph must be taken in patients with cervical spondylosis to measure the sagittal balance in addition to the MRI C-spine.\n\n\nEthics and consent\n\nThis is a retrospective study. Ethical approval was obtained from the Institutional ethical committee (IEC2:159/2022) of Kasturba Medical College and Hospital, Manipal India on 12th May 2022. This study aligns with the Declaration of Helsinki. The consent was wavied by ethical approval committee, as this is a retrospective study.\n\nAs this is a retrospective study, the data was collected from the patients who had undergone lateral radiograph in standing and MRI of C-spine in supine position within a time of one week between January 2016 to September 2022.", "appendix": "Data availability\n\nFigshare: F1000 Data of Cervical Spine, https://doi.org/10.6084/m9.figshare.28080251.v1.20\n\nThis project contains the following underlying data:\n\n• X-ray images of C Spine\n\n• MRI images of C spine\n\n• X-Ray and MRI C spine sagittal measurements (Excel sheet)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nFigshare: We used STROBE checklist for “Comparison of sagittal measurements of cervical spine in spondylosis patients between Magnetic Resonance Imaging and Radiograph”. https://doi.org/10.6084/m9.figshare.28080371.v1.10\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nScheer JK, Lau D, Ames CP: Sagittal balance of the cervical spine. J. Orthop. Surg. 2021; 29(1_suppl). Publisher Full Text\n\nAmes CP, Blondel B, Scheer JK, et al.: Cervical radiographical alignment: Comprehensive assessment techniques and potential importance in cervical myelopathy. Spine (Phila Pa 1976). 2013; 38(38): S149–S160. Publisher Full Text\n\nLamartina C, Berjano P: Classification of sagittal imbalance based on spinal alignment and compensatory mechanisms. Eur. Spine J. 2014; 23(6): 1177–1189. PubMed Abstract \| Publisher Full Text\n\nLee SH, Hyun SJ, Jain A: Cervical sagittal alignment: Literature review and future directions. Neurospine. 2020; 17: 478–496. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLe Huec JC, Thompson W, Mohsinaly Y, et al.: Sagittal balance of the spine. Eur. Spine J. 2019; 28: 1889–1905. Publisher Full Text\n\nAbelin-Genevois K: Sagittal balance of the spine. Orthop. Traumatol. Surg. Res. 2021; 107: 102769. Publisher Full Text\n\nRydman E, Bankler S, Ponzer S, et al.: Quantifying cervical spondylosis: Reliability testing of a coherent CT-based scoring system. BMC Med. Imaging. 2019; 19: 1–9.\n\nXing R, Liu W, Li X, et al.: Characteristics of cervical sagittal parameters in healthy cervical spine adults and patients with cervical disc degeneration. BMC Musculoskelet. Disord. 2018; 19: 10–15.\n\nLee HD, Jeon CH, Chung NS, et al.: Comparative Analysis of Three Imaging Modalities for Evaluation of Cervical Sagittal Alignment Parameters. Spine (Phila Pa 1976). 2017; 42: 1901–1907. PubMed Abstract \| Publisher Full Text\n\nPriyanka: Comparison of sagittal measurements of cervical spine in spondylosis patients between Magnetic Resonance Imaging and Radiograph. Strobe checklist. figshare. 2024.\n\nCheng J, Liu P, Sun D, et al.: Correlation of cervical and thoracic inlet sagittal parameters by MRI and radiography in patients with cervical spondylosis. Med (United States). 2019; 98: e14393. Publisher Full Text\n\nReddy MM, Gangavelli R, Priyanka P, et al.: Influence of Lumbar Spinal Canal Dimensions on Neurological Claudication Symptomatology- A Case Control Study. Biomed. Pharmacol. J. 2021; 14(2): 1019–1024. Publisher Full Text\n\nMuhaimil A, Pendem S, Sampathilla N, et al.: Role of Artificial intelligence model in prediction of low back pain using T2 weighted MRI of Lumbar spine. F1000Res. 2024; 13: 1035. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLee JS, Youn MS, Shin JK, et al.: Relationship between cervical sagittal alignment and quality of life in ankylosing spondylitis. Eur. Spine J. 2015; 24: 1199–1203. PubMed Abstract \| Publisher Full Text\n\nXing R, Zhou G, Chen Q, et al.: MRI to measure cervical sagittal parameters: a comparison with plain radiographs. Arch. Orthop. Trauma Surg. 2017; 137: 451–455. PubMed Abstract \| Publisher Full Text\n\nBernstein P, Hentschel S, Platzek I, et al.: The assessment of the postoperative spinal alignment: MRI adds up on accuracy. Eur. Spine J. 2012; 21: 733–738. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nZhang L, Cheng Z, Cui Z, et al.: Analysis of cervical sagittal parameters on MRI in patients with cervical spondylotic myelopathy. Chinese J. Reparative Reconstr. Surg. 2017; 31: 451–454.\n\nPark JH, Cho CB, Song JH, et al.: T1 slope and cervical sagittal alignment on cervical CT radiographs of asymptomatic persons. J. Korean Neurosurg. Soc. 2013; 53: 356–359. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nYang K, Li XY, Wang Y, et al.: Relationship between TIA minus C0-7 angle and C2-7 SVA: analysis of 113 symptomatic patients. BMC Musculoskelet. Disord. 2022; 23: 1–9.\n\nPriyanka: F1000 Data of Cervical spine. Dataset. figshare. 2024. Publisher Full Text" }	[ { "id": "358481", "date": "23 Jan 2025", "name": "Jaseemudheen MM", "expertise": [ "Reviewer Expertise Medical Imaging" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe full form of MRI is provided in the background (first part of the abstract). The repetition of MRI full form in brackets can be avoided in the same section. Mention the abbreviation alone. The table number was provided wrongly (Last paragraph: Result section) Check and correct the following sentence (Discussion): However, in a study by Xing et al., the mean value of TIA, T1S, and NT was lower compared to our study in MRI and radiograph. The difference between the mean values of the parameters in both the studies were since the values were measured on asymptomatic and our study had symptomatic patients.14,15\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] }, { "id": "358489", "date": "05 Feb 2025", "name": "Tarek Aly", "expertise": [ "Reviewer Expertise spinal disorders" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear authors, thanks for giving me the opportunity to read your valuable manuscript. It is a very important subject which is still unclear in the literature. Some points in the manuscript needs to be clarified: Title Radiography usually used for plain x-ray and CT. So, it is better to change to plain X-Ray. Results Last line in results section: (Table 1) this table for demographics only!!>>>>>>> (Table2) Discussion Line 6: similar to the findings of our study ( Table 3). Theses (These) difference …..\nYou did not mention about the difference in measurements regarding the gender, and different age groups??\nTables Table 1 did not add any information, so, it is better to be omitted.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] } ]	1	https://f1000research.com/articles/14-45
https://f1000research.com/articles/14-44/v1	08 Jan 25	{ "type": "Systematic Review", "title": "Exploring the clinical utility of postural outcome tools for back and neck pain clinical outcomes: a systematic scoping review", "authors": [ "Chinonso N Igwesi-Chidobe", "Esther U Anih", "Grace N Emmanuel", "Benjamin C Ozumba", "Esther U Anih", "Grace N Emmanuel", "Benjamin C Ozumba" ], "abstract": "The role of posture in spinal pain is unclear which might be linked to characteristics of postural outcome measures. This systematic scoping review mapped the clinical utility of postural outcome tools for spinal pain. Following Joanna Briggs Institute framework, twelve bibliographic databases were searched until 8th August 2023. Article selection, characterisation/mapping and synthesis using qualitative content analysis were performed by two independent reviewers. Clinical utility was defined by psychometric and clinimetric criteria. 85 eligible studies were identified from 89 publications. Twenty-eight distinct postural outcome tools plus bespoke measures were identified. Most tools were sophisticated computer-based electronic devices or complex time-consuming questionnaires, with limited applicability in non-occupational settings. Clinical utility domains most achieved were construct validity and inter/intra-rater reliability. Tools being underpinned by the biopsychosocial model of pain, sensitivity to clinical change, and predictive validity were the least achieved. Tools had limited clinical utility and were based on postural-structural-biomechanical pain model.", "keywords": [ "Outcome measures/tools", "Clinical utility", "Posture", "Postural outcome measures", "Spinal pain", "back pain" ], "content": "Practitioner summary\n\nThe unclear clinical relevance of posture in spinal pain may be linked to postural measurement. This scoping review mapped the clinical utility of postural outcome tools in spinal pain. Tools had limited clinical utility and were underpinned by postural-structural-biomechanical pain model rather than the biopsychosocial model underpinning spinal pain management.\n\n\nIntroduction\n\nGlobally, back and neck pain are leading causes of disability-adjusted life-years (DALYs) in the working population.1 The role of postural factors in first onset of pain and perpetuation of symptoms and disability are unclear and conflicting.\n\nSystematic reviews of longitudinal studies have found that increased and prolonged trunk flexion and twisting were associated with first onset low back pain (LBP).2–7 However, different thresholds were used in quantifying postural exposure which may explain the conflicting dose-response relationships. Prolonged kneeling or squatting were more likely to predict new onset LBP in newly employed workers,8 but the definition of prolonged duration appeared arbitrary and may have varying impact in different individuals. Bending and twisting were found to be associated with adverse employment outcomes such as leaving jobs and the inability to carry out normal duties,9 and may affect functional health in retirement.10\n\nInappropriate home postural habits (e.g., slumped sitting) were associated with acute LBP amongst adolescents in a cross-sectional study.11 However, majority of the adolescents frequently changed their position and did not have a preferred position.11 These results aligned with another cross-sectional study which found that sitting posture with increased kyphosis with crossed legs was associated with acute LBP; whilst sitting posture with upper back support and lumbar strain, with the feet supported on the floor was positively associated with chronic LBP.12 Duration of computer use was associated with acute and chronic LBP whilst supporting the hip and thigh in the seat were negatively associated with acute LBP.12\n\nA systematic review with meta-analysis of cross-sectional studies between 2009-2017 found that adults with neck pain have increased forward head posture compared with asymptomatic adults and that forward head posture is associated with neck pain outcomes in adults but not in adolescents.13 However, the direction of relationships is unclear, and posture might have been a consequence rather than a cause of neck pain. Unclear associations between posture and back pain was found in another cross-sectional study which found that neither children without back pain nor children with back pain had normal lumbar kyphosis or normal lumbosacral angle according to normality reference values.14 These findings suggest that normality reference values may be different in diverse people and that postural factors may be less important before adulthood. In concurrence, a cross-sectional study that acknowledged neck posture clusters found that none of the four distinct clusters of sitting neck posture (upright, intermediate, slumped thorax/forward head, and erect thorax/forward head) were associated with the odds of having neck pain amongst adolescents.15\n\nSome authors in high income countries have disputed the relevance of postural factors in predicting spinal pain outcomes due to lack of clear links to changes in anatomical structures.16 Other authors have concluded that any associations between posture and spinal pain outcomes are at best meagre, and that the direction of relationship is likely consequential rather than causative.17 Our previous population-based cross-sectional studies in Nigeria showed no clear associations between postural factors, and back and neck pain outcomes, although results might have been due to the way postural factors were measured and analysed.18–20 A cross-sectional study in Australia found significant differences in the perception of ‘good’ posture between people with and without postural neck pain but there was no difference between the habitual posture they adopted.21 The people with neck pain were individuals who perceived good neck posture as one with increased head protraction,21 possibly suggesting some postural control issues.\n\nThe impact of postural interventions might help to clarify the role of postural factors on back and neck pain outcomes. Unfortunately, the effectiveness of postural interventions in preventing or treating spinal pain is equivocal. A systematic review found limited and inconsistent evidence for the effectiveness of screening tools and the interventions guided by these tools in preventing musculoskeletal injuries, or reducing musculoskeletal discomfort, work absence, claims costs and health resource utilization, and improving safe workplace behaviour and self-rated health status.22 Notably, the studies included in this systematic review used different purpose-built non-validated outcome tools.22 In contrast, a recent high quality 3-arm, parallel-group cluster randomised controlled trial (RCT) that adjusted for biopsychosocial factors found that interventions that increased either active breaks or postural shifts reduced new onset of neck and back pain among high-risk office workers.23 Although this trial was placebo-controlled and active break and postural shifts were measured, the analyses did not link the reduction in new onset of neck and back pain to changes in postural factors making it difficult to pinpoint the contribution of postural factors to prevention of neck and back pain.23\n\nCognitive functional therapy (CFT) is a flexible and integrated biopsychosocial behavioural approach for individualizing the management of disabling LBP.24 CFT targets biopsychosocial factors such as external physical factors, internal physical factors, psychological factors, social factors, and lifestyle factors. The external physical factors include the levels and patterns of spinal loading, and awkward bending and twisting during daily life activities.24 CFT acknowledges “central” (central nervous system amplifies pain or perceives non-painful stimuli as painful), “peripheral” (“mechanical stimulus–pain response” i.e. pain is momentarily provoked and relieved by specific spinal postures, movements and activities) or mixed (central sensitisation subsequently facilitates posture and movements that aggravate pain) pain mechanisms. These pain mechanisms are then targeted and corrected in a reflective rather than a prescriptive process in the CFT.24 However, there is no evidence that a reduction in the exposure to postural risk factors which is targeted by the CFT contributed to the improvement in clinical outcomes associated with the CFT. This is because changes in the exposure to postural risk factors were either not measured25–31 or there were no changes in posture before and after CFT despite improvements in clinical outcomes.32\n\nThe evidence for the effectiveness of other postural rehabilitation programmes is also conflicting. Postural rehabilitation exercise programmes were effective in reducing pain intensity and disability which could not be linked to improvements in posture as no postural outcome was measured.33 Pilates exercise programme which targeted static posture and postural habits reduced severity of temporomandibular pain but had no effect on posture, postural habits, neck and back pain in young women with temporomandibular dysfunction.34 A pretest-posttest study investigated the effect of a 4-week self-stretching exercises on postural improvements in patients with chronic neck pain caused by forward head posture and found that this reduced muscle activity and changed neck alignment. However, the definition of optimal neck posture was unclear and could not be linked to the improved outcomes reported in that study.35 More recent research has been moving towards postural awareness36,37 or postural balance, postural realignment and rebalancing rather than specific ‘good’ or ‘bad’ postures.38,39 A study defined postural impairment as impaired proprioception without visual feedback.38\n\nThe overall conflicting evidence regarding the role of postural factors in spinal pain may be suggesting that there are no universal ‘good’ and ‘bad’ postures for back and neck pain as these may be different in different people. Moreover, posture may not even be an aggravating factor in some people. The evidence may also be suggesting that different postural habits may be associated with new onset back and neck pain, or aggravation of existing spinal pain in different ways in different people. Therefore, evidence-based postural outcome tools could focus on individuals being sensitive to their bodies to identify aggravating postures, and aggravating duration of sustained static positions, how much time is spent in regular movement and adoption of individually relieving postures and movement strategies as self-management strategies whilst acknowledging relevant biopsychosocial factors. This aligns with the evidence-based biopsychosocial model of spinal pain40–43 and the evidence-based recommendations for symptomatic relief during spinal pain episodes to increase participation in social, occupational, and recreational activities.44–46 It is unclear to what extent existing postural outcome tools align with these evidence-based recommendations, which might explain the conflicting findings regarding the role of postural factors in back and neck pain clinical outcomes.\n\nThis systematic scoping review aimed to map and summarise the clinical utility of existing outcome tools for measuring exposure to postural risk factors for back and neck pain clinical outcomes. These clinical outcomes included but were not limited to first onset of back and/or neck pain, chronicity/perpetuation of symptoms, pain including the nature and intensity, disability etc.\n\n\nMethods\n\nThis study followed the Joanna Briggs Institute (JBI) Manual for Evidence Synthesis (last update on 27 July 2023) procedures for scoping reviews47 which is detailed below. This paper is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Extension for Scoping Reviews (PRISMA-ScR) guidelines.48\n\nThis study was initially planned to be a systematic review and registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42022321427). The study protocol was subsequently modified following extensive internal and external discussions which highlighted the fact that the objectives of this study better aligned with a scoping review methodology.49,50\n\nIn summary, published full articles of primary studies that used postural outcome tools targeted at preventing first onset of mechanical back or neck pain in people without back or neck pain, or at improving clinical outcomes amongst people who already have mechanical back and/or neck pain were included. Unpublished primary studies, studies of people whose back or neck pain were due to underlying serious pathology, studies without primary data or not published in English were excluded. The illustration in Figure 1 summarises the eligibility criteria.\n\nInclusion criteria\n\n1. Population: All primary studies with human participants of all ages and gender with or without mechanical back and/or neck pain but with exposure to the postural risk factors for mechanical back and neck pain clinical outcomes. In populations without back and/or neck pain, the studies were aimed at preventing back and/or neck pain. Studies involving participants with back pain or neck pain were deemed eligible due to the nature of these conditions. As highlighted in the introduction, similar biopsychosocial factors are associated with first onset of back or neck pain, and subsequent transition to chronic back or neck pain and disability. Furthermore, these factors are the focus of interventions aimed at either preventing the first onset of back or neck pain, or to reduce chronicity and disability in people who already have back or neck pain.\n\n2. Concepts: For this study, posture was defined as the alignment or orientation of the body segments in space either whilst static such as standing, sitting, or lying down or during movement such as walking, running, or bending over.51,52 Postural outcome tool was defined as any tool or procedure that was utilised to measure or assess posture. The definition of clinical utility for this study was informed by a review of the psychometric and clinimetric criteria.53–56 Clinimetrics is the science of clinical measurements which is related to the identification of a clinical disorder and its causal variables, the tracing of the progression of the condition, and calculating its impact. Clinimetrics is a clinically based evaluation method whilst psychometrics is concerned with the theory and general techniques of measurement.56,57 The clinimetric and the psychometric approach are not contradictory, but serve different purposes, and emphasize different things. The clinimetric approach is required for the development of instruments that measure multiple constructs with a single index as observed in general clinical practice. In contrast, the psychometric approach is necessary to develop instruments that measure a single construct using multiple items which is common in psychology. The multiple constructs measured by the clinimetric approach usually include the causal variables associated with a health condition. In contrast, the single construct measured by the psychometric approach are usually indicator variables that correlate with the underlying construct to be measured but may not have causal relationships with this construct. Another difference is that clinimetrics is more content driven (with more focus on patient and clinician input or perspectives) whilst psychometrics is more statistically driven. In contrast to measures also informed by the clinimetric criteria, tools that exclusively focus on the psychometric criteria may have limited clinical applicability due to associated item redundancy where multiple items measure a single construct combined with increased length of administration.56 Limited attention to clinical utility and sensitivity in the clinical environment are other limitations of exclusively using the psychometric criteria.56 However, in terms of validity, reproducibility, or responsiveness, the differences between clinimetric and psychometric approaches become less obvious.58 For this review, the concept of clinical utility was defined as the extent to which the postural outcome tools can detect or predict symptom changes and treatment outcomes (construct validity, predictive validity, intra and inter rater reliability, sensitivity to change); the level of ease with which the tools can be potentially applied in clinical settings for practice or research (the ease of use – if training is required to use the tool and if specialist equipment required), the ability of the tool to facilitate clinician-patient interaction and collaboration (sensibility); and the format of the tool e.g., length of assessment, wording of items, and response format or calibration of items.56,59,60 Furthermore, as the biopsychosocial model which acknowledges that cognitive, emotional, psychological, behavioural, physical and social factors interact to perpetuate pain,18,61,62 is the evidence-based approach underpinning current spinal pain management, the model underpinning each postural outcome tool (postural-structural-biomechanical model of pain based on the assumption that there are specific correct and wrong postures, or a biopsychosocial model of pain based on the assumption that postural aggravating factors are different in different individuals and may require individuals to identify what these are and actively modify exposure to identified aggravating postural factors)24–26 was also included within the definition of clinical utility. Construct validity was defined as the extent to which an instrument measures the construct it was intended to measure.63,64 Predictive validity was defined as the ability of the outcome tool to predict a longitudinal response to treatment and clinical outcomes.56 Sensitivity to change was defined as the ability of a measure to detect subtle change and thereby discriminate patient groups, detect treatment effects and differentiate active treatment effects from placebo (in contrast to responsiveness which is the ability of an instrument to detect change over time).56\n\n3. Outcomes: All outcome tools and methods utilised to measure posture amongst people with back and/or neck pain (studies measuring treatment effects) and amongst people without back and/or neck pain (studies measuring the success of preventing back or neck pain) were eligible.\n\n4. Context: There was no restriction based on the setting for the application of the tools in the primary studies. All settings (clinical, school, occupational, community settings etc.) were eligible for inclusion.\n\n5. Study design: All primary studies that involved measurements using any postural outcome tool or method for people with back and/or neck pain were eligible for inclusion. Studies aimed at preventing back and neck pain in individuals without existing spinal pain using postural interventions are eligible for inclusion if they utilised a postural outcome tool for the cervical and/or lumbar spinal regions.\n\n6. Timing of assessment: There were no restrictions based on the timing of postural assessment.\n\n7. Language: Only studies published in English were eligible due to cost restrictions.\n\nExclusion criteria\n\nStudies in which all the included participants had back and/or neck pain which was due to serious underlying pathology such as radiculopathy, spinal stenosis, ankylosing spondylitis, rheumatoid arthritis or other inflammatory diseases, cauda equina syndrome, progressive paresis, fracture, suspected tumour, or local infection were excluded. Studies without a full report such as those published only as abstracts, and unpublished studies including those published in research repositories without peer review were excluded. Studies published as abstracts were excluded because of limited reported data regarding clinical utility and study characteristics. Exclusion of unpublished studies was to ensure that the postural outcome tools were already available for use and that the clinical utility data reported were peer reviewed.\n\nPubMed, CINAHL, CENTRAL, Global Index Medicus, African Index Medicus, African Journal Online, WPRIM (Western Pacific Region Index Medicus), LILACS (Latin American and Caribean Centre on Health Science Information), IMEMR (Index Medicus for South-East Asia Region), IRIS (WHO digital publications), and BLDS (British Library for Development Studies) were searched from inception up to 8th August 2023. Additional studies were retrieved from Google scholar and the reference list of relevant studies including systematic reviews.\n\nThe search strategies for the databases were informed by the Cochrane handbook,65,66 JBI framework,49,50 and PRISMA 2020 guidelines.67,68 The searches involved the combination of MeSH and free text terms and word variants for posture, spinal pain, back and neck pain, postural interventions, and outcome measurement. The search strategies (published as extended data)69 were piloted and adapted to improve sensitivity and specificity before final use.\n\nScreening of articles for eligibility was done in two phases. The first phase involved EUA and GNE independently screening the titles and abstracts of published papers for those that meet the inclusion criteria. Papers that met the eligibility criteria at this stage were moved to the second phase of screening. Disagreements at this stage were resolved by moving those papers to the second phase of screening. The second phase of screening involved EUA and GNE independently reading through the full texts of articles to confirm their eligibility. Disagreements regarding the inclusion of a study at this stage were resolved by discussions with CNI-C. Details of the study process is illustrated in a flow chart ( Figure 3).\n\nCNI-C developed the data charting form. CNI-C and EUA piloted the data charting form by independently extracting data from a random sample of studies including three observational studies and three intervention studies. CNI-C and EUA discussed inconsistencies in extracted data and improvements were subsequently made to the form to align with the objectives of the study. Data charting is the process of data extraction in a scoping review.50,70–73 First, we conducted a narrative (literal) extraction of study characteristics (from the studies included in this review) including authors’ citation, country in which the study was conducted, participants’ characteristics, study sample size, study design, the name of the outcome measures used, intervention setting (for intervention studies only), and who delivered the intervention (for intervention studies only). Finally, a descriptive analytical process was used to search, extract, and summarise data regarding the clinical utility of each instrument across the domains previously described in the eligibility criteria (concept). Information regarding the clinical utility of postural outcome tools were obtained from the included studies and/or other studies reporting each of the domains of clinical utility for each postural outcome tool. Where further information was needed, this was retrieved from other publications including those of the original developers of the postural outcome tools. Characterisation/mapping of the outcome tools was performed by CNI-C and EUA. The illustration in Figure 2 summarises the data charting process.\n\nCNI-C and EUA independently extracted, coded, and interpreted information in relation to the clinical utility of the postural outcome tools using qualitative content analysis. These included construct validity (yes or no); predictive validity (yes or no); sensitivity to change (yes or no); ease of potential use in clinical settings (Yes-little or no training is required to use the tool or No-significant training required to use the tool, and Yes-no specialist equipment is required for the tool or No-specialist equipment is required for the tool); sensibility of the tool (Yes-significantly facilitates clinician-patient interaction and collaboration through requiring feedback from or active involvement of the patient in the assessment process or No-minimal or no facilitation of clinician-patient interaction and collaboration through little or no feedback from the patient/active involvement of the patient in the assessment process); the format of the tool [including the length of assessment (Easy-completed within 30 minutes or Hard-takes longer than 30 minutes to complete74), wording of items (Simple-simple and easy to understand or Hard-complex terms were used and may be difficult to understand), response format or calibration of items (Easy-easy to complete with few response options or Difficult-difficult to complete with multiple response options)]; and the model of pain on which the postural outcome tool appears to be based (postural-structural-biomechanical model of pain based on the assumption that there are specific correct and wrong postures, or a biopsychosocial model of pain based on the assumption that postural aggravating factors are different in different individuals and may require individuals to identify what these are and actively modify exposure to identified aggravating postural factors24–26). Discrepancies in coding and synthesis were resolved by discussion of the entire review team including BCO and GNE.\n\n\nResults\n\nFigure 3 illustrates the process for the selection of studies included in this review. The initial search yielded 3,526 potential articles. 1,146 were removed during deduplication of records. The titles and abstracts of 2,380 papers were screened and 2,206 were excluded for not meeting the eligibility criteria. The full texts of 174 articles were assessed for eligibility with 85 full text articles excluded for failing to meet the eligibility criteria. A total of 85 studies (identified from 89 publications) included 50 cross-sectional studies, 9 pre-post-test studies; 11 RCTs, 7 prospective cohort studies, and 8 psychometric studies.\n\nTable 1 illustrates the characteristics of individual studies including the postural outcome tools that were utilised. The studies were published between 1995 and 2023 and were conducted in over 20 countries which included high, middle, lower-middle and low-income countries. Participants in the studies were aged 10 years and above with or without spinal pain. Twenty-eight specific postural outcome tools plus several self-developed (bespoke for individual studies) questionnaires, reports, observation, and demonstration were administered in the workplace, schools, computer laboratories, community centres, and hospitals or clinics in the included studies. There was a trend with more observational and psychometric studies using sophisticated computer-based or machine-based electronic devices, or complex time-consuming questionnaires and worksheets, and more intervention-based studies utilising mostly non-validated self-developed questionnaires specifically developed for each of the studies.\n\nCharacteristics of the included studies.\n\nTable 2 highlights the clinical utility of the postural outcome tools that have been used in the studies. Notably, none of the postural outcome measures scored positively on all the domains of clinical utility. The domain of clinical utility in a decreasing order of achievement was construct validity and inter and intra-rater reliability (24 tools each), followed by sensibility (16 tools), ease of use in clinical settings (13 tools), easy format (13 tools), predictive validity (5 tools), sensitivity to change (2 tools), and underpinned by a biopsychosocial model of pain (0 tool). The highest achieving tools in relation to clinical utility are BACKPEI (5 domains), PAI (5 domains), motion sensor (5 domains), plumbline (5 domains); followed by RULA (4 domains), inclinometer (4 domains), BEHALVES (4 domains), postural monitor and feedback device (4 domains), CROM device (4 domains), Q-BAPHYP (4 domains), which were followed by QEC (3 domains), REBA (3 domains), OWAS (3 domains), CUELA (3 domains), photogrammetry (3 domains), ORFQ (3 domains), 4D formetric device (3 domains), self-developed questionnaires (3 domains), self-reports (3 domains), diary (3 domains), demonstration (3 domains), and after these were DIPA (2 domains), NERPA (2 domains), PATH (2 domains), motion analysis system (2 domains), ALLA (2 domains), 3D Global Posture System (2 domains), PostureScreen mobile application (2 domains), Instrumented insole plus chest-mounted accelerometer (2 domains), video (2 domains), and finally there were computer-based 3D body scanner (1 domain), observation (1 domain) and electromagnetic measurement device (0 domain). Notably, all the postural outcome tools were underpinned by a postural-structural-biomechanical model of pain based on the assumption that there are specific correct and wrong postures. None of the postural outcome measures was based on a biopsychosocial model of pain with an underlying assumption that postural aggravating factors may be different in different individuals and may require individuals to identify their own aggravating postures and possible interacting psychosocial and biomedical factors, and actively modify exposure to the identified aggravating postural factors. Figures 4 summarise the relative achievement of the domains of clinical utility by the included postural outcome tools. Figure 5 depicts the performance of the included postural outcome tools in achieving overall clinical utility.\n\nClinical utility of the postural outcome tools.\n\n\nDiscussion\n\nThis is the first study to explore the clinical utility of outcome tools for measuring exposure to postural risk factors for back and neck pain clinical outcomes. Findings from this study suggest that existing postural outcome tools have low clinical utility for back and neck pain. Majority of the tools were sophisticated computer-based or electronic devices, complex time-consuming questionnaires, with limited utility in non-occupational settings. The objective instrument-based postural measures can hardly be utilized outside of a laboratory setting and mostly measure posture under artificial conditions.36 The easy-to-use tools were mostly unvalidated. The most achieved clinical utility domains were construct validity and inter/intra-rater reliability, and the least achieved domains were tools being underpinned by the biopsychosocial model of pain,40–43 sensitivity to clinical change, and predictive validity.\n\nPostural outcome tools that are based on the postural-structural-biomechanical model of pain have the underlying assumption that there are universal ‘good’ and ‘bad’ postures for back and neck pain. Therefore, individuals whose daily activities involve these postures may develop apprehension regarding those activities which may lead to the development of fear avoidance beliefs. The subsequent fear avoidance behaviours that result from this is associated with adverse back and neck pain clinical outcomes.16 The fear avoidance model explains how individuals avoid activities believed to cause pain, even when these activities are neither harmful nor painful, which can lead to disuse, deconditioning, and disability. Furthermore, fear avoidance beliefs may be associated with hypervigilance, and anticipation of pain during those activities of daily life in the postures understood as ‘incorrect’, which may in turn lead to muscle guarding and co-contraction, increasing pain and disability.18 It is possible that this might be counteracted by employing postural outcome measures that are based on the biopsychosocial model of spinal pain. Postural outcome tools based on the biopsychosocial pain model might enable individuals to understand that posture may not be an aggravating factor for everyone, and that those for whom posture is an aggravating factor, it may be different in different people, and can be driven by cognitive, emotional, psychological, behavioural, physical, and social factors which may interact to perpetuate pain. Measuring posture within a biopsychosocial pain model may be associated with several potential benefits. For instance, it might prevent the development of fear avoidance behaviour and subsequent disability. Postural outcome measures based on the biopsychosocial model may also support active self-management by encouraging people to identify their individual aggravating postures, the potential biopsychosocial factors driving the aggravating posture, how to actively modify the aggravating postures and the factors driving them, identification of relieving postures, and the need to keep moving by regularly changing posture. Using postural outcome tools based on the biopsychosocial model aligns with the biopsychosocial pain model40–43 and the evidence-based recommendations for symptomatic relief of spinal pain episodes to prevent participation restrictions and disability.44–46 A biopsychosocial approach in the assessment and management of spinal pain enables the identification of multiple interacting factors affecting the patient, and the management of the patient on multiple levels to target those factors, their interactions, and the impact of their interactions. Previous belief that poor posture can cause or aggravate back and neck pain through increased stress on the muscles, ligaments, and joints with good posture protecting the spine by decreasing stress on these structures, keeping the joints in alignment, and improving efficiency of the musculoskeletal system is simplistic at best. This is because important factors such as biological vulnerability, physical activity and fitness levels, duration of sustained posture, spinal loading, and other biopsychosocial factors are not taken into consideration. Moreover, many ergonomic postural tools overestimate the risk of injuries, with some tools almost always predicting risk every time that they have been used.182 Our recently completed but yet unpublished mixed-methods study suggests that many global spinal pain experts no longer believe in specific ‘good’ or ‘bad’ postures. However, a significant number of clinicians globally, and many spinal pain researchers in low and middle-income countries, may still believe in specific poor and good postures as risk factors for spinal pain and support their assessment and targeting.255 This belief is also held by ergonomic engineers from whom a significant number of the studies and outcome tools included in this review were produced.\n\nThe fact that only two, and five measures had documented evidence of sensitivity to clinical change and predictive validity respectively, could explain the conflicting evidence regarding the effectiveness of interventions with a postural component.33–35 Furthermore, the lack of sensibility, easy format, and ease of use in clinical settings by a significant number of the tools could explain why many studies that investigated the effectiveness of postural interventions or complex interventions with a postural component in clinical settings either did not measure posture or used self-developed easy-to-use but non-validated tools. Therefore, these studies could not link the reported clinical benefits of the interventions to postural changes.26–31,35,256–261 Another factor that could limit the applicability of the identified postural outcome measures is the restriction of measurement to only work-related risk factors. These tools did not acknowledge home related and other risk factors associated with daily living.\n\nThis scoping review has some limitations. Studies published in other languages apart from English, or in non-indexed journals, or studies that were not yet published at the time of this study might have contained more clinically useful postural outcome tools which were not included in this review. Another limitation is the possibility that some of the postural outcome tools which had low clinical utility may inherently have some of the defining features of clinical utility such as sensitivity to change, predictive validity etc., but these clinical utility domains had not been assessed in published studies at the time of this study. Finally, it is possible that the definition of ease of use of tools in clinical settings which was informed by the published literature and clinical experience might have been too stringent, thereby excluding potentially clinically useful postural outcome tools. However, this is unlikely since time consuming and highly technical tools may be difficult to implement in busy clinical settings.\n\nEvidence-based, simple, and clinically useful postural outcome tools that are based on the biopsychosocial pain model may be able to identify patterns of aggravating postures for different individuals as well as potential interaction of these postures with psychosocial and biomedical factors, and the impact of these interactions. This may be particularly useful in clinical settings as such short, simple, and easy to administer outcome tools will help to determine the multiple levels of factors that should be targeted by interventions. Furthermore, postural outcome tools based on the biopsychosocial pain model can be used in future epidemiological studies to clarify the relative contribution of postural factors to first onset of back and neck pain in different individuals. In addition, these tools may reduce the incidence, prevalence, and impact of fear avoidance beliefs due to the use of the current tools based on the postural-structural-biomechanical model of pain. Finally, new tools that are based on the biopsychosocial pain model may be useful in future clinical trials for isolating the impact of postural risk factors on clinical outcomes relative to potential interacting factors, and for understanding the mechanisms of action of clinical interventions.\n\n\nConclusions\n\nExisting postural outcome tools have limited clinical utility for back and neck pain. The domains of clinical utility reflected in studies in a decreasing order of achievement was construct validity and inter and intra-rater reliability (24 tools each), followed by sensibility (16 tools), ease of use in clinical settings (13 tools), easy format (13 tools), predictive validity (5 tools), sensitivity to change (2 tools), and underpinned by a biopsychosocial model of pain (no tool). Identified tools were mostly sophisticated computer-based or electronic devices; non-validated or complex time-consuming questionnaires; had limited predictive validity, sensitivity to change, and applicability in non-occupational settings; and were based on a postural-structural-biomechanical model of pain.\n\nThere are no ethical considerations for this study that utilised data from published studies.", "appendix": "Data availability\n\nNo data are associated with this article.\n\nFigshare: Exploring the clinical utility of postural outcome tools for back and neck pain clinical outcomes: a systematic scoping review, DOI: https://doi.org/10.6084/m9.figshare.28054454.v169\n\nThe project contains the following reporting guidelines:\n\n• Appendix 1 Search Strategy Postural Outcome tools F1000Research\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nFigshare: Exploring the clinical utility of postural outcome tools for back and neck pain clinical outcomes: a systematic scoping review, DOI: https://doi.org/10.6084/m9.figshare.28054454.v169\n\nThe project contains the following reporting guidelines:\n\n• PRISMA-ScR-Fillable-Checklist COMPLETED_10Sept2019.docx\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nVos T, Lim SS, Abbafati C, et al.: Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. 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PubMed Abstract \| Publisher Full Text" }	[ { "id": "359811", "date": "27 Jan 2025", "name": "Saturday Nicholas Oghumu", "expertise": [ "Reviewer Expertise Pain medicine", "orthopedics", "sport medicine", "physiotherapy", "rehabilitation", "exercise medicine" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear Editor, it is obvious that the authors of this manuscript have dedicated a great deal of effort in writing this scoping review on clinical utility of postural outcome tools for back and neck pain clinical outcomes. It is also commendable to say that the authors have carefully follow the methodology for conducting a systematic review and provided details with reference for modification to scoping review. However, the below comments are my submissions for authors consideration.\nAbstract The clause “Tools being underpinned by the biopsychosocial model of pain” may not be necessary here given that it is unrelated to the title, aim and cannot be accounted for by the articles reviewed in both the methodology and results of the study.\nIntroduction Although, I agree with the authors that “posture may not even be an aggravating factor in some people” authors inclination in aligning evidence-based postural outcome tools with evidence-based biopsychosocial model of spinal pain is not backed up with facts. What construct of the biopsychosocial (biologic, psychosocial & social) model of spinal pain does posture defines? Authors should provide information regarding how the combination of these constructs of biopsychocial model of spinal pain interplay in the complexity and multidimensional nature of spinal pain, as well as their corresponding clinical outcomes for the understanding of readership.\nMethod Inclusion criteria: The inclusion of studies of human participants with spinal pain of all ages may be too broad given the choice of mechanical pain. What influence does the participants age have in defining the mechanical nature of their pain? Authors should clarify, especially in the study limitation given the exclusion criteria of spinal pain of systemic pathology which may be unnoticeable in children with spinal pain? Does this in any way affect the outcome of the postural outcome tools in studies with these age categories? This should be discussed in the discussion section.\nResults Majority of the postural outcome tools assessed are patient reported outcome measures, but the minimal clinically important difference (MCID) of these tools were not accounted for. Why?\nDiscussion Provide clarity of postural outcome tools based on the biopsychosocial pain model. Are you implying that postural outcome tools should reflect the psychosocial components of the biopsychosocial model apart from assessing posture? Then briefly provide additional details of this possibility. Thank you.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable", "responses": [] } ]	1	https://f1000research.com/articles/14-44
https://f1000research.com/articles/14-43/v1	08 Jan 25	{ "type": "Research Article", "title": "Income-Based analysis of health security in Western Asia through an integrated GHSI, MCDM, and Clustering Model", "authors": [ "Adel A. Nasser", "Abed Saif Ahmed Alghawli", "Salem Saleh", "Amani A. K. Elsayed", "Adel A. Nasser", "Salem Saleh", "Amani A. K. Elsayed" ], "abstract": "Objectives Infectious diseases present significant challenges to global health security in contemporary, interconnected global environments. This study aimed to evaluate and compare health security performance in Western Asia (WA), with a focus on income group-based disparities and region-specific insights.\n\nMethods This study utilized the Global Health Security Index (GHSI) to assess health security across 17 WA countries categorized by income level. Health security indicators for 2019 and 2021 were analyzed using the D-CRITIC method to determine the relative importance of each indicator (Global Health Security Index, 2021): https://ghsindex.org/report-model/). A combined D-CRITIC-CoCoSo framework was employed to rank the countries, followed by K-means clustering for grading. The study also investigated correlations between financial allocation’s indicators and health security outcomes using Spearman’s rank correlation. A comparative analysis elucidated regional disparities across income categories.\n\nResults This study highlights WA’s progress in health security by prioritizing foundational health systems, detection/reporting, rapid response, and risk management. From 2019 to 2021, priorities varied by income group, with high-income countries focusing on detection, upper-middle-income countries focusing on risk environments, and low-income countries focusing on prevention. While some nations demonstrated improvement, others, such as Armenia, experienced decline, revealing persistent vulnerabilities. This study revealed significant variability in health security capacity, with both progress and setbacks among countries in different clusters. High- and upper-middle-income countries, such as Qatar and Georgia, leverage investments and international partnerships to improve their rankings, while conflict-affected, low-resource countries, including Iraq, Yemen, and Syria, face stagnation or decline. Strong correlations were observed between financial resource allocation indicators and health performance. Higher investments in countries like Armenia and Georgia led to significantly improved health outcomes, while minimal spending in Syria and Yemen weakened their resilience to health threats.\n\nConclusion Disparities in health resilience persist, underscoring the need for equitable resource allocation and regional cooperation to enhance public health security.", "keywords": [ "global health security", "Western Asia", "income", "K-means clustering", "CoCoSo", "D-CRITIC weighting method", "financial resource allocation" ], "content": "1. Introduction\n\nIn today’s interconnected world, infectious diseases threaten global security, as seen with COVID-19, Ebola, and tuberculosis. These outbreaks disrupt economies, overwhelm healthcare, and affect vulnerable populations (Berger et al., 2024; Chakaya et al., 2021). Surveillance data emphasize the rapid cross-border spread of disease (Han et al., 2020), highlighting urgent gaps in preparedness and the need for unified international response strategies (Khan et al., 2020). Enhancements in health security not only bolster a nation’s ability to respond to health crises but also promote global collaboration and trust among countries (Bellm & Nuzzo, 2021). By improving surveillance systems, health infrastructure, and access to vaccines, nations can detect and manage outbreaks more effectively (Nasser & Alghawli, 2024).\n\nWestern Asia emerges as a uniquely challenging region for health security, shaped by its intricate blend of geopolitical tensions, diverse populations, and varying health systems (Roy & Quamar, 2022). With a history of political conflict and large-scale migration, the region requires robust health strategies to ensure accessible healthcare across borders (Kalush & Lambert, 2023; World Health Organization, 2023). The effectiveness of health security systems here depends heavily on the region’s ability to monitor and respond swiftly to health crises, including infectious disease threats. Cross-border cooperation, resilient health infrastructure, equitable resource allocation, coordinated data-driven health security strategies, and policy interventions are essential pillars for addressing health risks (Nasser & Alghawli, 2024). Therefore, evaluation and comparing Western Asia’s health security practices, identifying priorities, and setting improvement directions are critical for effectively managing public health across this complex region.\n\nThe Global Health Security Index (GHSI) serves as a crucial tool for assessing national health security, encompassing various aspects such as prevention, detection, and swift response capabilities (Nasser & Alghawli, 2024; Bellm & Nuzzo, 2021).\n\nIn this paper, the first stage was analysing the current literature on the topic of study. Recent studies have made considerable progress in analysing and enhancing this index as a means to evaluate health security and public health resilience across countries, with numerous investigations highlighting its significance in shaping both national policies and global health security initiatives. For example, Boyd et al. conducted a study in 2020 examining the efficacy of the GHSI in measuring 195 nations’ readiness for biological threats, with a focus on how it might bolster future preparedness efforts. Assefa et al. (2020) investigated the connection between Global Health Security (GHS) and Universal Health Coverage (UHC) indices by utilizing Pearson’s correlation coefficient to measure the relationship between these two crucial global health metrics. That same year, Bezbaruah et al. (2021) explored the role of community health workers in reinforcing resilient health systems and health security. To demonstrate the need for additional funding, Yeh et al. (2021) delved into the risks and threats of infectious diseases in relation to the current political and socioeconomic contexts affecting GHS. Boyd et al. (2022) analysed the 2021 Global Health Security (GHS) Index Report, which indicates minimal improvement in global health security preparedness despite Worsley-Tonks et al. (2022) emphasizing the necessity to enhance disease surveillance worldwide, particularly in remote rural areas of low-income nations. A practical approach using Kenya as a case study was suggested. In 2020, Ravi et al. explored the practical applications of the GHS Index, potential uses to assist both professionals and policymakers in maximizing the tool’s utility, and the importance of ratings and rankings. Ledesma et al. (2023) employed indirect age normalization to assess the GHSI in order to examine the relationship between comparative mortality ratios of excess COVID-19 deaths and pandemic preparedness at the national level. Kumru et al. in 2022 studied the correlation between socioeconomic and demographic factors and COVID-19 mortality and morbidity rates in various countries. They also ranked the nations according to their COVID-19 rates. In 2024, Dobrovolska et al. utilized economic and mathematical modelling to examine the relationships between the GHSI and the Global Cyber security Index (GCSI) across 190 countries, with their findings underscoring the interdependencies between these indexes and illuminating potential synergies between health and cyber security. Concentrating on island nations, Boyd et al. (2024) investigated the connection between GHSI scores, excess mortality, and GDP per capita growth during the COVID-19 pandemic, underscoring the impact of health security on macroeconomic outcomes, especially in geographically isolated countries. Moreover, Ramírez-Soto and Arroyo-Hernández (2024) examined correlations between this index and MPOX case rates and discovered that high GHSI scores contribute to the early detection and response to outbreaks, reinforcing the index’s value in infectious disease preparedness.\n\nHowever, while all those studies emphasized that the GHSI plays a significant role in assessing global preparedness and shaping both national policies and global health security initiatives, it exhibits several limitations, particularly when compared to more sophisticated tools such as multi-criteria decision-making (MCDM) models and machine learning clustering techniques.\n\nOne of its key shortcomings is the insufficient weighting of health security factors, which can lead to inaccurate rankings (Nasser & Alghawli, 2024). Additionally, the absence of advanced ranking and clustering methods restricts the ability to differentiate between various subgroups, such as conflict versus non-conflict nations and countries with different income levels within the same region. These limitations, along with the lack of detailed comparative analysis or dynamic ranking clustering of nations, underscore the need for more nuanced methodologies that offer deeper insights into regional performance differences, hampering a comprehensive understanding of regional health security landscapes (Nasser & Alghawli, 2024). To address these challenges, a more sophisticated framework that applies advanced methodologies and provides deeper insights into regional variation is essential. Several studies have made significant contributions to this regard. For instance, Sun et al. (2024) applied the fuzzy analytic hierarchy process algorithm to analyse the Global One Health Index in 160 countries and territories worldwide. Five additional studies leveraged multi-criteria decision-making (MCDM) methods to assess the 2019 and 2019 GHSI. Huang et al. 2021, employing modified VIKOR and CRITIC weighting, found its rankings diverged from other MCDM methods, suggesting VIKOR captures unique aspects of health system performance. Altıntaş 2022, using MAIRCA on EU member states, revealed strong correlations between GHSI scores and most other MCDM methods, except MAUT, indicating a broad agreement on relative health security performance. Pereira et al. 2022, utilizing PROMETHEE II and SMAA, coupled with a clustering approach, revealed inconsistencies between GHSI classifications and observed COVID-19 performance, highlighting potential flaws in the GHSI’s predictive capabilities and advocating for its revision. Nasser and Alghawli, 2024, proposed an entropy TOPSIS k-means clustering approach for ranking and clustering African countries’ health security practices. Nasser et al. 2024a applied entropy-VIKOR-K means clustering methods to determine and compare the relative importance of health security indicators in the EMR region in both 2021 and 2019 and to rank cluster countries based on their overall performance. This study also utilized Pearson’s and Spearman’s rank correlation coefficients to assess the relationships between the indicators and overall performance. However, in addition to the previously defined limitations of the traditional statistical methods used by the GHSI, these studies found limited applications of the GHSI in global health security assessment and emphasized the need for new evaluation methodologies (Bulut et al., 2024; Nasser et al., 2024a; Nasser and Alghawli, 2024). Bulut et al. (2024) confirmed that methodologies that integrate MCDM with GHSI are very limited in the literature and have been used to a limited extent for the purpose of proposing new methodologies and ways to evaluate and rank countries’ performance, which is also in line with the findings of limited sophisticated ranking and clustering analyses that restrict the ability to compare health security across regions (Nasser et al. 2024a).\n\nIn summary, although numerous studies have analyzed health security performance through diverse methodologies, none have integrated income classification, the Global Health Security Index (GHSI), Distance Correlation-based Criteria Importance through Inter-criteria Correlation (D-CRITIC) weighting, the Combined Compromise Solution (CoCoSo), and K-means clustering techniques specifically to examine health security in the Western Asian region. This study presents a novel approach as it introduces an innovative framework for analysing health security in Western Asia, integrating the Global Health Security Index (GHSI), income-based country classification, advanced multi-criteria decision-making (MCDM) methods, specifically D-CRITIC weighting, CoCoSo ranking, and K-means clustering. While prior research has explored health security performance using various approaches, no study has applied this specific combination, which enhances the accuracy through the collaborative strength of MCDM methods. Focusing on 2019–2021 data, this framework evaluates health security performance across Western Asia, emphasizing the differences between income groups. By utilizing D-CRITIC, this study determines the relative importance of health security indicators, while CoCoSo ranks countries based on overall performance, allowing for comparative insights across income classifications. K-means clustering further identifies distinct health security profiles, offering a more comprehensive understanding of the variance between countries, and finally, the Spearman rank correlation method further investigates the relationship between the average performances of financial resource allocation indicators and the COCOSO health security performance scores throughout the study period.\n\n\n2. Methods\n\nThe methodology of this study followed a six-stage process. This section details each stage along with the integrated model used.\n\nThe Global Health Security Index (GHSI) is a comprehensive instrument for assessing countries’ preparedness and capabilities in addressing health security threats. However, its suitability as a research tool warrants careful consideration given the discrepancies observed between predicted and actual performance during the COVID-19 pandemic (Kaiser et al., 2021). The GHSI provides a multidimensional approach to evaluating health security, encompassing various aspects such as prevention (PR), detection, reporting (DR), rapid response (RR), health system capacity (HS), commitment and adherence (CA), and risk environment (RE) (Wang and Lyu, 2023; Nasser et al., 2024a; Nasser and Alghawli, 2024). The GHSI’s publicly accessible data support extensive research opportunities and offer a holistic perspective on a country’s health security preparedness, and its structured approach facilitates robust comparisons among nations, rendering it a potentially valuable tool for our research (Global Health Security Index, 2021). The World Bank classification, which categorizes countries into four income groups based on gross national income (GNI) per capita, delineates the 17 Western Asia (WA) countries as follows: Low-income countries (LIC) comprise Syria and Yemen; lower-middle-income countries (LMC) include Jordan and Lebanon; upper-middle-income countries (UMC) encompass Armenia, Azerbaijan, Georgia, Iraq, and Turkey; and high-income countries (HIC) consist of Bahrain, Cyprus, Israel, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates. For our comparative analysis, we extracted data for 17 countries in the WA region, including 2 LIC, 2 LMI, 5 UMC, and 8 HIC. To assess health security outcomes across these groups for each indicator, we examined performance metrics from 2019 and 2021 (Global Health Security Index, Global Health Security Index Data Model and Report. (2021). Available at https://ghsindex.org/report-model/). Comprehensive data can be found in Tables 1-3 of the supplementary file (Nasser, et al. 2024b) (available at: data repository https://doi.org/10.6084/m9.figshare.27992735.v3).\n\nFurthermore, to assess the relationship between the financial resources allocated to public health preparedness and the effectiveness of resource utilization from one perspective and the health security outcomes in the region from another, this study utilizes GHSI data on two indicators: F1, a financing indicator, and F2, public healthcare spending levels per capita. A financing indicator, in the context of health security, is a metric that quantifies the financial resources dedicated to enhancing a country’s capacity to prevent, detect, and respond to disease outbreaks. This indicator provides a comprehensive representation of the financial investments made in various domains related to health security, such as preparedness funding, commitments based on Joint External Evaluation (JEE) and Performance Verification System (PVS) assessments, emergency response financing, and accountability for international commitments. The second indicator refers to the domestic general government health expenditure per capita. Comprehensive data can be found in Table 4 of the supplementary file (Nasser, et al. 2024b) (available at: data repository https://doi.org/10.6084/m9.figshare.27992735.v3).\n\nThis study employed the modified version of the CRiteria Importance Through Inter-criteria Correlation (CRITIC) method, namely the Distance Correlation-based CRITIC (D-CRITIC) method to evaluate and compare the relative importance of health security indicators across Western Asia. D-CRITIC improves upon the original CRITIC method by incorporating distance correlation, enabling objective criteria weighting based on both variance and interdependency.\n\nThis approach was introduced by Krishnan et al. in 2021; it yields more valid and stable weighting and ranking results than traditional CRITIC, thus enhancing decision-making reliability (Krishnan et al., 2021). D-CRITIC offers significant advantages for multi-criteria decision-making (MCDM). By considering both linear and nonlinear relationships between indicators through distance correlation, it enhances the accuracy of objective criteria weighting (Duo et al., 2024). Its data-driven approach minimizes subjectivity and potential bias, leading to more equitable, stable, and valid outcomes compared to the CRITIC method (Duo et al., 2024).\n\nThe procedure typically encompasses six distinct steps (Krishnan et al., 2021):\n\nStep 1. Creating a decision matrix (DM), denoted by Uij as follows:\n\nThe score of country i on indicator j is represented by uij . Additionally, the variables m and n indicate the total number of alternatives (countries) and criteria (health security indicators), respectively.\n\nStep 2: Computing the normalized DM using (2):\n\nIn this scenario, uij denotes the score assigned to alternative i for criterion j, uj+ represents the highest score attained for criterion j, and uj− represents the lowest score recorded for criterion j.\n\nStep 3: Calculating Standard Deviation (SD j) for each criterion:\n\nThe symbol ( zj¯ ) represents the arithmetic mean (average) of the normalized values for criterion ‘j’ across all ‘m’ alternatives.\n\nStep 4: Exploring Inter-Criterion Relationships with Distance Correlation\n\nEquation (3) defines this calculation for any two criteria, represented as cj , and cj′ .\n\nHere, dCov(cj,cj′) represents the distance covariance between cj and cj′ , while dVar(cj)=dCov(cj,cj), represents the distance variance of cj , and dVar(cj′)=dCov(cj′,cj′) represents the distance variance of cj′ .\n\nStep 5: Computing Criterion Information Content:\n\nThe symbol Ij represents a metric that quantifies the amount of information contained within the jth criterion.\n\nStep 6: Compute the objective weights.\n\nIn this step, Equation (5) is used to calculate the objective weight of each jth criterion, reflecting its relative importance in decision-making.\n\nIn our study, this process was repeated eight times to assess the relative importance of health security indicators in the WA, LIC-LMC, UMC, and HIC groups of countries in the region for both 2019 and 2021. Detailed calculations for this step are readily available in supplementary file (Sec. 2) (Nasser, et al. 2024b) (Available at https://github.com/ProfAdelAbdulsalam/supplementary-material-and-softwares/tree/1.0.0) (https://doi.org/10.5281/zenodo.14541236).\n\nThe Combined Compromise Solution (CoCoSo) method, introduced by Yazdani et al. (2019), is a robust tool in Multi-Criteria Decision-Making (MCDM). This method effectively integrates the strengths of simple additive weighting (SAW) and the exponentially weighted product model, making it particularly adept at generating balanced and reliable rankings. Its intuitive design, adaptability, and capacity to deliver actionable insights have made it widely applicable across various decision-making contexts, enhancing its relevance to our study (Banihashemi et al., 2021; Naeem et al., 2022; Wang et al., 2023). It comprises the following implementation steps (Yazdani et al. (2019):\n\n• Step 1: Constructing Initial and Normalized Decision Matrices\n\nIn this step, the initial DM ( Uij ) is constructed as described in (1) and then normalized as outlined in (6):\n\n• Step 2. Computing the weighted comparability sequences, which are derived by (7) and (8):\n\nIn this context, the weighting vector ( wj ) indicates the relative significance assigned to the j-th indicator, while ( yij) represents the normalized performance score of the i-th alternative concerning the j-th indicator.\n\n• Step 3: Calculating the evaluation scores of the alternatives\n\nAt this stage, three distinct evaluation scores are calculated as follows:\n\nHere, the parameter λ, ranging from 0 to 1, allows the decision-maker to fine-tune the relative importance of two aggregation techniques in determining the final compromise solution: the additive weighted sum (S i) and the exponentially weighted product (P i). This parameter serves as a control mechanism for balancing the influence of these two methods. A common practice is to use a value of 0.5, which gives equal weight to both S i and P i, ensuring a balanced consideration of the two approaches in the final outcome. This equal weighting is often employed to achieve a balanced integration of both techniques in the ultimate result.\n\nStep 4: Calculating the composite score index and rank alternatives\n\nFinally, Equation (12) is used to calculate the composite score.\n\nIn this investigation, the aforementioned process was iterated twice to rank Western Asian countries based on their GHSI scores for both 2019 and 2021. The alternatives are arranged in descending order according to their calculated scores. For a comparative analysis, Western Asian-ranked countries were further categorized by income group. Detailed calculations for this procedure are available in the supplementary file (Sec. 3) (Nasser, et al. 2024b) (Available at https://github.com/ProfAdelAbdulsalam/supplementary-material-and-softwares/tree/1.0.0) (https://doi.org/10.5281/zenodo.14541236)\n\nK-means clustering is a widely used learning algorithm for data mining and pattern recognition (Chong 2021). It partitions n observations into k clusters, where each observation belongs to the cluster with the nearest mean. The algorithm operates by iteratively assigning data points to the closest cluster center and subsequently recalculating the cluster centers based on new assignments (Cui et al., 2013).\n\nThis method is well known for its efficiency, simplicity, and adaptability across various fields. The advantages of K-means include computational efficiency and ease of implementation, rendering it suitable for large datasets (Chong, 2021). The standard K-means algorithm follows these steps (Cui et al., 2013): 1) initialize k cluster centers, often randomly; 2) assign each data point to the nearest cluster center; 3) recalculate the cluster centers based on the new assignments; 4) repeat steps 2 and 3 until convergence or a maximum number of iterations is reached.\n\nIn this study, the aforementioned process was also repeated twice to cluster Western Asian countries based on their D-CRITIC-COCOSO scores for both 2019 and 2021. The countries were clustered using a five-tiered grading system, ranging from “excellent” (Grade 1) to “poor” (Grade 5). The Western Asian-clustered countries were further divided into income tiers for comparative research. The supplementary file contains detailed calculations for this process (Sec.4) (Available at https://doi.org/10.6084/m9.figshare.27992735.v3) (Nasser, et al. 2024b).\n\nWe utilized the Spearman rank correlation method to investigate the relationship between the average performances of financial resource allocation indicators (financing (F1), and public healthcare spending levels per capita (F2)) and the mean COCOSO health security performance scores (Ci) throughout the study period. This non-parametric technique is particularly appropriate for evaluating the association between two variables without assuming specific underlying distributions (Liu, 2017). The Spearman correlation coefficient (ρ) was determined by independently ranking the sample values of both variables and then inserting the squared differences between these ranks into a formula derived from the Pearson correlation (Zimmerman, 1994). This approach is beneficial as it emphasizes the relative positions of the values rather than their absolute disparities, making it resilient to outliers and nonlinear relationships (Liu, 2017). An alternative method involves converting the values of both variables into standard scores, ranking the combined standard scores in a single sequence, and then calculating the Pearson correlation between the ranks corresponding to the original scores. This modified approach has been shown to be slightly more powerful than the conventional Spearman method for various distributions and sample sizes, ranging from 8 to 30 (Zimmerman, 1994). In summary, the Spearman rank correlation method was chosen because of its ability to assess the strength and direction of the monotonic relationship between resource allocation indicators and COCOSO scores. This technique is particularly effective in situations where the relative rankings are more important than the exact values, making it well suited for comparing performance indicators across different domains (Liu et al., 2010; Liu, 2017).\n\nThis phase consolidates and evaluates the outcomes from previous stages, examining the comparative importance of indicators, national rankings, and grouping trends across Western Asia and its economic subdivisions. The evaluation centered on uncovering regional inequalities and crucial patterns in health security performance for both 2019 and 2021. The outcomes will guide the creation of specific suggestions to improve health security readiness in each income category and the region overall. The key findings are outlined in the following sections.\n\nTo determine the relative significance of health security indicators across Western Asian nations, we developed two advanced Excel-based software tools. Supplementary Software 1 - Distance Correlation-Based CRITIC Software. Source software available from (Available at https://github.com/ProfAdelAbdulsalam/supplementary-material-and-softwares/tree/1.0.0). Archived software available from (https://doi.org/10.5281/zenodo.14541236) (Nasser, et al., 2024b), License: OSI approved open license software is under GNU General Public License v3.0). This tool enables a detailed analysis by categorizing countries into income groups—Low-Income Countries (LIC), Lower-Middle-Income Countries (LMC), Upper-Middle-Income Countries (UMC), and High-Income Countries (HIC)—and provides valuable insights for the years 2019 and 2021. This tool specifically focuses on analyzing health security in low-income and lower-middle-income countries.\n\nFor the ranking analysis, we created Supplementary Software 2—An Integrated GHSI, MCDM, and Clustering Model for Health Security Analysis in Western Asia.\n\nSource software available from: (https://github.com/ProfAdelAbdulsalam/supplementary-material-and-softwares/tree/1.0.0). Archived software available from (https://doi.org/10.5281/zenodo.14541236) (Nasser, et al., 2024b), License: OSI approved open license software is under GNU General Public License v3.0). Supplementary Software 2 evaluates the health security performance of these nations for both 2019 and 2021, integrating weighting, ranking, clustering, and Spearman rank correlation analysis into a unified Excel-based tool, offering a robust framework for health security performance assessment.\n\nFor clustering analysis, the software Cluster Analysis for Marketing (2024) was utilized, which is available for free download at Cluster Analysis for Marketing - Free Download (https://www.clusteranalysis4marketing.com/a-marketers-guide-to-cluster-analysis/free-download/).\n\n\n4. Results and Discussion\n\nGenerally, in the D-CRITIC method, an indicator’s weight is directly linked to its information content (IC), with higher weights assigned to indicators that offer greater unique information, as measured by distance correlation. This adjustment ensures that indicators contributing more valuable information are weighted more heavily than those with less distinct content (Krishnan et al., 2021). Table 1 and Figures 1 and 2 present the computed information content values and corresponding weights.\n\n(Source: Authors).\n\nThis Figure chart illustrates the information content values for various health security-related dimensions, comparing them by income group and region over the years 2019 and 2021. The dimensions analyzed include Prevention (PR), Detection and Reporting (DR), Rapid Response (RR), Health Systems (HS), Commitments and Adherence (CA), and Risk Environment (RE). Data is presented for Western Asia (WA), stratified into Low-Income Countries (LIC), Lower-Middle-Income Countries (LMC), Upper-Middle-Income Countries (UMC), and High-Income Countries (HIC).\n\n(Source: Authors).\n\nThis bar chart illustrates the weight values assigned to various health security-related dimensions, comparing them by income group and region over the years 2019 and 2021. The dimensions analysed include Prevention (PR), Detection and Reporting (DR), Rapid Response (RR), Health Systems (HS), Commitments and Adherence (CA), and Risk Environment (RE). Data is presented for Western Asia (WA), stratified into Low-Income Countries (LIC), Lower-Middle-Income Countries (LMC), Upper-Middle-Income Countries (UMC), and High-Income Countries (HIC).\n\nTable 2 summarizes the results of a COCOSO analysis and K-means clustering on the health security performance of WA countries for 2019 and 2021. Countries are divided into LIC, LMC, UMC and HIC groups. Key metrics include the health security score (C i), regional rank (R i), cluster membership (S i), and changes in scores and ranks over the two years. Higher C i and R i indicate better performance, while cluster membership ranges from Cluster 1 (best) to Cluster 5 (worst).\n\nOur study used the Spearman rank correlation method to analyse the relationship between financial resource allocation indicators, specifically financing for health security initiatives (F1) and public healthcare spending per capita (F2), with overall health security performance scores (F3) across 17 countries. We found strong, positive correlations between both financial indicators and health security performance, with correlation coefficients of 0.98 for F1 and F3 and 0.97 for F2 and F3. These findings suggest a substantial association between financial investment in health security and the capacity to prevent, detect, and respond effectively to health threats.\n\n4.4.1 Health security priorities in western Asia (2019-2021)\n\nOur analysis reveals a consistent emphasis on strengthening foundational health infrastructure, highlighted by the sustained high weight of the Health System (HS) indicator, which received weights of 0.227 in 2019 and 0.189 in 2021. This underscores the robust commitment to developing a resilient healthcare system capable of addressing diverse health challenges. These findings align with the ASPR’s National Health Security Strategy (2019–2022), which emphasizes the necessity of a strong health system to manage emerging health threats and to enhance resilience against future crises (ASPR, 2019). The significant weight assigned to the Detection and Reporting (DR) indicator further illustrates the importance of timely and accurate information in health security. With weights of 0.189 in 2019 and 0.186 in 2021, this underscores the critical role of robust disease surveillance and reporting systems in mitigating public health emergencies, resonating with the U.S. government’s Global Health Security Strategy (David, 2024). While foundational health infrastructure and detection/reporting mechanisms remain central to Western Asia’s health security strategy, a noteworthy shift towards prioritizing rapid response (RR) and risk environment (RE) management has emerged in 2021. This change reflects the dynamic nature of health security challenges, as illustrated by the COVID-19 pandemic, which necessitates adaptive policymaking (Roasio et al., 2022).\n\nThe third-ranking indicator, commitments and adherence (CA), also gained prominence, with weights of 0.167 and 0.174 in 2019 and 2021, respectively. This trend indicates that policymakers are increasingly recognizing the importance of maintaining health protocols and international commitments as foundational for effective health security. Conversely, indicators such as RE, Prevention (PR), and RR initially exhibited lower weights, suggesting that they were deprioritized in favor of foundational elements. However, the increased weights for RR (0.157) and RE (0.156) in 2021 indicate a strategic pivot towards enhancing preparedness for immediate health crises and acknowledging the impacts of environmental health risks.\n\nThis adaptive approach in health security policymaking is further supported by studies highlighting the effectiveness of Rapid Response Teams (RRTs) in reducing mortality rates and improving patient outcomes in critical situations (Alves Silva et al., 2021). For instance, a systematic review demonstrated that RRT implementation significantly decreased the incidence of cardiac arrest and overall mortality in hospitals, emphasizing the essential role of timely intervention during emergencies. Additionally, the increased emphasis on RE reflects a growing awareness of how environmental factors can exacerbate health crises, as outlined by the Asia-Pacific Health Security Action Framework (World Health Organization, 2024), which advocates for multispectral strategies to strengthen resilience against public health emergencies. Our findings suggest that resource allocation should continue to prioritize foundational health systems and robust detection/reporting capabilities while also addressing the evolving need for effective rapid response mechanisms and comprehensive environmental risk management. Moreover, this strategic shift toward a more adaptive health security strategy addresses gaps identified by the Global Health Security Index (GHSI), which highlights deficiencies in public health emergency response plans in several countries (Bellm & Nuzzo, 2021). By prioritizing foundational infrastructure, detection/reporting, rapid response, and risk environment management, Western Asia is making strides to enhance its overall health security. The dynamic nature of health threats, especially as highlighted by the COVID-19 pandemic, necessitates an adaptive approach to health security policymaking (Roasio et al., 2022). The increased weights for RR and RE indicate a dual focus on responding to immediate crises and preparing for the future challenges posed by infectious diseases and environmental hazards. This aligns with Nasser and Alghawli’s (2024) assertion that effective decision-making requires continuous evaluation and comparison. By focusing on these key indicators, policymakers can significantly enhance health security outcomes, ultimately fostering a more resilient public health landscape in Western Asia.\n\n4.4.2 Health security priorities across income groups\n\nTable 1 and Figures 1 and 2 showcase the changes in D-CRITIC weightings of health security indicators for different income groups (HIC, UMC, LIC/LMC) from 2019 to 2021. High-income countries (HICs) consistently prioritized detection and reporting (DR), health systems (HS), and commitment and adherence (CA) in both years. In 2019, DR led to 0.277, followed by HS at 0.212 and CA at 0.172. By 2021, DR remains the top priority at 0.258, CA increases to 0.208, and HS decreases slightly to 0.172. This minor shift indicates slight reprioritization, with CA gaining prominence. Prevention scores remained consistently low, suggesting that this was not a primary concern for HICs.\n\nUpper-middle-income countries (UMCs) focus on health systems (HS), detection and reporting (DR), and risk environments (RE) as their main priorities. In 2019, HS had the highest weighting at 0.279, followed by DR at 0.175 and RE at 0.170. A notable shift occurred in 2021, with RE gaining importance and increasing to 0.210, surpassing DR at 0.197. This change likely reflects an increased awareness of environmental and external risks. HS remained a priority despite a slight decrease in weighting, whereas commitments and adherence continued to rank relatively low, similar to HICs.\n\nLow- and lower-middle-income countries (LICs/LMCs) have experienced a significant shift from 2019 to 2021. In 2019, DR (0.243), HS (0.195), and CA (0.176) were the focus. However, by 2021, prevention (PR), DR, and rapid response (RR) have emerged as top-weighted indicators. PR showed a substantial increase to 0.261, with a DR of 0.248 and an RR of 0.179. This change indicates a greater emphasis on proactive health security measures, with prevention becoming the primary focus. The lower weighting for HS may suggest resource limitations or the prioritization of other immediate needs over structural healthcare improvements.\n\nAcross all income groups, DR consistently received high weights, highlighting a universal priority for early health threat identification. HS showed a general decline in weighting over time, particularly in LICs and LMCs, possibly due to resource constraints that limit structural investments. The significant increase in the prevention of LICs and LMCs by 2021 may reflect the growing focus on preventive healthcare measures. These findings indicate evolving health security priorities, with LICs and LMCs increasingly emphasizing prevention, whereas HICs and UMCs focus on detection capabilities. This shift may be influenced by region-specific challenges and capacity differences, especially in response to the post-2019 health security events.\n\n4.4.3 Ranking and clustering results\n\nThis study’s regional analysis across Western Asia (WA) from 2019 to 2021 reveals important trends in health security, particularly as countries faced the COVID-19 pandemic’s far-reaching impacts. Results show a mixed picture: while a few countries improved or maintained their positions within their clusters, others experienced notable declines, underscoring persistent health security gaps across the region. These findings highlight the effects of shared vulnerabilities, resource constraints, and the role of international partnerships in bolstering public health systems. The implications of these results span clusters and point to strategic areas for policy intervention, targeted resource allocation, and regional collaboration.\n\n• Cluster 1: High Performers with Relative Declines\n\nAs shown in Figure 3, countries in Cluster 1, representing the highest health security performers in WA,, display trends that reveal both resilience and vulnerability in the face of regional pressures. Armenia, for instance, experienced a substantial decline in its Composite Index (Ci) score, dropping from 16.341 in 2019 to 9.635 by 2021. This significant reduction, attributed to internal challenges and exacerbated by pandemic-related constraints, mirrors findings by Zhang et al. (2021), who noted similar declines in regional health resilience under shared resource pressures (Zhang et al., 2021). Armenia’s retention of its top rank within WA, despite this decline, suggests that other countries in the region similarly struggled with pandemic challenges and that the gap between higher and lower performers may be widening.\n\n(Source: Authors).\n\nThis bar chart illustrates the distribution of Western Asia (WA) countries across clusters (S1 to S5) in 2019 and 2021. The clusters are categorized based on health security performance, where Cluster 1 (S1) represents excellent performance and Cluster 5 (S5) indicates poor performance. This visualization highlights changes in the health security status of WA countries over the specified years, offering insights into regional progress and disparities.\n\nIn contrast, Qatar’s health security investments yielded an improved regional ranking, moving from 6th to 4th between 2019 and 2021. Qatar’s progress highlights the role of high-income countries (HIC) in leveraging resources for health system reforms, as shown by Ravi et al. (2020), who documented how targeted investments enhance resilience and crisis response (Ravi et al., 2020). Georgia’s ascension to the second rank within Cluster 1 demonstrates the critical impact of sustained international partnerships, specifically its collaboration with the CDC, which has supported Georgia’s health infrastructure over decades (Biggs, 2020; Lal et al., 2022). This finding underscores the need for continuous external support to strengthen regional health security, especially for countries that lack the resources to maintain advanced health infrastructure independently.\n\n• Cluster 2: Incremental Improvements in Health Capacity\n\nAnalysis of Cluster 2 countries shows modest but notable improvements, particularly in detection (DR) and health system capacity (HS) metrics. For instance, Jordan and Cyprus moved from the third to the second cluster, although their regional rankings remained stable at seventh and eighth, respectively. Jordan’s 19% improvement in DR and 17% increase in HS scores underscore the role of digital health investments, including telemedicine, in bolstering health capacities during the COVID-19 pandemic, as Alsabi et al. (2023) demonstrated (Alsabi et al., 2023). Similarly, Cyprus’s gains in DR and HS indicate that even modest investments in health technology and infrastructure can have significant impacts on national health security.\n\nDespite these improvements, other high-income countries (HICs) in Cluster 2, such as Israel and Saudi Arabia, experienced slight declines in their regional rankings, falling from 2nd to 5th and 5th to 6th, respectively. This suggests that without sustained investment and regional cooperation, even high-income nations can see stagnation or regression in health security performance. Regional collaboration on health infrastructure, data sharing, and workforce development could provide a more stable foundation for health security in the region, as emphasized in studies on health resilience in high-income nations facing systemic constraints (Binagwaho et al., 2022).\n\n• Cluster 3: Variable Trends and Rising Health System Needs\n\nThe countries in Cluster 3 reveal both improvements and challenges. An increase in the number of WA countries from five (29%) in 2019 to six (35%) in 2021, as shown in Figure 3, reflects a slight increase in health security needs in this cluster, where most nations are either high-income (67%), lower-middle-income (LMC) (17%), or upper-middle-income (UMC) (17%). Oman’s improvement from the 10th to the 9th regional rank demonstrates incremental progress, likely supported by targeted investments in health capacity and detection infrastructure. Conversely, Bahrain and Kuwait experienced minor declines in their rankings, highlighting the need for continued investment in preventive and rapid response capabilities to sustain health security gains.\n\nLebanon and Azerbaijan’s advancement in regional and cluster rankings suggests that even under economic constraints, countries can improve health security by prioritizing critical areas, such as prevention (PR) and detection (DR). Research indicates that optimizing resource allocation towards these core functions, especially in times of crisis, can significantly improve a country’s health system resilience (Kruk et al., 2017). The trends in Cluster 3 suggest that WA countries could benefit from a model that emphasizes foundational health security investments even in the absence of extensive resources to ensure sustainability and incremental progress.\n\n• Clusters 4 and 5: Persistent Vulnerabilities in Low-Resource Nations\n\nThe most concerning findings relate to Clusters 4 and 5, where low-income and conflict-affected countries, such as Iraq, Yemen, and Syria, have faced regressions or stagnation in health security capabilities. Despite modest increases in certain health scores, Iraq’s decline from the fourth to the fifth cluster indicates insufficient systemic resilience to maintain previous gains. Iraq’s lower detection (DR) and prevention (PR) scores indicate gaps in disease surveillance and public health infrastructure; areas that are crucial for crisis response are often neglected in low-resource settings (Hamalaw et al., 2021).\n\nSyria and Yemen’s consistent positioning in the fifth cluster reveals systemic public health weaknesses exacerbated by ongoing political and economic instability. Yemen’s PR score of just 0.8 in 2021 underscores the severe limitations in preventive health capabilities, leaving the country highly vulnerable to disease outbreaks. Similarly, Syria’s low DR and HS scores illustrate critical deficiencies in early detection and health-system capacity, which is consistent with studies noting that crisis-affected regions require a comprehensive approach that combines infrastructure development, workforce training, community engagement, and policy reform to achieve long-term health security (Alhaffar & Janos, 2021).\n\n4.4.3 Spearman rank correlation results\n\nThe near-perfect correlations between financial resource allocation indicators, specifically financing for health security initiatives (F1) and public healthcare spending per capita (F2), with overall health security performance scores (Ci) across WA countries, underscore that financial investment plays a critical role in bolstering health security. Higher levels of both targeted health security financing (F1) (0.98) and general public healthcare spending (F2) (0.97) were consistently associated with higher health security performance (F3). This relationship is particularly relevant for countries with substantial financial inputs, such as Armenia and Georgia, which show high health security scores, reflecting the effectiveness of financial investments in achieving improved preparedness and response capabilities. Conversely, countries with minimal or no spending in these categories, such as Syria and Yemen, exhibit some of the lowest health security scores, highlighting a likely resource gap in public health infrastructure that limits their resilience against health threats.\n\nThe observed trends indicate shifting priorities in health security strategies tailored to resource levels and specific risks faced by different income groups. High-income and upper-middle-income countries continue to prioritize detection and reporting, emphasizing the early identification of health threats to support rapid responses. By 2021, low- and lower-middle-income countries are increasingly focusing on prevention as a top priority, reflecting a proactive approach in contexts where reactive capacities may be limited. The lower weighting for health systems across all groups suggests either resource limitations or strategic reallocation toward other critical health security areas, possibly in response to post-2019 health events. These evolving priorities underscore diverse approaches to health security, reflecting each income group’s unique challenges, resources, and public health goals.\n\nFurthermore, this study highlights considerable disparities in health resilience among countries shaped by income levels, resource availability, and political stability. High-income countries (HICs), such as Qatar and Georgia, improved their health security rankings by leveraging financial investments and strategic international partnerships, while conflict-affected, low-resource nations, namely Iraq, Yemen, and Syria, experienced stagnation or decline. These findings underscore the urgent need for a regional framework to address health security inequities, bridge the gap between high- and low-income nations, and foster sustainable public health resilience across the WA. The observed disparities align with the broader global patterns seen in low-income and politically unstable regions, where limitations in funding and infrastructure often constrain health security progress. Iraq’s mixed performance—with some improvements in detection and reporting (DR) but an overall cluster decline—illustrates the challenge of sustaining health system gains in volatile settings without consistent, comprehensive investment and policy commitment. Similarly, Yemen’s persistently low scores in prevention (PR) mirror challenges observed in sub-Saharan Africa, where under-resourced health systems struggle to prioritize preventive health measures, leading to high public health burdens and limited security capabilities (Nasser & Alghawli, 2024).\n\nThe results indicated that the challenges faced by Iraq, Yemen, and Syria in health security are intricately linked to substantial resource allocation issues. For Iraq, the decline from the fourth to the fifth cluster, despite some advances in specific areas, such as detection, suggests that targeted investments without a holistic, integrated approach may be insufficient. Improvements in specific functions such as detection capabilities offer limited, temporary benefits if not supported by robust health infrastructure, workforce training, and preventive care, which are necessary for long-term resilience (Emami et al., 2024). The persistently low PR and DR scores for Yemen and Syria emphasize the urgent need for foundational health infrastructure investments, particularly in crisis-prone regions where preventive measures are essential to mitigate disease spread. Research in crisis settings highlights that strengthening early detection and preventive health measures reduces the spread of communicable diseases and alleviates public health burden over time (Meckawy et al., 2022). Allocating resources to these core health security areas, such as early intervention, surveillance, and effective disease management, can enhance health resilience and reduce vulnerability to future crises.\n\nThe findings of the correlation analysis have important policy implications. First, they suggested that investments in health security financing (F1) and general healthcare spending (F2) are likely critical for achieving higher health security performance. Governments and international organizations aiming to enhance global health security might consider these financial indicators as key benchmarks for strengthening the health system. By strategically increasing F1 and F2, countries may improve their ability to meet international health security standards and enhance their response capabilities in line with the Joint External Evaluation (JEE) and Performance Verification System (PVS) recommendations. To mitigate the identified challenges, policy interventions that prioritize preventive care, detection, and overall health system resilience are crucial for countries facing stagnation or decline in health security. For Iraq, policy adjustments focused on integrating resources across crisis responses, infrastructure, and workforce development could promote a balanced health system and ensure sustainable improvement. For Yemen and Syria, persistently low PR and DR scores underscore the need for both regional and international support to establish a basic public health infrastructure. Regional cooperation can also standardize protocols, enhance healthcare workforce training, and align public health policies with international standards, thus enabling lower-resource countries to manage public health threats more effectively and reduce their vulnerability to crises.\n\nIn summary, the findings of this study highlight the essential need for a unified regional approach to health security in WA, encouraging equitable resource allocation, coordinated health strategies, and comprehensive policy interventions that collectively enhance public health resilience across various economic and political landscapes.\n\n\n5. Conclusion\n\nThis study provides a comprehensive assessment of health security performance across Western Asia (WA) from 2019 to 2021, revealing both progress and persistent vulnerabilities within the region. A significant finding from this study is the critical role of foundational health infrastructure, particularly in areas such as health system capacity (HS), detection and reporting (DR), rapid response (RR), and environmental risk management (RE). The consistently high weighting of the HS and DR indicators underscores their importance in achieving resilient health systems capable of mitigating public health threats. However, the increased emphasis on RR and RE in 2021 reflected an adaptive shift in health security priorities following the COVID-19 pandemic. This shift suggests that while stable health systems and robust detection mechanisms are essential, there is also a growing need for effective rapid response measures and environmental risk management to address immediate and evolving crises.\n\nThe findings highlight significant disparities in health security shaped by variations in income levels, political stability, and resource availability. High-income countries (HICs), such as Qatar and Georgia, demonstrated the benefits of strategic investments and international partnerships, which enabled them to improve their health security rankings despite regional challenges. Conversely, conflict-affected, low-resource nations, such as Iraq, Yemen, and Syria, faced stagnation or even regression, illustrating the difficulties of sustaining health security gains without consistent resources and support.\n\nThe cluster analysis illustrates that while some countries in WA managed incremental improvements in health security, others experienced setbacks, widening the gap between high- and low-performing nations. The decline of Iraq, Yemen, and Syria to lower clusters reveals the limitations of targeted short-term investments when not supported by a holistic and integrated approach. In these countries, challenges in resource allocation have hindered the capacity to develop comprehensive health systems. The low scores in prevention (PR) and detection/reporting (DR) highlight the urgent need for a foundational infrastructure that facilitates early detection and effective disease management. This trend aligns with global findings in similar low-resource settings, where limited preventive measures and weak surveillance systems increase the vulnerability to health crises.\n\nOur analysis also demonstrated a significant positive association between financial investments in health security and public healthcare spending and overall health security performance. The strong correlations suggest that increased funding in these areas could substantially enhance a country’s health security capabilities, thereby improving its resilience to public health threats. As global health risks continue to evolve, these findings advocate targeted financial investments as part of comprehensive health-security strategies.\n\nThis study’s implications point to the necessity of a unified regional health security framework in WA that fosters equitable resource sharing, coordinated health strategies, and robust international partnerships. Through the consolidation of resources and expertise, Western African countries can address disparities in health resilience more effectively, particularly in nations facing significant economic or political challenges. Regional cooperation has the potential to standardize health protocols, enhance healthcare workforce training, and align policies with international standards, thereby strengthening health security across the region. Furthermore, the findings of this study underscore the critical need for coordinated efforts to bridge gaps in health security and to position the region to foster a robust and sustainable public health landscape.\n\nCoCoSo (The Combined Compromise Solution): A MCDM ranking model.\n\nD-CRITIC (Distance Correlation-based Criteria Importance through Inter-criteria Correlation): A method for determining the relative importance of criteria.\n\nGlobal Health Security Index (GHSI): A comprehensive assessment tool that measures health security capabilities across countries, focusing on various indicators that contribute to national and global health security.\n\nMulti-Criteria Decision Making (MCDM): A set of methods and techniques used to evaluate and prioritize multiple conflicting criteria in decision-making processes.\n\nWA (Western Asia) A geographical region in Asia.\n\nNo Ethical approval or consent needed.\n\n\nAuthor contributions\n\nAdel A. Nasser: Conceptualization, methodology, formal analysis, software, writing—original draft preparation; Abed Saif Ahmed Alghawli: Conceptualization, methodology, formal analysis, funding acquisition, and writing—original draft preparation; S. Saleh: Data curation, validation, investigation, resources, writing—review and editing, supervision; Amani A. K. Essayed: Visualization, software, and writing—review and editing.\n\n\nDeclaration of generative AI and AI-assisted technologies in the writing process\n\nDuring the preparation of this work the author(s) used [paperpal, quillbot, aistudio, and ChatGPT] for language refinement and structure. After using this tools, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.", "appendix": "Data availability\n\nThe data supporting the findings of this study are publicly available and can be accessed through the following repository (Global Health Security Index, Global Health Security Index Data Model and Report. (2021), at https://ghsindex.org/report-model/), (Global Health Security Index, 2021).\n\n\n\n1. Figshare: Supplementary File 1- Income-Based Analysis of Health Security in Western Asia through an Integrated GHSI, MCDM, and Clustering Model.pdf. Comprehensive data can be found in Tables 1-3 of the supplementary file Doi: https://doi.org/10.6084/m9.figshare.27992735.v3 (Nasser, et al. 2024b)\n\nThis project contains the following extended data:\n\n• Supplement File 1.pdf\n\nData are available under the terms of the CC BY 4.0\n\n2. Zenodo: supplementary-material-and-softwares: 1.0.0 Doi: https://doi.org/10.5281/zenodo.14541236 (Nasser, et al. 2024b).\n\nThe data supporting the findings of this study are publicly available and can be accessed through the following repository (https://github.com/ProfAdelAbdulsalam/supplementary-material-and-softwares/tree/1.0.0 )\n\n• This project contains the following extended data: ProfAdelAbdulsalam-supplementary-material-and-softwares-37cf50a\n\n○ LICENSE\n\n○ README.md\n\n○ Supplement File 1- Distance Correlation-based CRITIC software1.xlsx\n\n○ Supplement File 1-Supplement File - Income-Based Analysis of Health Security in Western Asia through an Integrated GHSI, MCDM, and Clustering Model.pdf\n\n○ Supplementary Software 2-An Integrated GHSI, MCDM, and Clustering Model for Health Security Analysis.xlsm\n\nAll data, processing and analysis results, figures, and tables related to this study are presented in Supplementary software 2 (Nasser et al., 2024b). This file integrates the processes of weighting, ranking, clustering, and Spearman rank correlation analyses into a single Excel-based tool, offering a comprehensive framework for evaluating the health security performance of Western Asian nations across all income groups (LIC, LMC, UMC, HIC) for the years 2019 and 2021.\n\nSource software available from: ((https://github.com/ProfAdelAbdulsalam/supplementary-material-and-softwares/tree/1.0.0)). Archived software available from (https://doi.org/10.5281/zenodo.14541236 ) (Nasser, et al., 2024b).\n\nLicense: OSI approved open license software is under GNU General Public License v3.0).\n\nThis supplementary resource provides detailed support for replicating the study’s methods and results.\n\n\nAcknowledgments\n\nNot applicable.\n\n\nReferences\n\nAlhaffar MHDBA, Janos S: Public health consequences after ten years of the Syrian crisis: A literature review. Glob. Health. 2021; 17(1): 111. 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Publisher Full Text\n\nYazdani M, Zarate P, Zavadskas K, et al.: A combined compromise solution (CoCoSo) method for multi-criteria decision-making problems. Manag. Decis. 2019; 57(9): 2501–2519. Publisher Full Text\n\nZimmerman DW: A note on modified rank correlation. J. Educ. Behav. Stat. 1994; 19(4): 357. Publisher Full Text\n\nZhang W, Zhang Y, et al.: Clustering the health security scores of countries: A new approach to evaluate regional health resilience. Health Policy Plan. 2021; 35(3): 318–325. Publisher Full Text" }	[ { "id": "358024", "date": "17 Jan 2025", "name": "Laith R. Flaih", "expertise": [ "Reviewer Expertise Security", "Big data analysis" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReferee's Report\nTo: F1000Research Journal\nTitle of Paper: Income-Based\n\nanalysis of health security in Western Asia through an integrated GHSI, MCDM, and cloistering model.\nAuthors: Naser A. A., Alghawli ASA, Saleh S. and Elsayed AAK.\n\nOverall In general, the manuscript contains many good results and is considered a good scientific addition to the field of study in which a novel approach was used. Reviewer Comments The following are suggestions and comments for improving the manuscript: 1. Add novelty of this work at the end of introduction section. 2. The justification for using k-means clustering could be elaborated. 3. Add the study limitations section 4. While the manuscript is generally well written, minor issues should be revised, for example, in a conclusion section “Western African countries can address disparities in health resilience more effectively…….\" Recommendation I recommend accepting the paper with minor revisions to address the comments outlined above. The proposed enhancements will improve the manuscript’s clarity, accessibility, and impact, ensuring it meets the high standards of your journal. Best regards, Dr. Laith R.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] } ]	1	https://f1000research.com/articles/14-43
https://f1000research.com/articles/12-1003/v1	18 Aug 23	{ "type": "Case Report", "title": "Case Report: Orbital cellulitis with panophthalmitis during pregnancy: a rare case in Bangladesh", "authors": [ "Md Iftekher Iqbal", "Fariah Osman", "Fariah Osman" ], "abstract": "Background: It is uncommon to develop vision-threatening orbital cellulitis with panophthalmitis during pregnancy. Typically, the reasons are trauma-related or endogenous. It requires immediate diagnosis and treatment, but this has proven difficult because of local and systemic medications’ safety and adverse effects during pregnancy. Globe salvage has a poor prognosis, with most patients undergoing enucleation or evisceration of the diseased eye. Case presentation: We presented a 22-year-old woman in her third trimester of pregnancy who encountered orbital cellulitis with panophthalmitis caused by methicillin-positive Staphylococcus aureus (MSSA). Despite rigorous intravenous and topical antibiotics, she underwent evisceration of the affected eye. However, the pregnancy, progressed without incident, with the delivery of a healthy baby at full-term. Conclusion: Bacterial infection is uncommon during pregnancy, but may cause endogenous panophthalmitis and orbital cellulitis, especially in immunosuppression and anemia, with a poor visual outcome.", "keywords": [ "orbital cellulitis", "panophthalmitis", "endophthalmitis", "pregnancy", "bangladesh", "epistaxis" ], "content": "Introduction\n\nOrbital cellulitis with panophthalmitis is a rare ocular condition, typically trauma-related or endogenous. Panophthalmitis is a severe form of inflammation of all eye coverings and intraocular contents from an internal or external source.1 There are no reports regarding orbital cellulitis with panophthalmitis other than endogenous endophthalmitis (EE). However, EE during pregnancy is extremely rare.2 It’s critical to distinguish endophthalmitis from panophthalmitis. Though both endophthalmitis and panophthalmitis are on the same variety of ocular infection, panophthalmitis is more complicated and happens when worsening endophthalmitis covers the all layers of eyeball, including the orbital contents.\n\nEE is a potentially harmful eye disease that occurs after an organism from the bloodstream reaches the eye, and 2–8% of cases of endophthalmitis are endogenous bacterial endophthalmitis (EBE). Recent research on EE from India reported no systemic infective foci in 67.6% of incidents. The infectious agents retrieved were 48% gram-positive bacteria, 37% gram-negative bacteria, and 15% fungi.3\n\nSpecific measures, e.g., surgical procedures or an intravenous line insertion, are established risk factors for endogenous endophthalmitis and panophthalmitis. Moreover, pregnancy, a subtle immunosuppression state in which the body minimizes its natural proinflammatory host responses to protect the developing fetus.4\n\nEE is a rebellious condition since the systemic infectious foci and the ocular inflammation must be managed immediately and appropriately. The patient requires a thorough systemic evaluation to identify the septic foci and treat that with suitable germicides for an extended period. Regardless, the visual outcome can be poor.3 In this case, the management of EE patients presents distinct problems because of the violent nature of EE and concerns about the newborn safety of the systemic and intravitreal medication.2\n\nDespite extensive treatment, panophthalmitis due to S. aureus has poor visual outcomes. All previously described cases of simultaneous orbital cellulitis and panophthalmitis required evisceration or enucleation, with a poor prognosis for globe salvage.5\n\nTo our knowledge, orbital cellulitis with endogenous panophthalmitis in pregnant women has never been recorded in Bangladesh or any other South Asian nation. We discussed this unusual presentation of such due to Staphylococcus aureus (SA) in a 33-week pregnant lady with a history of left-sided spontaneous epistaxis to raise awareness of this deadly, vision-threatening complication during pregnancy.\n\n\nCase report\n\nA 22-year-old primigravida, in her third trimester (33 weeks) of gestation, came to us with abrupt, painful vision loss in the left eye coupled with eyelid chemosis, forward bulging of the eye, and purulent discharge for two days.\n\nShe reported having several episodes of left-sided spontaneous epistaxis, a 102°F fever, and generalized weakness eight days before she started experiencing visual symptoms. Her obstetrician was consulted about these symptoms, and she was admitted to the hospital for additional assessment and treatment.\n\nShe had unremarkable medical history with no personal or familial bleeding tendencies. She was not taking any medications and had a normal range of blood pressure. She had never had any episodes of epistaxis before.\n\nAt that time, her blood reports showed mild anemia (normocytic normochromic) with septicemia: 7.2 g/dL of hemoglobin (normal: 10–14 g/dL) and neutrophilic leukocytosis with a total white blood cell count of 12,300/L (normal: 4,000–11,000/L) with 82% neutrophils (normal: 40–75%) and a high serum IgE level of 369.81 KIU/L (normal: 100–150 KIU/L).\n\nThe coagulation profile showed no abnormalities. Human immunodeficiency virus (HIV), hepatitis B and C viruses, TPHA, VDRL, QuantiFERON-TB Gold, and Toxoplasmosis IgM and IgG were negative. Routine microscopic urine examinations and renal and hepatic function tests were within normal physiological limits. Consecutive blood and urine cultures showed negative results as well. There were no foci of active infection on systemic examination.\n\nDuring her hospital stay, she was treated by an otolaryngologist, who applied a nasal pack soaked with a topical vasoconstrictor under the guidance of a nasoendoscope, which halted the bleeding. The nasal pack was removed after 7 hours without any further history of epistaxis. She also received two doses of intravenous dextrose infusion, one bag of B-positive fresh blood (450 ml) transfusion for mild anemia (7.2 gm/dl), and two doses of broad-spectrum injectable antibiotic.\n\nOn ocular examination, she only perceived light with an inaccurate ray’s projection in the left eye and 6/6 in the right eye. There were tense lid edema and proptosis (Figure 1) with severely restricted eye movement in all gazes. There were severely chemosed conjunctiva, circumcorneal congestion and edematous cornea, and no further visibility of the anterior and posterior segments. A B-scan ultrasonogram (USG) showed moderate hyperechogenic shadows with cavitations in the vitreous cavity, which disappeared at low gain with attached retina and increased choroidal thickness in the left eye (Figure 2). So diagnosed as a case of left-sided orbital cellulitis with endogenous endophthalmitis (EE).\n\nTreatment included intravenous (IV) injection of amoxicillin-clavulanic acid (1.2 g, two times daily) for five days, topical 0.5% moxifloxacin every hour, prednisolone acetate 1% eye drop every two hours, and 1% atropine sulfate eye drop every eight hours.\n\nFollowing the therapy, however, the patient’s condition worsened. She presented with a melted cornea with frank purulent discharge and uveal tissue the following day (Figure 3). While examining the left eye, there was no light’s perception; no notable pathology in the right eye with a 6/6, N5 visual acuity. The injection site looked healthy, with no signs of infection when checking for the source of infection. So, a diagnosis of orbital cellulitis with endogenous panophthalmitis was made in the left eye.\n\nAt that time, her blood investigations came out as a mild anemia with septicemia: 9.6 g/dL hemoglobin, leukocytosis with counts of 13,200/μL, and thrombocytopenia with counts of 2,94,000/μL. The coagulation profile was within normal limits except for a raised activated partial thromboplastin time (APTT) of 45 seconds (control: 30.0 seconds).\n\nAfter counselling the patient and her husband, evisceration of the left eye was advised. Intraoperatively, the sclera-corneal melting was evident, and completely removed all intraocular contents. All removed ocular contents were sent for microbiological analysis, and significant growth of Staphylococcus aureus (SA) was reported. We continued the previous treatment regimen during the immediate postoperative period.\n\nAs her condition improved clinically, we discharged her on the third postoperative day with oral levofloxacin tablets of 750 mg once a day for seven days, moxifloxacin eye drops every four hours for a month, and prednisolone phosphate 1% eye drops every two hours for three days, followed by six times for seven days, four times for seven days, thrice for seven days, and twice for another seven days. She had been on regular follow-ups for the last two months with no further ocular or obstetric complications.\n\nMeanwhile, routine scans for fetus at regular intervals were done to confirm the fetus’s viability. In contrast, the last ultrasonogram of the pregnancy profile showed about 34+ weeks of a single live pregnancy with cephalic presentation. The patient delivered a healthy male infant at 36 weeks without complications.\n\n\nDiscussion\n\nPregnancy is a unique immunological condition characterized by several physiological modifications in the maternal immune system. The aggressiveness of infectious uveitis during pregnancy and early postpartum may be due to the relative immune suppression during pregnancy.6 At 33 weeks of pregnancy, our 22-year-old primigravida patient presented with abrupt, severe hazy vision in her left and eyelid chemosis, proptosis, and purulent discharge.\n\nDuring an eye examination, she perceived light with an inaccurate projection of rays in the left eye, while the right eye had 6/6 vision. There was moderate proptosis, eyelid and conjunctival chemosis, ciliary congestion with corneal edema, and no other view of both segments of the left eye (Figure 1). A clinical diagnosis of orbital cellulitis with endogenous endophthalmitis (EE) was made, and B-scan USG findings were suggestive of endophthalmitis (Figure 2). Uncontrolled diabetes mellitus, use of catheters, low neutrophil count, immunosupressed patients, and patients on chemotherapy were predisposed to EE. Despite reports of anecdotal cases, pregnancy is not associated with higher EE rates.2 These cases had a history of either septic abortion, handling of an intrauterine device, or IV fluid infusion.2 Our patient received intravenous injections of dextrose infusion, fresh blood transfusion, and broad-spectrum injectable antibiotic as her initial blood reports showed 7.2 g/dL Hb (normal: 10–14 g/dL) and 12,300/μL total white blood cells count (normal: 4,000–11,000/μL) with 82% neutrophil (normal: 40–75%), which her gynecologist prescribed. Her other hematological and urine analysis, including blood and urine cultures, were negative for any organisms, and there were no systemic foci of infections.\n\nWhile the treatment of endophthalmitis is the similar regardless of the cause, the endogenous endophthalmitis in pregnancy presents unique difficulties, particularly regarding the welfare of intravitreal and systemic medications. Additionally, the safety of any interventional procedure for a pregnant patient is a concern.2 As penicillin, cephalosporins, and erythromycin are the best option in pregnancy,2 we initiated the treatment with IV injection of amoxicillin-clavulanic acid (1.2 g, two times daily) for five days, topical 0.5% moxifloxacin every hour, prednisolone acetate 1% eye drop every two hourly and 1% atropine sulfate eye drop eight hourly. However, the patient’s condition worsened by the next day, and she presented with the features of orbital cellulitis with panophthalmitis in the left eye (Figure 3). Her blood reports reflected the anemia and sepsis even after blood transfusion and broad-spectrum antibiotics.\n\nAlthough endophthalmitis and panophthalmitis are distinct kinds of ocular infections, severity of panophthalmitis is more, developing once endophthalmitis deteriorates and spreads to the whole globe and all layers of the eyeball. Panophthalmitis with concurrent orbital cellulitis is rare and has a low likelihood of saving globe, with all earlier documented cases necessitating evisceration or enucleation.1 Under the prior treatment regimen, we chose to eviscerate the left eye and send the ocular samples for microbiological examination, which came back positive for MSSA despite a positive blood culture. 2-8% of all cases of EE belongs to the endogenous bacterial endophthalmitis (EBE).7\n\nAdditionally, some forms of immunosuppression were reported in all cases, which adds to the highly violent course, with mostly having cellulitis shortly after symptoms begin.\n\nDespite intensive treatment, panophthalmitis with S. aureus has been shown to have poorer result. Surgical procedures, or any IV insertions, are known to increase the risk of EE and panophthalmitis.4\n\nBefore the visual complaints, she experienced bouts of left-sided epistaxis, for which the otolaryngologist used an anterior nasal pack soaked with a vasoconstrictor to successfully control the bleeding. Epistaxis is prevalent during pregnancy, although most episodes do not need medical treatment. Several circumstances increase the risk of epistaxis during pregnancy. Elevated estrogen levels, in particular, promote the nasal mucosal vascularity, and the incidence is 20.3% in pregnant women where 6.2% in nonpregnant women.8 We ruled out epistaxis caused by nasal lesions such as granuloma gravidarum and nasal polyps, as well as clotting problems.\n\nHer blood IgE level was 369.81 KIU/L (normal: 100–150 KIU/L), although she had no rhinosinusitis or allergy symptoms. Pregnancy and allergic rhinitis frequently coexist. Attention deficit hyperactivity disorder (ADHD) is highly linked to total IgE levels in the mother’s prenatal blood but not to levels in her early life or childhood.9 We advised the patient to get the newborn infant checked regularly.\n\nWe believe that the combination of immunodepression and, in conjunction with it, anemia may have contributed to our patient’s ophthalmic situation rapidly progressing from early feature of hazy vision and eye ache to total blindness and proptosis with restricted ocular motility in less than 24 hours. According to Chaudhry et al.,10 the following are possible explanations for orbital cellulitis’ rapid blindness loss:\n\n1. Optic neuritis as a result of a neighboring or contiguous infection,\n\n2. Thrombophlebitis-induced ischemia in the valveless orbital veins, or\n\n3. Ischemia caused by compression or pressure may result in central artery blockage.\n\nAfter improvement of the patient’s condition post-operatively, she was discharged and followed-up regularly. We ensured her fetal well-being throughout the pregnancy period and later delivered a healthy male baby at her 36-weeks of pregnancy without any complication.\n\nThis sort of case scenario requires multidisciplinary team including infectious disease specialist or an internist along with the ophthalmologist and gynecologist and obstetrician to manage promptly and safely.\n\n\nConclusion\n\nPregnancy poses a significant immunocompromised state when any infection, particularly with the women in impoverished countries like Bangladesh, should be identified as soon as possible to prevent further infection, particularly ocular and periocular regions. Orbital cellulitis with panophthalmitis has a disastrous prognosis and nearly invariably requires eye removal. It is critical to intervene quickly to eliminate the infective focus and treat the incidence of anemia in pregnancy. Because of its intricacy, it is a condition that warrants collaborative care by infectious disease, ophthalmology, and perinatal specialists.\n\n\nDeclaration of patient consent\n\nWritten informed consent for publication of their clinical details and clinical images was obtained from the patient.", "appendix": "Data availability statement\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReferences\n\nAulakh S, Nair AG, Gandhi R, et al.: Orbital Cellulitis with Endogenous Panophthalmitis Caused by Methicillin-Sensitive Staphylococcus aureus in Pregnancy. Jpn. J. Infect. Dis. 2017; 70(3): 314–316. PubMed Abstract \| Publisher Full Text\n\nSahu C, Kumar K, Sinha MK, et al.: Review of endogenous endophthalmitis during pregnancy including case series. Int. Ophthalmol. 2013; 33: 611–618. PubMed Abstract \| Publisher Full Text\n\nSingh SR, Bhattacharyya A, Dogra MR, et al.: Endogenous endophthalmitis due to Staphylococcus aureus in a lactating woman. Indian J. Ophthalmol. 2020; 68: 2595–2597. PubMed Abstract \| Publisher Full Text\n\nSingh N, Perfect JR: Immune reconstitution syndrome and exacerbation of infections after pregnancy. Clin. Infect. Dis. 2007; 45: 1192–1199. PubMed Abstract \| Publisher Full Text\n\nMaccheron LJ, Groeneveld ER, Ohlrich SJ, et al.: Orbital cellulitis, panophthalmitis, and ecthyma gangrenosum in an immunocompromised host with pseudomonas septicemia. Am J. Ophthalmol. 2004; 137: 176–178. PubMed Abstract \| Publisher Full Text\n\nKump LI, Cervantes-Castañeda RA, Androudi SN, et al.: Patterns of exacerbations of chronic non-infectious uveitis in pregnancy and puerperium. Ocul. Immunol. Inflamm. 2006; 14: 99–104. PubMed Abstract \| Publisher Full Text\n\nJackson TL, Paraskevopoulos T, Georgalas I: Systematic review of 342 cases of endogenous bacterial endophthalmitis. Surv. Ophthalmol. 2014; 59: 627–635. PubMed Abstract \| Publisher Full Text\n\nPiccioni MG, Derme M, Salerno L, et al.: Management of Severe Epistaxis during Pregnancy: A Case Report and Review of the Literature. Case Rep. Obstet. Gynecol. January 2019; 2019: 1–3. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nStraughen JK, Sitarik AR, Johnson CC, et al.: Prenatal IgE as a Risk Factor for the Development of Childhood Neurodevelopmental Disorders. Front. Pediatr. May 2021; 9: 9. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nChaudhry IA, Al-Rashed W, Arat YO: The hot orbit: orbital cellulitis. Middle East Afr. J. Ophthalmol. 2012; 19: 34–42. PubMed Abstract \| Publisher Full Text \| Free Full Text" }	[ { "id": "198374", "date": "22 Jan 2024", "name": "Hidehiro Oku", "expertise": [ "Reviewer Expertise ophthalmology" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article describes cooccurrence of orbital cellulitis and pan ophthalmitis in a pregnant lady. The authors propose a possibility of immunosuppressive state during pregnancy may contribute the present vision threatening condition. As the authors state, these 2 conditions are distinct condition and rarely combined. I understand that undergoing imaging tests during pregnancy carries risks to the fetus, but I would like to know how the diagnosis of orbital cellulitis was made and where the source of infection might be.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes", "responses": [ { "c_id": "10948", "date": "13 Apr 2024", "name": "Md Iftekher Iqbal", "role": "Author Response", "response": "Thank you so much for agreeing to review this. Most probably patient had chronic sinusitis from the beginning which was unrecognized by her and during the pregnancy it flared up and ended up like this at the end. As radiological imaging was not possible during the pregnancy state, clinical features, B-scan report, and hematological findings were evaluated to reach the diagnosis of orbital cellulitis initially." } ] }, { "id": "220831", "date": "30 Dec 2024", "name": "Pradeep Kumar Panigrahi", "expertise": [ "Reviewer Expertise Vitreo-retina", "surgical retina", "medical retina" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have described a case of orbital cellulitis and panophthalmitis in a pregnant female.\n1. How was the diagnosis of orbital cellulitis reached at?\n2. The patient presented with loss of vision, proptosis, discharge, no view of fundus, increased choroidal thickness and exudates in the vitreous. All these point to the fact that the patient presented with panophthalmitis to the authors rather than EE. EE might have been present during her previous hospitalisation, but when the patient presented to the authors, it was already panophthalmitis. So rather than saying orbital cellulitis, I think the diagnosis is panophthalmitis. 3. Did the authors look for the T-sign in USG? 4. What broad spectrum antibiotic was used in the previous hospital stay?\n5. What is the possible source of infection in this case? 6. Why did not the authors plan sending any ocular sample for microbiological analysis? Was the eviscerated material sent to microbiology?\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly", "responses": [ { "c_id": "13049", "date": "08 Jan 2025", "name": "Md Iftekher Iqbal", "role": "Author Response", "response": "Thank you for reviewing the article. I am trying my best to convince you to approve the article with the following clarification as you've pointed out: 1) As the patient came to us with painful proptosis with dimness of vision, periocular swelling, and restricted ocular motility, we clinically diagnosed the case as an orbital cellulitis with endogenous endophthalmitis, which was supported by the B-Scan initially. 2) During her hospital stay, two days before arriving to us, her clinical condition and hematological profile were mentioned in the case presentation, which didn't show endophthalmitis but rather an inflammatory response at that time. 3) A T-sign was not present when we did the B-scan, which could be an indicator of posterior scleritis. 4) Ceftriaxone was used in the previous hospital stay. 5) We believe pregnancy (as a state of immunosuppression), the presence of anemia, and the application of a nasal pack could contribute to this presentation. 6) As mentioned in the case presentation, eviscerated materials were sent for microbiological tests and came out positive for staphylococcus aureus. Thank you and best regards." } ] } ]	1	https://f1000research.com/articles/12-1003
https://f1000research.com/articles/13-747/v1	05 Jul 24	{ "type": "Research Article", "title": "Deciphering the significance of neutrophil to lymphocyte and monocyte to lymphocyte ratios in tuberculosis: A case-control study from southern India", "authors": [ "Poorva Bakshi", "Rakshatha Nayak", "Sharada Rai", "Shikha Jayasheelan", "Poorva Bakshi", "Sharada Rai", "Shikha Jayasheelan" ], "abstract": "Background Diagnosis of tuberculosis (TB) in resource-limited countries relies primarily on bacteriological confirmation using Ziehl-Neelsen (ZN) stain or culture. However, this method has low sensitivity due to suboptimal sampling and techniques. Neutrophils, monocytes, and lymphocytes are crucial in the pathogenesis of granulomatous inflammation and immune reactions. We investigated the usefulness of the haematological parameters and their ratios, like the Neutrophil to Lymphocyte ratio (NLR) and Monocyte to Lymphocyte ratio (MLR), for diagnosing tuberculosis.\n\nMethods We retrospectively grouped 114 patients with fever into those diagnosed with TB and control groups. We obtained their haematological data and calculated their derived ratios. The ratios obtained from the two groups were compared. Their sensitivity and specificity were calculated.\n\nResults Haematological parameters like MLR were higher in TB patients than in the control group. Although NLR was not significantly increased, MLR was significantly increased with p values <0.05. These tests had low sensitivity but high specificity.\n\nConclusion Serum NLR and MLR emerge as valuable tools in TB diagnosis. Their simplicity and cost-effectiveness render them particularly suitable for screening and recurrence monitoring in rural and remote settings, thereby mitigating loss to follow-up.", "keywords": [ "NLR", "MLR", "Tuberculosis", "Infectious diseases", "Hematology" ], "content": "Introduction\n\nTuberculosis (TB) is a chronic disease caused by the bacterium Mycobacterium tuberculosis, which has led to significant mortality and morbidity worldwide. Global statistics indicate that 10 million people have been diagnosed with TB.1 In particular, India bears the highest burden of TB, with an estimated 26.4 lakh cases.2 The impact of socioeconomic factors on TB outcomes in India has been well-documented.3\n\nThe most common, rapid, and cost-effective diagnostic method for TB in India is the microscopic detection of Acid-Fast Bacilli (AFB) using Ziehl-Neelsen (ZN) staining. However, this method’s sensitivity decreases when the bacterial load is less than 10,000 bacilli/ml, and it requires high-quality and large samples.4 Nucleic acid amplification tests (NAAT), which are more sensitive, are typically conducted in tertiary centers but are limited in rural areas of developing countries due to resource constraints.5 While the National Health Mission guidelines suggest diagnosing and treating TB based on high clinical suspicion, studies indicate lower survival rates among patients who receive empirical TB treatment compared to those with laboratory-confirmed TB infection.4 Despite being curable, late diagnosis, ineffective treatment, and loss of follow-up can result in relapse or the development of multidrug-resistant tuberculosis (MDR-TB) or extensively drug-resistant tuberculosis (XDR-TB). Late detection is primarily due to the unavailability of cost-effective and rapid tests in rural areas, exacerbating the TB burden in India. Loss of follow-up and relapse are often attributed to difficulties in accessing these tests. Timely, accurate, and affordable diagnostics are crucially needed, as delays in diagnosis can worsen outcomes and increase transmission rates.\n\nTB is characterized by granulomatous inflammation and caseous necrosis, with neutrophils playing a significant role in its pathogenesis.6–9 Activated macrophages release tumor necrosis factor (TNF) and chemokines, recruiting more monocytes and ultimately leading to the death of the mycobacterium.10 Hematological parameters such as neutrophils, lymphocytes, and monocytes exhibit variations in TB patients.11–13 In recent years, ratios derived from various hematological parameters have been explored as markers of inflammation in multiple diseases. NLR and MLR have demonstrated both diagnostic and prognostic value in TB.6–17 These tests are simple, rapid, cost-effective, and readily available even in rural areas, promising potential as adjunctive biomarkers for diagnosing and screening clinically suspected TB patients and detecting relapse in patients under follow-up.\n\n\nMethods\n\nThis is an analytical observational case-control study. The study was conducted at our tertiary hospital in Karnataka state of South India, from June to August 2022. The study included inpatients and outpatients who presented with a fever, had undergone laboratory tests in our institutional hospital to rule out tuberculosis, and had adequate clinical data. All terminally ill patients, patients with known comorbidities and on treatment were excluded from the study. The sampling process involved two stages. At first, a non-probability, convenience sampling method was employed to identify potential participants based on their presentation with fever and undergoing TB testing. Subsequently, purposive sampling was applied to select participants, strictly meeting the inclusion and exclusion criteria to minimize selection bias and ensure the representation of relevant clinical characteristics within each group. In this study, an effect size of 0.5 was chosen based on prior knowledge or expected differences in the variables under investigation, and a power of 80% (or 0.80) was selected. Kelsey’s formula was employed to calculate the sample size required for each group. This formula incorporates the effect size, power, and significance level to determine the minimum sample size needed to detect a significant difference between groups. A minimum sample size of 55 participants per group was calculated and deemed sufficient to detect the specified effect size with the chosen power level. The patients were divided into a TB group if the patients had a fever and tested positive for TB either by AFB culture, ZN stain, or NAAT and a control group if patients had a fever but tested negative for TB by the above-mentioned methods. The clinical details were procured from the case files. For the hematologic evaluation, for all groups, the following blood parameters: differential neutrophil, lymphocyte, and monocyte counts, were measured by an automated haematology analyser. The NLR was calculated by dividing the differential neutrophil count by the differential lymphocyte count, and the MLR by dividing the differential monocyte count by the differential lymphocyte count. Data was collected from laboratory software or case files and presented as mean±standard deviation (SD). It was recorded using Microsoft Excel. Statistical Package for the Social Sciences, version 29 software was used for statistical analysis. The T-test was used for continuous variables, and the chi-square test for categorical variables. A p-value of <0.05 was considered statistically significant.\n\nWe obtained approval from the Institutional Ethics Committee. (Kasturba Medical College, Mangalore), Reg. No. ECR/541/Inst/KA/2014/RR-20, DHR Reg. No. EC/NEW/INST/2020/742 with Protocol No. IECKMCMLR-11/2021/343. The approval was given on 17th November 2021. The committee permitted a waiver of consent to participate from the patients as patient details and data were sourced from case files, and tracing the patients proved challenging.\n\n\nResults\n\nIn total, 114 cases were included in the study, evenly distributed between the TB group (n=57) and the control group (n=57). Key hematologic markers assessed included Neutrophils, Lymphocytes, and Monocytes, with Neutrophil to Lymphocyte Ratio (NLR) and Monocyte to Lymphocyte Ratio (MLR) derived for each participant.18\n\nDifferential lymphocyte counts were found to be significantly elevated in TB cases compared to controls (P value=0.048), while MLR showed a significant increase in TB cases compared to controls (P value=0.031). However, no significant differences were observed in the counts of Neutrophils, Monocytes, and NLR between TB cases and controls. To distinguish between TB patients and controls, the cut-off values were established using Receiver Operating Characteristic (ROC) curve analysis. The cut-off value for NLR was set at >5 (Figure 1), while for MLR, it was set at >0.5 (Figure 2). Individually, NLR and MLR exhibited limited sensitivity in predicting TB, but demonstrated better specificity. However, when combining these parameters, there was significant increase in specificity, as shown in Table 1.19\n\n\nDiscussion\n\nTuberculosis remains a significant cause of morbidity worldwide, especially in low-income countries, emphasizing the critical need for accessible and cost-effective diagnostic methods. Despite the availability of rapid tests like the NAAT assay, challenges persist, particularly for diagnosing extra-pulmonary, pediatric, and smear-negative TB cases. Conventional methods such as smear tests are outdated, while serological tests lack accuracy.16,17\n\nOur study focused on key hematological parameters including neutrophil count, lymphocyte count, monocyte count, neutrophil-to-lymphocyte ratio (NLR), and monocyte-to-lymphocyte ratio (MLR) in patients presenting with fever, comparing those diagnosed with TB to others. Previous research has underscored NLR and MLR as significant markers for TB diagnosis and prognosis.6–16\n\nIn our investigation, MLR emerged as a standout parameter, exhibiting a statistically significant increase in TB patients compared to those without TB. This finding underscores the involvement of activated macrophages and monocytes in chronic granulomatous inflammation characteristic of TB. However, contrary to some prior studies, NLR did not demonstrate a significant role in TB diagnosis, possibly due to the involvement of neutrophils in non-granulomatous and acute inflammatory conditions. While NLR and MLR have shown associations with TB disease severity and treatment outcomes in some studies, their predictive value is not universally consistent.14–17 Factors like comorbidities, immune status, and TB strain virulence can influence the relationship between these ratios and clinical outcomes. NLR and MLR can also vary significantly between individuals based on factors like age, sex, and ethnicity and can fluctuate over time due to stress, medications, and physiological changes.15\n\nWhile individual hematological parameters showed limited sensitivity, combining MLR and NLR substantially improved sensitivity, specificity, and positive predictive value. This suggests the potential for a combined approach to aid in TB detection.\n\nAcknowledged study limitations include the lack of information about the diagnosis of the control group with fever, unknown hidden comorbidities, unsuspected infections or immune status of both control and cases, and the unknown virulence of the TB strain, potentially introducing variability in laboratory findings. Other limitations include the possibility of selection bias in the patient selection process despite strict adherence to inclusion and exclusion criteria due to a lack of relevant investigations of the desired population. Notably, individuals with TB who did not present with fever were excluded, potentially limiting the study’s representativeness of the TB population.\n\nDespite these limitations, our study highlights the importance of utilizing hematological parameters, particularly MLR, in TB diagnosis. While these ratios are non-specific, have inter-individual variation and limited predictive value, limiting their reliability as standalone markers of TB severity or treatment response, combining these ratios with established tests like elevated Erythrocyte Sedimentation Rate (ESR) offers promise for TB screening in resource-limited settings.\n\n\nConclusion\n\nIn conclusion, MLR emerges as a promising, cost-effective tool for early TB diagnosis. Utilizing a combined approach with NLR enhances screening efficacy, especially in cases with strong clinical suspicion. Moreover, this combined strategy holds the potential for monitoring patients during follow-up, mitigating relapse risks, and alleviating the TB burden, particularly in underserved regions and rural areas of low-income countries. Variations in study populations, laboratory methods, and analytical techniques contribute to inconsistencies in cutoff thresholds, hindering comparability and generalizability across studies. Therefore this avenue warrants further research to know its hold in clinical implications and also to validate their diagnostic accuracy, prognostic value, and predictive capabilities across diverse patient populations and clinical settings.", "appendix": "Data availability statement\n\nThis project contains the following underlying data:\n\n1. Data Excel sheet for Deciphering the significance of neutrophil to lymphocyte and monocyte to lymphocyte ratios in tuberculosis: A case-control study from southern India, Figshare: https://doi.org/10.6084/m9.figshare.23684778.v5 18\n\n2. Statistical analysis of Deciphering the significance of neutrophil to lymphocyte and monocyte to lymphocyte ratios in tuberculosis: A case-control study from southern India, Figshare: https://doi.org/10.6084/m9.figshare.23684859.v5 19\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain\n\n\nReferences\n\nWorld Health Organization: Tuberculosis (TB). [Accessed 9 February 2022]. Reference Source\n\nTBFacts: TB Statistics, India. [Accessed 9 February 2022]. Reference Source\n\nBhargava A: Social determinants of tuberculosis: context, framework, and the way forward to ending TB in India. Taylor & Francis; [Accessed 26 July 2022]. 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PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMiyahara R, Piyaworawong S, Naranbhai V, et al.: Predicting the risk of pulmonary tuberculosis based on the neutrophil-to-lymphocyte ratio at TB screening in HIV-infected individuals. BMC Infect. Dis. 2019; 19: 667. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nIliaz S, Iliaz R, Ortakoylu G, et al.: Value of neutrophil/lymphocyte ratio in the differential diagnosis of sarcoidosis and tuberculosis. Ann. Thorac. Med. 2014 Oct; 9(4): 232–235. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nChen G, Wu C, Luo Z, et al.: Platelet-lymphocyte ratios: a potential marker for pulmonary tuberculosis diagnosis in COPD patients. Int. J. Chron. Obstruct. Pulmon. Dis. 2016 Nov 3; 11: 2737–2740. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nIqbal S, Ahmed U, Khan MA: Haematological parameters altered in tuberculosis. Pak. J. Physiol. 2015 Mar 31; 11(1): 13–16.\n\nOkeke CO, Amilo GI, Ifeanyichukwu MO, et al.: Longitudinal assessment of the impact of tuberculosis infection and treatment on monocyte–lymphocyte ratio, neutrophil-lymphocyte ratio, and other white blood cell parameters. Egypt. J. Haematol. 2020 Apr 1; 45(2): 97. Publisher Full Text\n\nYoon NB, Son C, Um SJ: Role of the neutrophil-lymphocyte count ratio in the differential diagnosis between pulmonary tuberculosis and bacterial community-acquired pneumonia. Ann. Lab. Med. 2013 Mar 1; 33(2): 105–110. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nJeon Y, Lee WI, Kang SY, et al.: Neutrophil-to-Monocyte-Plus-Lymphocyte Ratio as a Potential Marker for Discriminating Pulmonary Tuberculosis from Nontuberculosis Infectious Lung Diseases. Lab. Med. 2019 Jul 16; 50(3): 286–291. Publisher Full Text\n\nRees CA, Pineros DB, Amour M, et al.: The potential of CBC-derived ratios (monocyte-to-lymphocyte, neutrophil-to-lymphocyte, and platelet-to-lymphocyte) to predict or diagnose incident TB infection in Tanzanian adolescents. BMC Infect. Dis. 2020; 20(1): 609. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nThe Lancet Infectious Diseases. Correction to Lancet Infect. Dis. 2020. published online Feb 18.\n\nJarosławski S, Pai M: Why are inaccurate tuberculosis serological tests widely used in the Indian private healthcare sector? A root-cause analysis. J. Epidemiol. Glob. Health. 2012; 2(1): 39–50. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nNayak R, Rai S: Data Excel sheet for Deciphering the significance of neutrophil to lymphocyte and monocyte to lymphocyte ratios in tuberculosis: A case-control study from southern India. figshare. [Dataset]. 2024. Publisher Full Text\n\nNayak R, Rai S: Statistical analysis for Deciphering the significance of neutrophil to lymphocyte and monocyte to lymphocyte ratios in tuberculosis: A case-control study from southern India. figshare. [Dataset]. 2024. Publisher Full Text" }	[ { "id": "308652", "date": "21 Aug 2024", "name": "Sivaporn Gatechompol", "expertise": [ "Reviewer Expertise Infectious disease", "focus on TB and HIV" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI am pleased to review this work. This is a case-control study in a tertiary hospital in India. The study aimed to assess the usefulness of Neutrophil to Lymphocyte ratio (NLR) and Monocyte to Lymphocyte ratio (MLR) for diagnosing tuberculosis. I have some comments as following\nMethods 1. The TB case definition is not clear. Which type of TB were included in the study (i.e pulmonary, extrapulmonry, or both) ? 2. What is the HIV status of the participants ? Since HIV has direclty effect on both NLR and MLR.\n\n3. The patients who had fever but tested negative for TB by AFB culture, ZN stain, or NAAT were assigned to the control group. How can the authors exclude smear/culture negative TB for this group ?\n\nResults 1. The authors mentioned in discussion that NLR and MLR can also vary significantly between individuals based on factors like age, sex, and ethnicity. But the authors did not provide these informations in the results or compare between cases and controls.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "13045", "date": "08 Jan 2025", "name": "Rakshatha Nayak", "role": "Author Response", "response": "Dear Madam, Thank you for reviewing our article and providing us with your valuable insights. In response to your suggestions, we have made the following revisions: The study included all patients with fever, encompassing both pulmonary and extrapulmonary TB cases. This information has been added to the inclusion criteria in the methodology section. We have excluded patients with known comorbidities as mentioned in Version 1. But as per your suggestion, we have specified few such as diabetes and HIV, as noted in the exclusion criteria section of the article in version 2 The controls were classified as true negatives after evaluating all clinical, radiological, microbiological, and molecular findings. This update has been reflected in the methodology section. There was no significant difference between age groups or sexes, and we have updated the results accordingly. Regarding ethnicity, we acknowledge the complexity of making comparisons in India due to the immense diversity across ethnic, linguistic, religious, and cultural lines, as well as historical, social, political, and genetic factors. As such, broad comparisons or generalizations about ethnicity would oversimplify the situation, and we have refrained from including such comparisons in the article. The article has been updated as per the suggestions provided by the reviewers. We kindly request you to review the updated version of the article and share your valuable feedback and approval. We have put sincere efforts into refining the study to enhance its accuracy and applicability, particularly in remote areas, to help reduce the global burden of tuberculosis. We look forward to your feedback." } ] }, { "id": "336227", "date": "13 Nov 2024", "name": "Tutik Tutik Kusmiati", "expertise": [ "Reviewer Expertise Pulmonology and Respiratory Medicine" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nin abstract: I agree that ZN has low sensitivity, but the culture sensitivity is very good.\nin introduction: In the introduction: you only wrote the reason for studying MLR because ZN is not sensitive and the source of funds for molecular examination is expensive. In my opinion, a more appropriate reason is: the difficulty of obtaining sputum samples to evaluate treatment because in more than 2 weeks of treatment the patient's complaints have decreased so that it is difficult to produce sputum because they are no longer coughing\nin Method: In the control group that was included only fever, why was the cough not asked, why was a chest X-ray not performed to rule out that the patient really did not have TB? As we know, there is clinically confirmed TB, namely if there are complaints that point to TB, the CXR results support TB but the bacteriological results are negative. To minimize bias, do you exclude patients with Diabetes and HIV because they are immunocompromised patients which can affect MMR and NLR values?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "13046", "date": "08 Jan 2025", "name": "Rakshatha Nayak", "role": "Author Response", "response": "Dear Madam, Thank you for reviewing our article and providing valuable feedback. In response to your suggestions, we have made the following revisions: We have revised the abstract to mention the other disadvantages of AFB culture, as opposed to focusing solely on its sensitivity, as per your recommendation. We agree with your point that obtaining sputum can be difficult in patients who do not present with a cough. We have added this concern as an additional point in the introduction to highlight the challenges involved. The study involved all patients presenting with fever, including those with extrapulmonary TB. Therefore, while we did inquire about symptoms such as cough and other clinical features, these were not specifically emphasized in the article. Following your suggestion, we have now included this information under the inclusion criteria in the methodology section (Version 2). We selected controls based on clinical, radiological, microbiological, and molecular findings to ensure that only true negative TB cases were included. We did not include TB patients without fever, as the subjects were selected from a fever OPD, which is mentioned in the study's limitations under discussion. Despite this limitation, we believe the study remains highly relevant, given that fever is the most common symptom in both pulmonary and extrapulmonary TB cases. We have excluded patients with known comorbidities as mentioned in Version 1. But as per your suggestion, we have specified few such as diabetes and HIV, as noted in the exclusion criteria section of the article in version 2. The article has been revised in accordance with the suggestions provided by the reviewers. We kindly request you to review the updated version of the article and share your valuable comments and approval. We have put sincere efforts into refining the study to enhance its accuracy and applicability, particularly in remote areas, to help reduce the global burden of tuberculosis. We look forward to your feedback." } ] } ]	1	https://f1000research.com/articles/13-747
https://f1000research.com/articles/13-1019/v1	06 Sep 24	{ "type": "Case Report", "title": "Case Report: Gastric Metastasis revealing a Disseminated Skin Melanoma: A Case Report and Literature Review", "authors": [ "Ramzi Tababi", "Amal Khsiba", "Moufida Mahmoudi", "Asma Ben Mohamed", "Manel Yakoubi", "Ghada Gharbi", "Abir Chaabane", "Emna Chelbi", "Mouna Medhioub", "Mohamed Lamine Hamzaoui", "Amal Khsiba", "Moufida Mahmoudi", "Asma Ben Mohamed", "Manel Yakoubi", "Ghada Gharbi", "Abir Chaabane", "Emna Chelbi", "Mouna Medhioub", "Mohamed Lamine Hamzaoui" ], "abstract": "Abstract\nBackground Melanoma, an aggressive malignant skin cancer, has the ability to spread both locoregionally and to distant sites. The risk of metastasis is correlated to invasion depth and the presence of ulceration. Although gastrointestinal (GI) metastases are uncommon, gastric involvement is particularly rare.\n\nCase presentation We report a case of a 62-year-old male who presented with abdominal pain, dyspepsia, anorexia, and weight loss. On physical examination abdominal masses and hepatomegaly were detected. Radiological imaging showed widespread masses in the abdominal and thoracic regions. Upper GI endoscopy identified an umbilicated protruded lesion with central dark pigmentation at the antro-fundic junction. Histopathological examination and immunohistochemical staining were consistent with melanoma. A subsequent rigorous skin examination uncovered a primary malignant skin melanoma. Due to worsening general condition, the patient received palliative hospice care.\n\nConclusion This report highlights the critical need for vigilant skin examination when encountering gastric lesions with dark pigmentation, which led to the identification of initially undetected cutaneous melanoma.", "keywords": [ "Melanoma", "Gastric metastasis", "Multi-organ metastases", "Digestive endoscopy", "Histopathology" ], "content": "Introduction\n\nThe incidence of melanoma is on the rise, particularly in developed countries with lighter skin populations, representing 1.7% of global cancer cases.1 It also constitutes 10% of all skin cancers and remains the primary cause of death among these malignancies.2 In fact, melanoma embodies a heterogeneous tumour group of distinct precursor cells, biological signature and presentations.1,2 Nodular melanoma is notably a malignant subtype, known for its aggressive behaviour and accounting for 16% to 25.6% of invasive cutaneous melanoma.2\n\nThe most frequent metastatic sites include the skin, lungs, liver, central nervous system and bones. Less frequently, metastases occur in the kidneys, adrenal glands, and gastrointestinal (GI) tract, with gastric involvement being particularly rare.3\n\nIn this report, we present a rare case of gastric metastasis from melanoma that led to the discovery of the initially unnoticed primary skin lesion. We describe the endoscopic and histopathological findings, as well as the nonspecific clinical symptoms that prompted the diagnostic investigation.\n\n\nCase report\n\nA 62-year-old Caucasian male patient, with a medical history of hypertension and coronary artery disease, presented with diffuse abdominal pain, along with dyspepsia, anorexia and weight loss for the past 6 months. Physical examination revealed abdominal tenderness, as well as multiple fixed and hard nodules of the thoracic and abdominal walls, as well as in the Douglas pouch on rectal examination, suggestive of carcinomatosis. An enlarged, firm, and tender liver was also noted. No jaundice or palpable lymph nodes were observed.\n\nLaboratory findings were within the normal range, notably for complete blood count and liver function tests.\n\nAbdominal ultrasound (US) showed a non-dysmorphic liver with a heterogenous lobulated hypoechoic mass, vascularised on Doppler, measuring 83 × 60 mm, associated with omental adipose tissue nodule of 37 mm, sharing the same characteristics. On the CT scan (Figure 1), the hepatic mass was isodense, poorly defined, spanning segments V, VII and VIII, showing weak enhancement with contrast, measuring 100 × 60 mm. There were also multiple scattered tissue masses enhanced with contrast, located in the peritoneum, in the retroperitoneum, and sub-peritoneal, as well as in the left adrenal gland. The pancreas was normal. Plus, multiple solid pulmonary nodules were observed, involving all segments, alongside mediastinal and abdominal lymphadenopathies.\n\n(A): Subcutaneous soft tissue nodule of the anterior right thoracic wall (arrow). (B): Bilateral pulmonary nodules. (C): Hypodense hepatic mass in the right lobe on the portal phase, measuring 100 × 60 millimeters. (D): Intraperitoneal adenomegalies (circle) and heterogeneous nodules in the right perirenal retroperitoneal region. (E): Heterogeneous peritoneal nodules (arrows) and small subcutaneous soft tissue nodules in the right lateral abdominal wall (circle).\n\nAt this point, widespread metastases were the leading considered diagnosis based on the clinical context and radiological presentation. Alpha-fetoprotein and prostate specific antigen levels were normal.\n\nIn the investigation for the primary cancer, and given the recent dyspepsia and epigastric pain, an upper gastrointestinal endoscopy was performed revealing a polypoid lesion at the antro-fundic junction measuring 20 mm in diameter, with a depressed and ulcerated centre, containing dark pigmentation (Figure 2). The histological examination showed a tumour proliferation extensively invading the antro-fundic mucosa, formed by clusters of flattened and disintegrated cells. The tumour cells were frequently small, with hyperchromatic nuclei. In certain areas, larger cells with ballooned, clarified, or vacuolated cytoplasm were seen. Some cells displayed nuclear monstrosity, and deposits of brownish pigments were also noted. Immunohistochemistry analysis revealed positive staining for melanocytic markers Melan-A, S100 protein and HMB45 (Figure 3). Other markers were negative, namely pancytokeratin, TTF 1, CD 45, chromogranin, and synaptophysin. These findings were consistent with a gastric localisation of a poorly differentiated tumour with an immunohistochemical profile compatible with a melanoma.\n\nRetroflexion shows an elevated lesion at the antrum-fundus junction with a depressed centre, resembling a volcano appearance, with brown pigments.\n\n(A): Hematoxylin & eosin staining on x200 magnification shows malignant proliferation infiltrating the gastric mucosa. Tumour cells are pleomorphic and disaggregated, exhibiting marked nuclear atypia with hyperchromatic and sometimes monstruous nuclei (black arrows). Some larger cells with clear cytoplasm were present (white arrows). Deposits of brown pigments are also seen (). Immunohistochemistry demonstrated positive staining with Melan-A (B) and PS 100 (C).\n\nWith these results in mind, a thorough skin examination was thus undertaken unveiling a cutaneous lesion in the back, manifesting as a circumscribed pink nodule of 8 mm with brown discoloration (Figure 4).\n\nIt appears as a circumscribed dark pink nodule measuring 8 millimeters in diameter with areas of brown discoloration. The lesion also has a slightly irregular surface and a surrounding area of erythema.\n\nHistological assessment of the skin lesion biopsy showed the presence of a cellular proliferation in the dermis composed of vaguely naevoid cells and larger cells with abundant eosinophilic cytoplasm, atypical pleomorphic nucleolated nuclei and no junctional activity. On immunohistochemistry, tumour cells exhibited positive staining with Melan-A, HMB45, and p16 (Figure 5). These findings were suggestive of cutaneous nodular melanoma.\n\n(A): Hematoxylin & eosin staining on x100 magnification shows malignant cellular proliferation () in the dermis. Tumour cells have various size and shape with marked cytological atypia. On immunohistochemistry, they exhibit positive staining with HMB45 (B), Melan-A (C), and p16 (D).\n\nUltimately, the diagnosis of malignant cutaneous melanoma with diffuse multi-organ metastases, particularly involving the stomach, was confirmed. Subsequently, the patient’s general condition deteriorated, precluding the initiation of planned palliative chemotherapy. Supportive care was provided, including pain management, with a documented follow-up of 6 months.\n\n\nDiscussion\n\nThe stomach is an unusual metastatic site, though it can be a localisation of secondary lesions for certain cancers in 2.6% of cases, particularly breast cancer as well as lung cancer and melanoma.4,5 In fact, melanoma is one of the most frequent malignancies that metastasise in the GI tract. It can spread beyond the primary site to almost all organs. It is hypothesised that tumour cells disseminate through lymphatic nodes to systemic blood circulation via the thoracic duct.3 It has also been noted that cutaneous melanoma preferentially metastasises to upper GI tract, while uveal melanomas are more prone to spread to the liver.4 According to an autopsy study involving 216 patients with advanced malignant melanoma, the GI system was the second most prevalent site of metastases, following the lymph nodes (73.6%) and the lungs (71.3%).6 In this series multiple-organ metastases were most commonly involved (95%). Consistent with these findings, our patient presented disseminated disease affecting the lungs, the liver, the stomach, the subcutaneous tissue, the adrenal gland, the peritoneum, and lymph nodes. Secondary gastric melanoma was observed in 49 cases (22.7%) in that study. The other GI metastases comprised the liver (58.3%), the peritoneum (42.6%), the pancreas (37.5%), the small bowel (35.6%), the spleen (30.6%), the colon (28.2%), the oral cavity and the oesophagus (9.3%), and the biliary tract (8.8%). A previous autopsy series of 100 patients with cutaneous melanoma reported comparable prevalence, with gastric involvement in 26%.7 Although, GI metastases might not seem infrequent in autopsy, they are very likely to be subclinical, given that their incidence in clinical series are less high, namely intestinal metastases for instance which are found in only 1% to 7% of patients.3\n\nMelanoma gastric metastases may either be present at the primary diagnosis or occur even decades later indicating recurrence.8 In our study, the gastric lesion confirmed the melanoma diagnosis and motivated a further physical examination, uncovering a skin lesion that was initially missed during the first assessment. In fact, endoscopy was driven by the presence of upper abdominal discomfort. Nevertheless, metastases to the stomach are rarely detected pre-mortem owing to nonspecific symptoms that could be taken on the account of the general disease burden. As an illustration, the gastric localisation in our case could have been missed if epigastric pain and dyspepsia were attributed by default to a potential extrinsic compression by the liver mass or the peritoneal nodules, eventually sparing the patient upper GI endoscopy. This observation underscores the importance of GI endoscopy for patients with digestive symptoms in the context of malignancy. That can also provide a diagnostic confirmation and spare the patient from more invasive procedures, such as deep organ biopsies.\n\nA recent systematic review by Reggiani et al.9 included 113 patients with gastric metastases of melanoma, predominantly of primary skin site (62%). They were mostly male patients (64%) with a median age of 63 years old. They were asymptomatic in only 10% of cases, however the main symptoms included bleeding (34,5%), abdominal pain (34,5%), anorexia and weight loss (23%), as well as nausea and vomiting (17.7%). Dyspepsia was noted in only 5.3%. Gastric metastases were single in 42.5%, located mainly in the gastric body in 60.2% of cases. Yet, the diverse descriptions of lesions across the included studies resulted in significant variability, preventing the extraction of consensus uniform endoscopic characteristics in this review.\n\nHowever, an endoscopic classification was proposed by Nelson et al.10 in 1978 which identified three types of GI tract melanoma metastases: the first type comprises melanotic nodules of different sizes generally emerging on the top of normal folds, often with ulcerated tips. The second type consists of an elevated submucosal lesion with ulcerated centre with or without visible melanin, consistent with the lesion observed in our study. This type usually displays the “bull’s eye” aspect on radiological examination. The third type covers mass lesions with different extent of necrosis and melanosis. Plus, the morphology of raised lesions with ulcerated centre and no edge infiltration is often termed as volcano-like or donut-shaped,9 also resembling the lesion’s appearance in our case. Accordingly, such protruding lesions, especially with brown deposits, should suggest the possibility of gastric melanoma. Besides, other endoscopic descriptions have been deployed such as polypoid mass, small nodules, ulcers, and small black spots.5,8,11\n\nGI melanoma metastases can also mimic the appearance of primary gastric cancer or other gastric metastases.5,9,11 Therefore, histopathological examination along with immunohistochemical staining are key for final diagnosis. These metastases usually exhibit evident melanocytic characteristics, including cytological atypia, pleomorphism, sheet-like growth pattern, and increased proliferative activity, alongside positive staining with melanocytic markers,12 as found in both gastric and skin lesions in the current case. Nonetheless, typical immunophenotypic features can be lost in metastatic or primary lesions during tumour progression, known as phenotypic switching or cellular plasticity, as it has been reported cases of dedifferentiated and undifferentiated melanoma which were negative for melanocytic markers, namely Melan-A/MART 1, HMB45, S100 protein, and SOX 10.12,13 In these cases, molecular testing could help establish diagnosis detecting melanoma-compatible mutations like BRAF, NRAS and NF 1.13 In the case of our patient, the diagnosis of melanoma was supported by the histopathological findings and typical immunohistochemical profile of both gastric and skin lesions, requiring no further investigations.\n\nMetastatic melanoma undoubtedly carries a poor prognosis. Distant metastatic burden has been recognized as an important prognostic indicator. Plus, factors such as non-pulmonary visceral metastases and elevated serum lactate dehydrogenase (LDH) have been associated with an even more dismal survival, resulting in a one-year survival rate of only 33%.14,15 In the above-mentioned systematic review of gastric melanoma metastases, the median survival time was 3 months, with 16% and 4% survival rates at 1 year and 2 years respectively.9 There was also a significantly lower survival in case of multiple gastric lesions compared to single metastasis.\n\nGI resections have been performed in localised metastasis, with evidence of possible prolonged remission, or as an emergency procedure for complicated cases like GI bleeding or perforation.8,16 However, our patient presented extensive metastatic disease and hence was not a proper candidate for surgery. Patients with metastatic melanoma are more suited for systemic treatment, especially as in recent years, immunotherapy has shown promising results in improving survival, becoming the recommended first-line treatment.17 Nevertheless, immunotherapy drugs were not available at the time, and our patient general status worsened rapidly preventing chemotherapy treatment.\n\nIn summary, this case report provides a comprehensive documentation of the clinical, endoscopic, histological, and immunohistochemical features of gastric metastasis from melanoma, which is a rare occurrence. The strength of this report lies in its detailed presentation of these aspects, contributing valuable insights into the diagnosis of such metastases. However, the limitations of this study include a short follow-up period and the absence of specific treatment due to the patient's overall condition and the unavailability of immunotherapy.\n\n\nConclusion\n\nMetastases to the gastrointestinal tract are considered rare, particularly in the stomach. However, melanoma is known to be the most common cancer that metastasises to this site. This report presents a case where malignant cutaneous melanoma was initially uncovered by a gastric metastasis, confirmed through endoscopic, histopathological, and immunohistochemical findings. Importantly, a protruding gastrointestinal lesion with dark pigmentation observed during endoscopy should raise suspicion of melanoma and prompt a thorough skin examination to identify any potentially overlooked lesions. Histopathological assessment and immunohistochemistry are the gold standards for diagnosis. For widespread disease, palliative systemic treatment, including chemotherapy or immunotherapy, is preferred, while surgery is typically reserved for selected oligometastatic cases. Despite these treatments, the prognosis remains poor.\n\n\nConsent\n\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the patient.", "appendix": "Data availability\n\nNo data are associated with this article.\n\nZenodo: CARE checklist for ‘Case Report: Gastric Metastasis revealing a Disseminated Skin Melanoma: A Case Report and Literature Review’. DOI: https://zenodo.org/doi/10.5281/zenodo.13387861 18\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgements\n\nNo acknowledgments to declare.\n\n\nReferences\n\nSaginala K, Barsouk A, Aluru JS, et al.: Epidemiology of Melanoma. Med. Sci. 2021; 9(4): 63. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nDessinioti C, Geller AC, Whiteman DC, et al.: Not all melanomas are created equal: a review and call for more research into nodular melanoma. Br. J. Dermatol. 2021; 185(4): 700–710. PubMed Abstract \| Publisher Full Text\n\nDamsky WE, Rosenbaum LE, Bosenberg M: Decoding Melanoma Metastasis. Cancers. 2011; 3(1): 126–163. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWHO Classification of Tumours Editorial Board: Digestive System Tumours. 5th ed.International Agency for Research on Cancer; 2019.\n\nDe Palma GD, Masone S, Rega M, et al.: Metastatic tumors to the stomach: clinical and endoscopic features. World J. Gastroenterol. 2006; 12(45): 7326–7328. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPatel JK, Didolkar MS, Pickren JW, et al.: Metastatic pattern of malignant melanoma. A study of 216 autopsy cases. Am. J. Surg. 1978; 135(6): 807–810. Publisher Full Text\n\nGupta TKD: Metastatic Melanoma of the Gastrointestinal Tract. Arch. Surg. 1964; 88(6): 969. Publisher Full Text\n\nLa Selva D, Kozarek RA, Dorer RK, et al.: Primary and metastatic melanoma of the GI tract: clinical presentation, endoscopic findings, and patient outcomes. Surg. Endosc. 2020; 34(10): 4456–4462. PubMed Abstract \| Publisher Full Text\n\nReggiani HC, Pongeluppi ACA, Ferreira VFMM, et al.: Endoscopic diagnosis of gastric metastases from malignant melanoma: systematic review. Clin. Endosc. 2022; 55(4): 507–515. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nNelson RS, Lanza F: Malignant melanoma metastatic to the upper gastrointestinal tract: Endoscopic and radiologic correlations, form and evolution of lesions, and value of directed biopsy in diagnosis. Gastrointest. Endosc. 1978; 24(4): 156–158. PubMed Abstract \| Publisher Full Text\n\nMaksimaityte V, Reivytyte R, Milaknyte G, et al.: Metastatic multifocal melanoma of multiple organ systems: A case report. World J. Clin. Cases. 2022; 10(28): 10136–10145. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSaliba E, Bhawan J: Aberrant Expression of Immunohistochemical Markers in Malignant Melanoma: A Review. Dermatopathology. 2021; 8(3): 359–370. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAgaimy A, Stoehr R, Hornung A, et al.: Dedifferentiated and Undifferentiated Melanomas: Report of 35 New Cases With Literature Review and Proposal of Diagnostic Criteria. Am. J. Surg. Pathol. 2021; 45(2): 240–254. Publisher Full Text\n\nBalch CM, Gershenwald JE, Soong SJ, et al.: Final Version of 2009 AJCC Melanoma Staging and Classification. J. Clin. Oncol. 2009; 27(36): 6199–6206. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nGershenwald JE, Scolyer RA, Hess KR, et al.: Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J. Clin. 2017; 67(6): 472–492. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPatel K, Ward ST, Packer T, et al.: Malignant melanoma of the gastro-intestinal tract: a case series. Int. J. Surg. Lond. Engl. 2014; 12(5): 523–527. PubMed Abstract \| Publisher Full Text\n\nSeth R, Agarwala SS, Messersmith H, et al.: Systemic Therapy for Melanoma: ASCO Guideline Update. J. Clin. Oncol. 2023; 41(30): 4794–4820. PubMed Abstract \| Publisher Full Text\n\nTababi R: CARE checklist for “Case Report: Gastric Metastasis revealing a Disseminated Skin Melanoma: A Case Report and Literature Review.”.August 28, 2024. Publisher Full Text" }	[ { "id": "325913", "date": "05 Nov 2024", "name": "Gerardo Ferrara", "expertise": [ "Reviewer Expertise Anatomic Pathology", "Dermatopathology" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall the manuscript seems to be worth of indexing, because physical examination of the skin may be neglected when a patient discloses severe systemic symptoms. I have the following suggestions: 1. I suggest the Authors to rethink of the title by looking for some appealing features of the case (e.g.: can you see the elephant in the room?) 2. The manuscript must be shortened; no need to define melanoma; no need to itemize the cytomorphological feature of the cells on gastric biopsy 3. Besides being too long, the discussion is untidy. I suggest grouping clinical studies on one side, and autopsy studies on the other one\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes", "responses": [ { "c_id": "12903", "date": "16 Dec 2024", "name": "Ramzi Tababi", "role": "Author Response", "response": "We greatly appreciate your constructive feedback on our manuscript. We have carefully considered your suggestions and made the following revisions: Title Revision: In response to your suggestion, we have revised the title to make it more engaging and reflective of the core aspect of the case. We believe the new title highlights the critical role of the gastric metastasis in revealing the previously undetected cutaneous melanoma, aligning with the key feature of the case. Manuscript Shortening: As recommended, we have shortened the manuscript by removing the definition of melanoma and the detailed itemization of the cytomorphological features in the gastric biopsy section. Several sentences have also been reformulated in order to reduce the word count. These changes have streamlined the manuscript, keeping the focus on the essential points of the case. Discussion Structure: We have reorganized the discussion section as per your suggestion. We have followed a structured approach in presenting this section, starting with the frequency of GI and gastric metastasis (referencing two autopsy studies in the first paragraph to highlight the prevalence of GI involvement). Subsequent sections discuss (in order) clinical presentation, endoscopic findings, histopathological findings, prognosis, treatment, and finally, the strengths and limitations of the case. Autopsy studies were only included in the first paragraph to support the epidemiology of GI metastasis, while the remainder of the references are clinical studies. To improve conciseness and readability, we have streamlined the discussion by removing redundant sentences without compromising key points. We believe these revisions have enhanced the clarity and focus of the manuscript. Thank you once again for your valuable suggestions, which have significantly improved our work." } ] }, { "id": "322061", "date": "06 Nov 2024", "name": "Hanen Jaziri", "expertise": [ "Reviewer Expertise gasroenterology" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis an original case report because gastric metastasis of melanoma is very rare and uncommon and in this case the metastases revelled the skin melanoma Vigilant skin examination is very important because the prognosis of this tumour is worse This case is illustrated by computed tomography scan endoscopic and histological fundings No modification is needed\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes", "responses": [ { "c_id": "12902", "date": "02 Dec 2024", "name": "Ramzi Tababi", "role": "Author Response", "response": "Thank you for your positive feedback. We appreciate your recognition of the rarity and significance of the case, as well as the importance of vigilant skin examination in such patients. We are also glad that the use of imaging and histological findings was well-illustrated." } ] } ]	1	https://f1000research.com/articles/13-1019
https://f1000research.com/articles/13-1079/v1	20 Sep 24	{ "type": "Research Article", "title": "Influence of Smartphone Usage on development of Sexuality among Late Adolescent Boys in Health Sciences Colleges of South India", "authors": [ "Sharath M Manya", "Jayashree K", "Prasanna Mithra", "Preeti M Galagali", "Sara J Ommen", "Sharath M Manya", "Prasanna Mithra", "Preeti M Galagali", "Sara J Ommen" ], "abstract": "Background Better affordability of data plans and an increase in “budget” smartphones have resulted in an exponential rise in internet and smartphone users. The ease of access to sexually explicit material (SEM) coupled with adolescents’ impulsivity makes them prone to excessive SEM exposure and may affect the development of sexuality via the perceived realism of such content. This study was done to study the influence between problematic smartphone usage (PSU) and sexuality development among late adolescent boys.\n\nMethods One hundred and thirty-four adolescents aged 18-19 years, studying in a medical university, participated in this cross-sectional study. Smartphone Addiction Scale – short version (SAS-SV) to evaluate PSU and a content validated semi-structured proforma to evaluate gender identity, sexual orientation, sources of information on pubertal changes, and exposure to pornographic content was used. We expressed results as proportion and summary measures (Mean±SD), Chi-square test to find influence between PSU and adolescent sexuality development.\n\nResults We found a 45.5% prevalence of PSU. Among study participants, 88% were attracted to the opposite sex, 6% were attracted to the same-sex, and 6% were attracted to both sexes. Three per cent of participants liked wearing clothes of the opposite sex, 7.5% wanted to be members of the opposite sex, whereas 10.4% were not comfortable with their genitalia. They obtained information regarding pubertal changes from friends (85) and media (78). Many had exposure to pornographic content (90%), with the youngest being nine years old.\n\nConclusion Nearly half of the late adolescents have PSU. Pornographic contents are accessed through Smartphones.", "keywords": [ "Adolescent boys", "sexual orientation", "gender identity", "smartphone addiction", "pornography", "problematic smartphone usage" ], "content": "Introduction\n\nAdolescence is a stage of transition from childhood to adulthood that includes rapid physical, cognitive, and psychosocial growth.1,2 It is a critical period, as many behavioral patterns emerge during this period, which may persist throughout life.3 Psychological well-being and overall health of adolescents are major concerns worldwide.4 Adolescents engage in life-threatening behaviors, such as alcohol and substance use, unsafe sex, poor eating, and heightened risk-taking, which affects their psychological well-being.4,5 According to the 2011 census, in India, 1/4th of the population are adolescents (253 million), and 54% belong to the 10-14 age group, and nearly 46% are in the 15-19 years of age.6\n\nAdolescents are highly attracted to modern technologies because they are psycho-socially immature and more prone to smartphone addiction due to the influence of the environment and peers.7 Reports highlight that adolescents are highly addicted to smartphones, equivalent to substances and various types of behavioral addiction.8 A meta-analysis by Davey et al. showed prevalence of smartphone abuse among Indian adolescents to be approximately 39% - 44%.9 Billieux et al. documented that problematic smartphone use (PSU) is defined as “an inability to regulate one’s use of the smartphone, which eventually involves negative consequences in daily life”.10 It is a type of behavioral or psychological dependence on mobile devices that is closely linked to excessive digital media use, such as Internet addiction disorder.11 PSU has been associated with various psychopathologies.12\n\nAdolescents with PSU are highly exposed to viewing sexualized content through videos and reality programs. In addition to these sources, social media platforms and various mobile applications have increased sexual content.13 The adolescents are more frequently engaged in online sex chat, and are thereby exposed to cyberbullying and online harassment.14 PSU may lead to impulsiveness, which plays a pivotal role in an increased number of sexual partners.15\n\nThe term sexual orientation refers to the sex to which individuals are sexually or romantically attracted. Gender identity refers to an individual’s basic sense of being male, female, transgender, or something else.16 Gender orientation is biologically determined, and sexual expressions have many external influences, such as the media. However, there is a paucity of information on how PSU affects sexuality in adolescence. The present study aimed to understand the existing patterns of smartphone usage among late adolescents and their association with the development of adolescent male sexuality.\n\n\nMethods\n\nWe conducted a cross-sectional study among male students pursuing medical, dental, and allied health sciences courses aged between 18 and 19 years at a medical university in Mangalore, an urban area in the South Indian State of Karnataka. Late adolescent boys who were unwilling to participate were termed non-responders and were excluded from the study. The study duration was 11 months (November 2019–September 2020). We followed a convenience sampling method to recruit study participants. The STROBE guidelines were adhered to, and a complete checklist was provided in the reporting guidelines.\n\nAll male students aged between 18 and 19 years who pursued the above-mentioned courses in the study institute were screened, and those over age and unwilling to participate were excluded from the study. The study flow diagram is shown in the following Figure 1:\n\nFollowing the consenting process, a content-validated semi-structured questionnaire (Google Form) was electronically mailed to all participants who were willing to participate in the study, and responses were collected. Students who had not completed the Google form were reminded using a WhatsApp message (24 hours after sending the questionnaire) and telephonic conversation (48 hours after sending the questionnaire). The questionnaire included demographic details, The Smartphone Addiction Scale – short version (SAS-SV),17 and questions on gender identity, sexual orientation, sources of information regarding pubertal changes, and body image issues. Smartphone usage and addiction using SAS-SV developed by Kwon et al.,17 consists of 10 items with 6 point Likert type scale. The scale items were scored from 1 to 6, with 1 being ‘strongly disagree’ and 6 being ‘strongly agree.’ The total possible score was between 10 and 60, with higher scores indicating higher chances of smartphone addiction. Based on the findings of a previous study, the cut-off for smartphone addiction was determined to be 31 in the present study.17\n\nData analysis was performed using IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp. Results are expressed as proportions and summary measures (mean ± standard deviation) using appropriate tables and figures. The influence between smartphone usage and sexual development was assessed using the chi-square test and independent sample t-test. Statistical significance was set at P <0.05.\n\n\nResults\n\nA total of 149 students were screened, and nine were excluded from the study because they were older. Among the remaining 140 students, 6 were unwilling to participate in this study; hence, they were excluded. The response rate was 95.7%. Of the 134 students, 98 were medical students, 20 were dental students, and 16 were allied health sciences students. Among the students, 90.3% were permanent residents of India, followed by 6.7% nonresidential Indians, and 3% foreign nationals. Most of the students resided in the hostel (85.1%), while 13.4% of the students lived at home, and 1.5% stayed in an apartment with friends.\n\nIn the present study, based on a predetermined cut off score of 31 on SAS-SV, the prevalence of problematic smartphone use (PSU) was 45.5% among the students.\n\nAs shown in Figure 2, 85 students obtained information about pubertal changes from friends, followed by books/magazines (81), schoolteachers (79), and movies (78). In contrast, fewer adolescents turned to mothers,16 fathers,17 or doctors18 for information related to pubertal changes,16 fathers,17 or doctors18 for information related to pubertal changes.\n\nAs shown in Table 1, regarding sexual orientation and gender identity among the students, 3% of the students desired to wear the dress of the opposite sex, while 94.8% did not, and 2.2% were not unsure. Among these students, 87.3% were happy with their current sexual identity, while 7.5% of them wanted to be members of the opposite sex. 86.6% Of students were comfortable with their genitalia, whereas 10.4% were unsatisfied. Romantic feelings towards the opposite sex were perceived to be normal by 91.8% of the students, while 5.2% felt abnormal, and 3% were not unsure. Out Of these students, 88% were attracted to the opposite sex, while 6% were attracted to the same sex, and 6% were attracted to both sexes.\n\n* ≥31 on SAS-SV scale was considered problematic for smartphone use.\n\nTable 2 shows no significant association between PSU and gender identity or PSU and sexual orientation. Regarding the knowledge of adolescent sexuality, 72% attended classes on the topics related to sex in schools, 19% had not attended, and 9% were not sure.\n\nRegarding normal male sexuality, 92.5% of the students were aware of the mental changes occurring during puberty, 90.3% were aware that adolescence was the final opportunity for growth (final height), and 83.6% of the study population indulged in masturbation. Among the adolescents indulged in masturbation, 28% felt guilty after masturbation, 30% felt masturbation caused severe damage to health, and 99.1% of the students preferred masturbation in private and thought it was not normal to masturbate in public. There was no statistically significant association between PSU on gender identity and sexual orientation (Table 3)\n\nIn our study, 90% students had watched pornographic content and one of the students had watched when he was 9 years old, 4.2% watched porn content before they turned 10, and 58% watched the porn content between 15-18 years. Most of the students (95%) wanted to watch the porn content alone, and 90.8% watched the porn content through smartphones. Regarding the frequency of watching porn content, 45% viewed less than once a week, and 37% watched 2-3 times per a week.\n\nAfter watching the pornographic content, the psychological behaviour shows that 7.5% of the students felt altered perception of communicating with the opposite sex, 11.7% responded that watching porn content had altered the study pattern, and 12.5% answered that it affected their academic performance. However, 71% of the students revealed that they had been sexting at least once. Our study did not find a statistically significant association between PSU and exposure to pornographic content (Table 4).\n\n\nDiscussion\n\nSexuality, which involves showing interest in a desired activity, orientation, and preference, is a normal phenomenon during adolescence. Adolescent sexuality includes an array of factors, such as intimate partnerships, gender identity, sexual orientation, religion, and culture.19 Adolescent sexuality development correlates better with the biopsychosocial model.20 The array of biological, psychological, and social factors plays a predominant role in the progression of adolescent sexuality. Social factors such as parents’ attitudes related to sexuality, parenting style, relationship with peers, and cultural influence are the major attributes of adolescent sexual attitudes.21 Recently, the media have also greatly influenced adolescent sexuality. Adolescents have easy access to information on sexuality, sex crimes, and violence through the media, influencing their perceptions and attitudes toward sexuality.22 Further, television and the Internet also provide fast access to sexual content, altering adolescents’ perception towards sexuality.23 Smartphone provides various benefits such as fast internet access, video calling, easy access to social media, and gaming.24 Increased smartphone use leads to addictive behavior. One commonly referred term is Problematic Smartphone Use (PSU), similar to behavioral addictions such as substance-related, gambling, and Internet addiction disorder.25 Adolescents are more vulnerable to problematic smartphone use because of the imbalance between the reward and behavioral control systems.18 A recent meta-analysis showed that Indian adolescents are highly addicted to smartphones and exhibit problematic sexual behaviors.9 So, we conducted the present study to evaluate the impact of problematic smartphone use on male adolescent sexuality development.\n\nThe prevalence of smartphone addiction based on the SAS-SV cut off score of 31 was found to be 45.5%, which reflects a higher PSU as compared to Chinese students (38.5%),26 European countries Belgium (21.5%)25 and American university students (20.1%).15 This discrepancy might be due to differences in sampling methods and the rapid development of telecommunication with cheaper and faster internet along with an increase in the budget of smartphones in India.27\n\nIn our study, transvestism, is observed in 3% of the students. Among the participants, 10.4% reported dissatisfaction with their genitalia. Men’s attitudes toward genitals have been shown to affect their psychological status. Thus, in men with dissatisfied genitals, it creates a state of insecurity, and in men with contented genitals, it gives confidence.28 The majority of the participants, 91.8%) thought romantic feelings towards their female counterparts were normal. Romantic relationships during adolescence are essential for development and well-being. Further, it has a positive association with the development of personal identity, self-esteem, and social competence and is useful for career planning. It has been positively associated with the formation of personal identity, adaptability to change, self-esteem, social competence, scholastic achievement, and career planning.29 Late adolescence (16–18 years) occurs when consolidation of romantic bonds occurs, elevating the risk of a poor-quality romantic relationship.30 In our study, normal romantic relationships towards the opposite sex might be due to a greater preference for cyber-relationship applications such as web chats and social networking chat rooms. These social networking chat rooms offer online romantic relations, which might be heightened by excessive or problematic internet use.31 We report 6% of same-sex attraction among the students; however, in a study conducted by Nama et al. among Canadian medical students in Ottawa, 18% of the medical students were involved in same-sex attraction or gay behavior.32 Further, our study reported no significant associations between sexual orientation, gender identity, and PSU. In this study, a higher number of students (85%) obtained information regarding the pubertal changes from their friends. Previous studies have also revealed that males share information regarding puberty and first wet dreams with their friends.33\n\nIn this study, 72% of adolescents attended sex education in schools. In a study done by Kumar et al. shows that 97.1% of students like to have sex education during their school life period.34 Further, genital growth in boys has been reported to be associated with altered cognitive function.35 In this study, 92.5% of students were aware of mental changes during puberty, 90.3% aware that adolescence is a final opportunity for growth, and 83.6% of students had self-explored genitalia.\n\nIn this study, 28% of students felt guilty after masturbation, 30% felt masturbation could induce serious damage to health, and 99.1% preferred private masturbating practice and not in public. Similar to our report, a study conducted among Chinese students showed an association between floating anxiety, somatic and hysterical symptoms, and masturbation.2\n\nIn our study, 90% of the students had viewed porn content, which is comparable to other studies conducted among adolescent boys in Sweden (98%)36 and Australia (87%).37 In the current study, 45% viewed porn content less than once a week, and 37% watched 2-3 times per a week, which is higher as compared to a study done among Polish students, where 34% viewed pornographic content once a week and 24% few times a week.38\n\nIn this study, watching pornographic content did not influence students’ psychological behavior and study patterns. Similar to our report, a study conducted on Croatian adolescents showed that viewing pornography displayed no significant negative alteration in adolescent subjective well-being, depression or anxiety, or self-esteem.39 In a study conducted by Šević et al. among Croatian adolescents, watching porn content or sexually explicit material online did not affect academic grades, study patterns, or well-being.40 In contrast, Beyens et al. reported that watching online pornographic content has a negative association with students’ academic performance when compared between baseline and six months.41 Further, we did not observe a significant association between problematic smartphone use and pornographic content exposure.\n\nThe strength of this study is that it is the first of its kind to correlate adolescent sexuality with smartphone usage using a standardized questionnaire (Smartphone Addiction Scale – short version, SAS-SV). This study has some limitations. Considering the smaller sample size and enrolment of only health sciences students, the results cannot be generalized.\n\nThis study implies the formulation of structured awareness programs to be carried out by health professionals and to educate parents about handling adolescent issues. In addition, it encourages adolescent health programs to create knowledge about risky behaviors and community support groups. This study highlights the need to include comprehensive sex education as part of the school curriculum and to educate young Internet users on the safe and responsible use of the Internet.\n\n\nEthics and consent\n\nThe study was approved by the Institutional Ethics Committee on 15/01/2020 (approval number: IEC KMC MLR 01/2020/36) and the Head of the Institute. Eligible participants were contacted individually using the MS Teams platform. The purpose of the study, the role of their participation, the study procedure, and confidentiality were explained, and informed consent was obtained online using google forms from each participant.", "appendix": "Data availability\n\nOpen Science Framework: Influence of Smartphone Usage on the development of sexuality among Late Adolescent Boys in Health Sciences Colleges of South India. https://doi.org/10.17605/OSF.IO/KVM4A 42\n\nThis dataset contains the following underlying data:\n\n• Excel Data file\n\nOpen Science Framework: Influence of Smartphone Usage on development of Sexuality among Late Adolescent Boys in Health Sciences Colleges of South India. https://doi.org/10.17605/OSF.IO/KVM4A 42\n\nThis dataset contains the following underlying extended data:\n\n• Participant information sheet.\n\n• Informed consent form\n\n• Study Questionnaire\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0)\n\nOpen Science Framework: Influence of Smartphone Usage on development of Sexuality among Late Adolescent Boys in Health Sciences Colleges of South India. https://doi.org/10.17605/OSF.IO/KVM4A 42\n\nIt contains the STROBE checklist for the Influence of Smartphone Usage on the development of sexuality among Late Adolescent Boys in Health Sciences Colleges of South India.\n\nThe pre-print version of this study is available online from: https://doi.org/10.21203/rs.3.rs-1800750/v1 43\n\n\nAcknowledgements\n\nWe thank the participants.\n\n\nReferences\n\nSexual and Reproductive Health and Research (SRH): [cited 2024 Apr 6]. 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Publisher Full Text\n\nBeyens I, Vandenbosch L, Eggermont S: Early adolescent boys’ exposure to Internet pornography: Relationships to pubertal timing, sensation seeking, and academic performance. J. Early Adolesc. 2015; 35(8): 1045–1068. Publisher Full Text\n\nManya S, Jayashree K, Mithra P, et al.: Influence of smartphone usage on development of sexuality among late adolescent boys in health sciences colleges of South India. (Dataset). 2024. Reference Source\n\nManya S, Jayashree K, Mithra P, et al.: Influence of smartphone usage on development of sexuality among late adolescent boys in health sciences colleges of south India. Research square. 2022. Reference Source" }	[ { "id": "326604", "date": "11 Oct 2024", "name": "Sudhir Prabhu", "expertise": [ "Reviewer Expertise Immunization", "Adolescent health", "Primary health care" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe research article submitted by the authors clearly answers the research question about the impact of problematic smartphone usage and sexuality among late adolescent males, both of which are important public health issues. However I have a few concerns about the study which I would seek clarification from the authors :\nMajor : 1. How was development of sexuality defined for this descriptive study : was it sexual orientation or sexual identity or something else ? 2. Sexual awareness may begin at early adolescents (9-12 yrs) , what was the reason authors tried to address or justify development of sexuality or influence of smartphone on sexuality at the age of 18-19 yrs ? Was this based on any observations or references or any other issues specific in your region? 3. Discussion section mentions about friends/peers being the major source for information, but results also show magazines and videos also which may be due to stigma to discuss with teachers, family or health professionals. Kindly elaborate this as it is relevant for the study objective with smartphone being the most easily handy and private source for all information for an adolescent.\nMinor 1. Abstract mentions about \"exposure to pornographic content with youngest being 9 years old\" study subjects being late adolescents does this mean at the age of 9 ? 2. Are smartphone addiction and problematic smartphone usage used as synonyms for this study?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "12954", "date": "07 Jan 2025", "name": "Jayashree K", "role": "Author Response", "response": "Major: How was development of sexuality defined for this descriptive study: was it sexual orientation or sexual identity or something else? Author response: Thank you for the comment. Sexuality has different components which includes biological sex, gender identity, social sex-role, and sexual orientation. In the present study we considered gender role identification, gender orientation as development of sexuality. The same has now been incorporated in the introduction section. 2.Sexual awareness may begin at early adolescents (9-12 yrs), what was the reason authors tried to address or justify development of sexuality or influence of smartphone on sexuality at the age of 18-19 yrs ? Was this based on any observations or references or any other issues specific in your region? Author response: Yes, it begins at early adolescence but there is lot sexual experimentation with respect to how they dress up and their activities/ likes/dislikes/ whom they hang out with/ gender roles etc, occur throughout the adolescent period and it keeps changing. But by the time they enter late adolescence a stable sexuality usually develops. Another reason why we didn’t take early adolescence is smartphone usage with respect to questions related to different components of sexuality may pose ethical issues also they are not mature enough to understand the questionnaire. The same has now been added to our Discussion section for further clarity. 3.Discussion section mentions about friends/peers being the major source for information but results also show magazines and videos also which may be due to stigma to discuss with teachers, family or health professionals. Kindly elaborate this as it is relevant for the study objective with smartphone being the most easily handy and private source for all information for an adolescent. Author response: Thank you for the suggestion. Our study found that friends/peers are the major source of information about pubertal changes followed by books/magazines as mentioned in the results section. We also found that only a small proportion of them turned to parents or health professionals for any information or concerns regarding the same. These findings aligned with other studies as described in the discussion section. As you rightly pointed out, smartphones, with their private nature, have emerged as a primary source of information for adolescents. This is especially true for sensitive topics where young people may feel uncomfortable engaging in open dialogue with adults. We have further elaborated on this in our discussion section. Minor: Abstract mentions about \"exposure to pornographic content with youngest being 9 years old\" study subjects being late adolescents does this mean at the age of 9? Author response: Thank you. It means the study subject who is a late adolescent started watching porn when he/she was 9 years old. The same has been mentioned in the sentence of Results section “In our study, 90% students had watched pornographic content and one of the students had watched when he was 9 years old…………………..” 2.Are smartphone addiction and problematic smartphone usage used as synonyms for this study? Author response: Yes. We used the Smartphone Addiction Scale-Short Version (SAS-SV) to identify Problematic Smartphone Use (PSU) among study participants. Participants scoring 31 & above on the SAS-SV were considered to have problematic smartphone use. Throughout the study, the terms 'problematic smartphone use' and 'smartphone addiction' are used interchangeably. For better clarity, we have now mentioned this in the introduction section." } ] } ]	1	https://f1000research.com/articles/13-1079
https://f1000research.com/articles/12-1053/v1	29 Aug 23	{ "type": "Research Article", "title": "Association between care-seeking at health centres preceding hospital admission and in-hospital child mortality in rural Malawi", "authors": [ "Annlaug Selstø", "Carina King", "Helena Hildenwall", "Beatiwel Zadutsa", "Lumbani Banda", "Everlisto Phiri", "Charles Makwenda", "Carina King", "Helena Hildenwall", "Beatiwel Zadutsa", "Lumbani Banda", "Everlisto Phiri", "Charles Makwenda" ], "abstract": "Background: Mortality among children with acute illness in low-income countries remains high. Referral issues and limitations in emergency care are major challenges to child health and a hypothesis is that care at lower-level facilities delays quality emergency care. This study investigates the extent of care-seeking at health centres prior to hospital admission for sick children, and its association with inpatient mortality in Malawi. Methods: We conducted a retrospective cohort study of children aged 0-12 years admitted to hospitals in Mchinji district, Malawi. Data was collected from September 2019 to April 2020 from one district hospital and three community hospitals. Information was collected from caregivers of admitted children, patient files and ward admission registers. The primary analysis assesses the association between referral from a health centre and in-hospital outcomes using logistic regression. Result: A total of 4926 children were included. The majority (n=4265, 86.6%) had gone straight to hospital without being referred from another health facility. The most common diagnoses were malaria (n= 3345, 67.9%), meningitis or sepsis (n= 1047, 21.3%) and pneumonia (n= 656, 13.3%). Children that were referred from a health centre had a case fatality rate of 5.3%, while those that came straight to the hospital had a case fatality rate of 2.5%. Children who had been referred from a health centre had higher odds of dying (AOR: 2.0, CI 95%: 1.3-3.0), compared to self-referred children. Children with anaemia (AOR: 4.1, CI 95%: 2.7-6.3) and malnutrition (AOR: 6.3, CI 95%: 2.7-14.6) had significantly higher odds of dying, than those without these conditions. Conclusion: Most children admitted to hospital had been taken there without a referral, and these children had better survival than those who had been referred. A better understanding of care-seeking pathways, including referral challenges, may direct interventions to improve timely provision of care for sick children.", "keywords": [ "In-hospital child mortality", "Care-seeking", "Referral", "Paediatric", "Malawi", "low-income country" ], "content": "Introduction\n\nMany countries, mostly in Sub-Saharan Africa, continue to suffer from a high child mortality rate.1 In 2018, The Lancet Global Health Commission on Quality Healthcare argued that poor quality of healthcare is a now a bigger barrier than access to care in reducing child mortality and accounts for as much as 60% of avoidable deaths in low and middle- income countries (LMIC).2 Under the Integrated Management of Childhood Illness (IMCI) and integrated Community Case Management (iCCM) programs, children with signs of severe illness in the community/health centre should be referred to higher level facilities for further management.3 IMCI does not include any components of emergency case management, and primary healthcare facilities in low-income countries commonly lack the resources to treat severely ill children.4 Furthermore, challenges in the identification of severely ill children have been reported under IMCI, potentially leading to missed referrals.5\n\nDelays in care seeking for young children in LMIC have been reported due to guardians’ inability to recognise illness, household challenges in mobilising resources and/or deciding to seek care, especially in poor and less educated households.6–8 This, along with referral challenges within the health system including waiting times, poor triage, and lack of referral transport, could lead to increased risks for children who are brought to primary care with an acute illness, as adequate care at a higher-level facility may be further delayed.\n\nThis study was performed to assess the care-seeking patterns prior to being admitted to hospital, and to establish the association between pre-admission referrals and inpatient mortality for children in Mchinji District, Malawi.\n\n\nMethods\n\nMalawi is one of ten countries in Sub-Saharan Africa that achieved the Millennium Development Goal 4 to reduce child mortality.9 Despite the improvements in child mortality in Malawi, the mortality rate still falls short of the Sustainable Development Goal target to reduce mortality among children less than five years of age to below 25 deaths per 1,000 live births by 2030. Malawi adopted and implemented IMCI in 1999 and iCCM was introduced in Malawi in 2007. The World Health Organisation (WHO) Emergency Triage Assessment and Treatment (ETAT)10 has been implemented in Malawian tertiary and secondary hospitals.\n\nMchinji is a district in the Central Region of Malawi with a mainly rural population and with an under-five population of approximately 90,000 in 2018. Data was collected at the pediatric department of the main district hospital, Mchinji District Hospital (MDH) and the three community hospitals within the district. The health centers in the district do not offer any inpatient care, and children in need of admission are referred to hospital for further care.\n\nThe recruitment and data collection were planned for one year from the 9th of September 2019 but was stopped in April 2020 due to the Covid-19 pandemic.\n\nThis was an observational retrospective cohort study involving all children admitted to hospitals within Mchinji district during the study period.\n\nChildren aged 0-12 years old who were admitted to a paediatric ward at any of the four hospitals within Mchinji District during the study period were eligible for enrolment to the study. Neonates (age <28 days) who were born within the included hospitals and admitted into the neonatal unit were not included. Referral is the exposure and inpatient mortality the outcome.\n\nData collection involved interviews with guardians and patient file review which was performed by study data collectors, two were based at MDH and one each in the three community hospitals. The data collectors had a minimum education of completed secondary school and could read and write in English and Chichewa. All data collectors attended one week of training on the study protocol and ethics in research and were supervised on a weekly basis by field supervisors and a clinical officer. Data collectors approached caretakers of admitted children in the hospitals and asked for their consent to participate in the study. Following consent, data was collected on whether the caretaker had brought the child straight to the hospital, or whether another health facility had been visited before coming to the hospital. Patient demographics, including patient age, sex and admission diagnosis of the child, and the time and day of the hospital admission and outcomes were recorded from patient files and ward admission books. Data was entered into password protected tablets using Open Data Kit (ODK) for electronic data collection. The data was then exported to Stata for analysis but data can also be analysed in other software such as R. As data was collected at the hospital during admission, and records were kept over all patients, the risk of loss to follow up bias was minimal. All admitted children in the relevant age groups were invited to participate, eliminating the risk of selection bias.\n\nThe plan was to include all admitted children for one year using routine hospital admission data from the Mchinji district. While all district in Malawi were not included it is assumed that data from Mchinji is sufficiently representative to comfortable make generalisations to the whole population of interest.\n\nThe primary outcome variable for the analysis was inpatient mortality, and primary exposure was if the child had been referred from elsewhere prior to hospital admission. Age and sex of the child, day and time of admission and admission diagnosis were considered to be potential confounders. Sex was determined from medical records and any difference was explored as there are differences in mortality patterns between sexes in children under-five. All variables were converted into categorical variables. Admission days were categorized as weekdays (Monday to Friday) or weekends (Saturday and Sunday), and time as “day” (8 am to 8 pm) or “night” (8 pm to 8 am). This gave an indication if hospital admissions outside of daytime working hours, when there are less staff on the wards, were associated with higher mortality. Children could be assigned multiple admission diagnoses, we created binary variables for diagnosis category, meaning a total of more than 100% is presented in the diagnosis variable.\n\nProportions were stratified by facility type (district hospital versus community hospitals) and compared using chi2. Logistic regression analysis was done to determine the associations between the main exposure and outcome. All statistical analysis was preformed using Stata/IC 16.1. Stata was chosen as the researchers had license and experience using this software. Alternatively, the free statistical software R could have been used.\n\nThe study was approved by the College of Medicine Research and Ethics Committee in Malawi. Guardians were informed about the study and provided verbal consent for their minors to participate in the study prior to any data was collected. Due to literacy levels, study information was given verbally in Chichewa, and consent given verbally –the informed consent was subsequently recorded in the electronic data collection form. Refusal to participate had no impact on the care provided to the patients and study procedure including consenting was approved by the Malawi College of Medicine Research and Ethics Committee (reference: P11/18/25389).\n\n\nResults\n\nA total of 4926 children were admitted to hospitals in Mchinji district during the study period. Of these, 4265 (86.6%) had been brought straight to hospital, and 661 (13.4%) children had been referred from another health care provider (Table 1). The proportion of admitted children that had been referred was higher at the district hospital compared to the community hospitals (29.0%, vs 3.9%, p<0.001). Out of the 4926 children who were admitted, 141 died with an overall in-hospital mortality of 2.9%. The in-hospital mortality was 5.3% for referred children compared to 2.5% for the self-referred cases (p<0.001). The in-hospital mortality was 3.3% at the district hospital compared to 2.1% at community hospitals for self-referrals (p=0.021). For referred cases, the in-hospital mortality was 5.3% at the district hospital and 5.2% at the community hospitals (p=0.998). The overall in-hospital mortality was higher at the district hospital at 3.9%, compared to 2.2% at the community hospitals (p=0.01).\n\n* Admission any time from 8 pm to 8 am the following day.\n\nFor the different age-groups, neonates (age <29 days) represented 3.6% of all admissions (172/4926), with a Case Fatality Rate (CFR) of 3.6%. Infants, aged one to 12 months, represented 16.9% (852/4926) of the admitted children and had the highest CFR at 4.1%. The biggest group of admitted children were between one and five years of age (2758/4926, 56.0%) while 1138 children (23.1%) were between five to 12 years of age. The one-five year olds had a CFR of 3.0% and the CFR for children aged five-12 years old was 2.0%. No mortality difference was seen depending on sex, with 52.9% of the admitted children being males and 47.1% females, and with a CFRs of 2.7% and 3.1%, respectively (p-value: 0.437).\n\nThe diagnosis with the highest CFR was malnutrition at 13.8%, followed by anaemia at 8.5%. A bigger proportion of children died from malnutrition at the community hospitals than at the district hospital, however the result was not significant (20.8%, vs 8.8%, p<0.191). The proportion that died of anaemia was higher in the district hospital (11.7%) than at the community hospitals (6.2%, p=0.039).\n\nMore children who were admitted during weekdays died; 3.1% versus 2.1% in weekends (p=0.06). The CFR among children admitted during the day was 3.0% versus a CFR of 2.2 for children admitted during the night (p=0.18).\n\nThe adjusted odds ratio of in-hospital mortality was 2.0 (95% CI:1.3-3.0) for children who were admitted to hospital who had been referred compared to those who had self-referred. Table 2 presents the unadjusted (UOR) and adjusted Odds Ratios (AOR) for the variables included in the logistic regression analysis.\n\n* More than one diagnosis per child possible.\n\nMost of the other included factors did not show any statistical significance. The exceptions were children in the age-group from five to 12 years, whose AOR for in-hospital mortality was 0.3 compared to neonates (95% CI: 0.1-0.9). Children who were diagnosed with anaemia or malnutrition at the point of admission had higher odds of dying: anaemic children had an AOR of 4.1 (95% CI: 2.7-6.3) and malnourished children had an AOR of 6.3 (95% CI 2.7-14.6).\n\n\nDiscussion\n\nWe observed a higher in-hospital mortality among children who had been referred from a lower-level facilities compared to children who were brought straight to hospital in a rural Malawian setting. Most children who are admitted to hospital had been brought there without seeking any previous care at lower-level facilities. In terms of diagnosis, the evidence suggests children with malnutrition and anaemia carry an increased mortality risk.\n\nThe in-hospital mortality was twice as high for children who had been referred to hospital from a lower-level facility compared to children who were brought straight to the hospital. While the study did not establish the actual causes of the mortality, and whether those referred were sicker than the self-referred children, one explanation to the mortality difference could be that adequate care was delayed during the time it took to seek and receive care elsewhere, followed by the time it took to complete referrals. Lower-level facilities have limited abilities to offer stabilisation of severely ill children with transport issues for referrals reported as a main constraint.11,12 Delays may also occur within facilities including the decision to refer a child.13 While IMCI was rolled out in 1999 and include guidelines on when to refer a sick child, challenges in the sustainability have been reported including limitations in equipment, training, and adherence to guidelines.12,14 To ensure that all in need are referred early, current IMCI guidelines may need more objective definitions for timely stabilisation.15,16\n\nThe majority of children admitted to the included hospitals had come straight to the hospital. This may suggest a good awareness among guardians on when a child’s illness requires hospital care. Alternatively, there is a general preference for hospital care which could be due to lack of trust lower level facilities.17 A study conducted in Southern Malawi showed that patients satisfaction with the primary healthcare system demonstrated considerable variation18 and better facility quality is associated with a higher utilisation of sick child healthcare services.19\n\nThe highest mortality was seen among children diagnosed with malnutrition and anaemia. This confirms findings from previous studies20–22 and children with these diagnoses also suffer an increased risk of post-discharge mortality.23,24 It is possible the ETAT guidelines need to pay more attention to malnourished children with multiple diagnoses for priority and stabilisation at admission, and IMCI and iCCM should focus on earlier referral for children with malnutrition and anaemia. For age differences, young children had the highest mortality. While neonates generally suffer the highest mortality rates, in this study the mortality was highest among infants. Part of this may be explained by the study exclusion of babies born within the facilities, a recent study on place of death and care-seeking prior to death that poor illness recognition is a major driver in neonatal deaths, whereas death despite care-seeking among older children indicates inadequate quality care and referral.25\n\nThis study has several limitations. First, it is possible that referred children as a group were suffering from more severe conditions than the ones who were self-referred. The study did not collect any information on the symptoms at the time the decision to seek care was made or whether a progression occurred during the time spent on care seeking prior to reaching the hospital. Also, we did not collect any data on total numbers of completed referrals compared with those referred from health centres. There may have been children who did not make it to the hospital, who died on the way. There is also the possibility that caretakers who were recommended referral to hospital could not make their way there, causing an under-estimation of post-referral mortality. Similarly, we did not assess post-discharge mortality which is reportedly high in many sub-Saharan African settings.23\n\nTo conclude, the higher in-hospital mortality demonstrated between children who were referred from a health centre compared to self-referred cases may be linked to poor quality care at primary healthcare facilities, inadequate guidelines for when to refer a sick child and/or or difficulties to completing referrals. Future studies to better understand the demonstrated mortality pattern should include data on illness severity and caretaker’s reasons for care-seeking choices. The vulnerability of children with malnutrition and/or anaemia should be especially considered when assessing sick children at all levels of the health care system.", "appendix": "Data availability\n\nRepository: Harvard Dataverse: Mchinji ward admission data. https://doi.org/10.7910/DVN/E9ZJNH. 26\n\nThis project contains the following underlying data:\n\n• 230522 Ward Admission Data.xls (variables used in analysis)\n\n• Data dictionary Mchinji hospital data.xlsx (data dictionary)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgements\n\nWe would like to thank all the children and their parents/caretakers who participated in this study, and the healthcare workers who supported our data collector teams in their work. We are also grateful to the data collectors for their hard work, and the Mchinji District Health Management Team for their input and support.\n\n\nReferences\n\nHug L, Sharrow D, You D: Levels & Trends in Child Mortality, Report 2019.2019 [cited 2019 29th December]. Reference Source\n\nKruk ME, et al.: High-quality health systems in the Sustainable Development Goals era: time for a revolution. Lancet Glob. Health. 2018; 6(11): e1196–e1252. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWHO: Integrated Management of childhood Illness Chart Booklet.2014 [cited 2020 18th April]. Reference Source\n\nJohansson EW, et al.: Accessibility of basic paediatric emergency care in Malawi: analysis of a national facility census. BMC Public Health. 2020; 20(1): 992. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKrüger C, Heinzel-Gutenbrunner M, Ali M: Adherence to the integrated management of childhood illness guidelines in Namibia, Kenya, Tanzania and Uganda: evidence from the national service provision assessment surveys. BMC Health Serv. Res. 2017; 17(1): 822. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAhmed T, et al.: Healthcare utilization and maternal and child mortality during the COVID-19 pandemic in 18 low- and middle-income countries: An interrupted time-series analysis with mathematical modeling of administrative data. PLoS Med. 2022; 19(8): e1004070. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKällander K, et al.: Barriers on the pathway to survival for children dying from treatable illnesses in Inhambane province, Mozambique. J. Glob. Health. 2019; 9(1): 010809. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nNoordam AC, et al.: Association between caregivers’ knowledge and care seeking behaviour for children with symptoms of pneumonia in six sub-Saharan African Countries. BMC Health Serv. Res. 2017; 17(1): 107. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMolyneux M, Molyneux E: Reaching Millennium Development Goal 4. Lancet Glob. Health. 2016; 4(3): e146–e147. Publisher Full Text\n\nWHO: Emergency Triage Assessment and Treatment (ETAT) course.2005 [cited 2020 18th April]. Reference Source\n\nKing C, et al.: Paediatric Emergency Triage, Assessment and Treatment (ETAT) - preparedness for implementation at primary care facilities in Malawi. Glob. Health Action. 2021; 14(1): 1989807. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nRobertson SK, Manson K, Fioratou E: IMCI and ETAT integration at a primary healthcare facility in Malawi: a human factors approach. BMC Health Serv. Res. 2018; 18(1): 1014. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKing C, et al.: Care-seeking patterns amongst suspected paediatric pneumonia deaths in rural Malawi. Gates Open Res. 2020; 4: 178. Publisher Full Text\n\nKilov K, et al.: Integrated Management of Childhood Illnesses (IMCI): a mixed-methods study on implementation, knowledge and resource availability in Malawi. BMJ Paediatr. Open. 2021; 5(1): e001044. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKing C, et al.: Prospective cohort study of referred Malawian children and their survival by hypoxaemia and hypoglycaemia status. Bull. World Health Organ. 2022; 100(5): 302–314B. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nThunberg A, et al.: Hypoxemia, hypoglycemia and IMCI danger signs in pediatric outpatients in Malawi. Plos Global Public Health. 2022; 2(4): e0000284. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKahabuka C, et al.: Why caretakers bypass Primary Health Care facilities for child care - a case from rural Tanzania. BMC Health Serv. Res. 2011; 11(1): 315. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nDullie L, et al.: Performance of primary care in different healthcare facilities: a cross-sectional study of patients’ experiences in Southern Malawi. BMJ Open. 2019; 9(7): e029579. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLiu L, et al.: Exploring the association between sick child healthcare utilisation and health facility quality in Malawi: a cross-sectional study. BMJ Open. 2019; 9(7): e029631. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBerkley JA, et al.: Prognostic indicators of early and late death in children admitted to district hospital in Kenya: cohort study. BMJ. 2003; 326(7385): 361. Publisher Full Text\n\nNgwalangwa F, et al.: Risk Factors for Mortality in Severely Ill Children Admitted to a Tertiary Referral Hospital in Malawi. Am. J. Trop. Med. Hyg. 2019; 101(3): 670–675. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nObonyo CO, et al.: In-hospital morbidity and mortality due to severe malarial anemia in western Kenya. Am. J. Trop. Med. Hyg. 2007; 77(6 Suppl): 23–28. PubMed Abstract \| Publisher Full Text\n\nChildhood Acute I, Nutrition N: Childhood mortality during and after acute illness in Africa and south Asia: a prospective cohort study. Lancet Glob. Health. 2022; 10(5): e673–e684.\n\nKwambai TK, et al.: Post-discharge morbidity and mortality in children admitted with severe anaemia and other health conditions in malaria-endemic settings in Africa: a systematic review and meta-analysis. Lancet Child Adolesc. Health. 2022; 6(7): 474–483. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPrice J, et al.: Place of death, care-seeking and care pathway progression in the final illnesses of children under five years of age in sub-Saharan Africa: a systematic review. J. Glob. Health. 2019; 9(2): 020422. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHelena H: Mchinji ward admission data. Harvard Dataverse. 2023; V3. Publisher Full Text" }	[ { "id": "248631", "date": "21 Mar 2024", "name": "Faisal Ahmed", "expertise": [ "Reviewer Expertise I am a urologist. I have worked for 5 years in the field with governmental hospitals in Yemen mainly in the field of surgery and trauma." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors present a useful study of the Association between care-seeking at health centers preceding hospital admission and in-hospital child mortality. Instead of an interesting study, it still needs extensive revision. My comments/queries:\nAbstract:\nBackground: Please enrich the background with a few extra details. Method: The main outcome of your method needs to be clearly defined. Result: The data does not clearly show what percentage of the children had risk factors associated with death. Additionally, some factors not mentioned, such as prematurity, failure to thrive, etc, may associated with death.\n\nIntroduction:\nBriefly mention the difference in health care facilities offered in different other health facilities in your country. Several analogous studies exist in the current literature. It is essential to underscore the significance of integrating this study into the existing body of research.\nMethod:\nPlease mention the exclusion criteria. The sample size should be revised. For larger populations, such as a population of 10,000, a comparatively small minimum ratio of 10 percent (1,000) of individuals is required to ensure the representativeness of the sample. Please define the outcome and variables included in your study such as mortality, risk factors included, etc.... What are the reasons for being referred by another healthcare provider? It should be mentioned. The authors need to mention which protocols were followed for the collected data of mortality to validate the results. How was the checklist pre-validated? Authors can mention that all collected that reviewed, and checked by the Supervisor and the principal investigator for completeness, and consistency, and if any missing info was found, mitigation was done. Authors need to mention in more detail the drawbacks of a retrospective study, especially since they have had no control over many variables. The authors also need to emphasize that no causation was advocated for. Furthermore, the data was collected from a secondary source. I think a table of the components and indicators of the Pathway to Mortality would have been good to include so it could be compared to the components chosen for this analysis. Please mention the statistical analysis section including how you present the qualitative data, quantitative data, statistical tests used, etc…\nResult:\nGive characteristics of study participants (eg demographic, clinical, social). Please mention the patients' age, and gender, then go to specific details. The low number of people who sought care from community health workers is interesting but the reason for this is not explained. Table 1: The data does not clearly show what percentage of variables. Please include the percentage for each variable. Please mention the case fatality rate on your method. This section is hard to follow, and it should be improved. Please start with a general description of the study participants. Then, mention the specific analysis comparison between your groups. the tables also should be revised similarly. Before mentioning the adjusted OR table, you should mention the table of univariate analysis. The disease severity is not mentioned. Why? The duration of hospital admission should be mentioned. Where is the reference group for each variable in Table 2? The OR should be in the reported range of 95%CI, however, some adjusted OR are out of the reported period. Please recheck your analysis. \">1-5 years, >6-12 years\"; please revise it through the tables.\nDiscussion: - The first paragraph should summarize your result. Not a selected part of the study. Please revise this section. - Please mention additional Strengths and limitations of your study. - The factors discussed are very few. Please discuss the important findings of the obtained study and compare the findings with previous reports with accurate justifications.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "12999", "date": "07 Jan 2025", "name": "Annlaug Selstø", "role": "Author Response", "response": "Dear Editors Thank you for the opportunity to review our manuscript. We appreciate the comments form the reviewers and have revised the manuscript accordingly. Please see our responses to the reviewers listed under each comment below. Abstract: Background: please see information added in new version. Method: The main outcome has been clarified under abstract methods. Results: Thank you for this comment. While we agree there are multiple potential mortality risks, it was beyond the scope of this study to address all potential risk factors as the main focus is on comparing hospital outcomes and previous referral-history. Introduction Information on the Malawian health system has been added under “study setting” as we think it fits better there than in the introduction. Information has been added to the introduction to highlight the difference in child mortality and progress to SDG 3 in Malawi compared to SSA as a whole. Method: The exclusion criteria have been clarified. As all children admitted to the four included hospitals in the whole of Mchinji district were included we expected to have enough numbers to identify any significant difference. Despite the need to stop the study earlier than expected due to Covid, we still included enough children to demonstrate a statistically significant difference. The exposure and outcome variables as well as potential confounders are listed under “data analysis”. Malawian health workers are supposed to adhere to national guidelines on referral decisions. We did not collect data on specific reasons for referrals in this study. A sentence has been added to “data sources” to clarify that data collectors were present at all hospitals to follow up on outcomes, verified from patient files and hospital records. Information on completeness checks has been added under “data sources”. A presentation of the different limitations in this study, including the unavailability of information on reason for referrals, is available at the end of the discussion section. The limitations of not having all possible risk factors available in this report are mentioned at the end of the discussion section. We agree with the reviewer that multiple additional components could have been included to get a more thorough understanding of all factors leading to fatal outcomes. However, this is a small study with the main aim to compare differences between children brought straight to hospital with those being referred. The limitations of being a small study are discussed under study limitations. This was, as stated under study design, a cohort study. An explanation of statistical methods used is available under “data analysis”. The study did not include any qualitative data. We have added reference to the two included tables under “data analysis”. Results: We did not collect data on social and demographic factors. Background characteristics are presented in Table 1 and text has been added to the first part of the result section. We did not collect any specific information on referral numbers from community health workers, thus we do not fully understand this question. The limitations caused by the unavailability of pre-referral data are discussed at the end of the discussion. Thank you for the feedback. The percentage symbol has been added in the heading of the table. The case fatality rates are presented in Table 1 as well as in the end of the first section of “results”. We have changed the text to present more on general description of study participants before moving in the comparisons between groups. Table 2 presents the unadjusted/univariate as well as the adjusted ORs. We did not collect any specific data on illness severity on condition. The limitations of this approach are discussed at the end of the discussion section. Our primary outcome is hospital mortality, and the duration of admission is thus not included in this study. The reference group is the first group mentioned for each variable, indicated with an UOR of 1.0 as in our experience is common practice in scientific reports. Thank you for pointing out concern on 95%-CI – we have revised all the numbers reported to ensure they are correctly reflecting the analysis done. These are the age groups used in our analysis; <29 days ,1-12 months, >1-5 years and >5-12 years The > indicates that a child of 5 years and one day will be in the >5-12 years group while a child of exactly 5 years will be in the >1-5 years group Discussion: We present our main findings at the start of the discussion. This aligns with the objective of the study. Strengths and limitations are discussed at the end of the discussion section. As this is not a big study, we think we can only discuss what we have found, highlight the limitations of our study and relate our findings to previous work done." } ] }, { "id": "319089", "date": "18 Sep 2024", "name": "Bryan Vonasek", "expertise": [ "Reviewer Expertise Under 5 mortality in Malawi" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript focuses on a very important topic and includes a large dataset to explore associations with in-hospital mortality. However, there are several major limitations in the study design and interpretation of results that need to be addressed.\n\nMAJOR CONSIDERATIONS 1. The title and elsewhere seem to indicate \"care-seeking\" as what is being explored as an exposure variable. But the main exposure variable being explored is clearly whether participants were referred or not, which is completely different than \"care-seeking.\" When I think of \"care-seeking,\" it is the decision making (or lack thereof) from sick individual or his/her caregiver or community. This isn't directly assessed at all in this manuscript. All sections of the manuscript need to be revised to address this issue. 2. The study design is stated as an \"observational retrospective cohort study\"--but then enrollment with informed consent is described. Please clarify about the study design. 3. The methods for calculation of unadjusted and adjusted odds ratios are not described at all. 4. Given that you seem to capture data from all four government hospitals in the district, is it possible to evaluate those referred to MDH from the community hospitals, in comparison to those admitted to the community hospital that weren't referred to MDH? At least report how many of the referrals to MDH were referred from the three community hospitals in the study.\n\nMINOR CONSIDERATIONS 1. Methods > Study Setting: The goal of <25 deaths per 1000 is stated. It would be informative to include what this number is currently (maybe at the national level). 2. Methods > Participants: No need to also mention the exposure and outcome variables here. 3. Ethical considerations: No need to mention COMREC twice. 4. Why are the diagnoses of meningitis and sepsis combined? 5. Table 1 - add CFR units 6. Is it necessary to present both chi-square results and odds ratios? Probably don't need chi-square results if the ORs are there for the same comparisons.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "13020", "date": "07 Jan 2025", "name": "Annlaug Selstø", "role": "Author Response", "response": "Dear Bryan Vonasek Thank you for your thorough reading and review of our article. We appreciate your comments and have revised the manuscript accordingly. Please see our responses listed below. Pleas also see our lates updated version of our manuscript. For your major considerations: 1. Thank you for this valuable comment on our title. We agree with the feedback that \"care-seeking\" is not correctly reflecting what has been studied in this work. Referral is just one factor out of several in the process of reaching out for professional medical care. We have revised the title and the manuscript to better describe what has been done. 2. On the matter of study design we agree with your comment and has removed the wording retrospective throughout. Children and their guardians were approached at the hospital where they were admitted and asked to consent to the study whereby we received approval to collect outcome information data. 3. Conserning UOR and AOR we describe that a logistic regression was done under “data analysis”. This was a univariate analysis followed by multiple logistic regression to achieve adjusted odds ratios. 4. Thank you for the useful comment on referrals to MDH versus community hospitals. We have added information on the numbers of referred from community hospitals to the district hospital. We have also added some sentences in the discussion to reflect on this. Please note that the community hospitals are CHAM facilities while the district hospital is under the government. MINOR CONSIDERATIONS 1. Thank you for the comment requestibg information on child mortality in Malawi under Study setting.. The information requested is written in the beginning of the introduction. 2. Under methods/participation we have removed information on the exposure and outcome variables. 3. Duplicate on ethical considerations has been removed. 4. Results on meningitis and sepsis were combined as the diagnosis of meningitis commonly is made without any lumbar puncture there may be a big overlap between meningitis and sepsis why we choose to combined these. But there are very few with \"meningitis\" in our dataset so we chose to separate these after your comments. 5. In table 1 CFR units (%) has been added. 6. We have changed the result section to report primarily on ORs, thus removing results from chi square analysis. Kind regards, on behalf of the research team Annlaug Selstø" } ] }, { "id": "319092", "date": "21 Oct 2024", "name": "Sumathi Swaminathan", "expertise": [ "Reviewer Expertise Nutrition", "Public health", "Epidemiology" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nYour Report\nPlease provide a full report, expanding on your answers to the questions above. In particular, if you answered “no” or “partly” to any of the questions, please give constructive and specific details as to how the authors can address any criticisms. Please indicate clearly which points must be addressed to make the article scientifically sound. (50 words min.)\nThe manuscript describes the type of admissions at one district hospital and 3 rural or community hospitals in the Mchingi district at Malawi. The aim of the study as per the authors, is to “assess the care-seeking patterns prior to being admitted to hospital, and to establish the association between pre-admission referrals and inpatient mortality for children in Mchinji District, Malawi”. In the hierarchical health care system, the highest level of health care in a district must be the district hospital with more advanced facilities compared to the rural or community hospitals followed by the health centers available. While this needs to be described, it should be noted that the issue of inpatient mortality due to “self-referrals and referrals” does not arise here. Obviously lower-level hospitals with much less facilities will need to refer those children requiring advanced facilities for treatment based on the severity of their illness, to the community or district hospital depending on the level of treatment required. Self-referrals to district hospitals are likely only among those caregivers who live close to the district hospital rather than those who live in far off rural communities. Mortality is dependent on the severity of illness and the most severe cases are referred from the lower-level hospitals to the district hospital or community hospitals. Self -referrals may not necessarily be for children requiring intensive and advanced medical care as the degree of severity in condition may not be high. So, it is not surprising that mortality among referred cases is higher. And self-referrals lower.\n\nFor the study exposure is defined as the referral and outcome as mortality. Do the authors mean referral to be type of referral? Based on the argument above, the type of referral as an exposure will not be a good choice for this study. Instead, the factors associated with mortality among those referred to higher facilities may be a better question to be examined. From my readings of a government and World Bank documents, healthcare in Malawi and particularly Mchinji district operates through both government and private hospitals run by the Christian Health Association of Malawi. One document indicates that the Central Malawi region had 8 district hospitals and 16 Rural hospitals. It is not clear why the specific district was chosen and how the hospitals were chosen for the study. Authors state that “While all district in Malawi were not included it is assumed that data from Mchinji is sufficiently representative to comfortable make generalizations to the whole population of interest.” The sampling needs to be clearly explained. The authors state that this is an observational retrospective study design. This needs to be explained as the rest of the methods states that consent was taken from caregivers as the children got admitted. From my understanding the hospital case records as and when children were admitted must have been referred to. Therefore, this must have been a prospective study. In Table 2, there are 2 types of referrals mentioned- not referred and referred. There is no reference to self-referral. From this table it is obvious that the factors associated with mortality in referred cases is important to be studied. The duration of hospital stays before death also needs to be reported. The data uploaded does not give specific details of diagnosis, duration and severity of condition. It should be noted that children are referred only if they cannot be managed by lower-level healthcare providers. From the present minimal data shown, most children have died within a couple of days of admission, whether self-referred or referred by a healthcare provider. There is not sufficient data to indicate why the mortality occurred. Further several children have had co-morbidities apart from the primary condition. This has not been reported in the analysis. There are several with “other” diagnosis done as per the raw data. What this refers to is not clear. With minimal data presented, the discussion can obviously not be clearly written. Overall, the whole manuscript should be based on more robust data collected.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No", "responses": [ { "c_id": "13016", "date": "07 Jan 2025", "name": "Annlaug Selstø", "role": "Author Response", "response": "Dear Sumathi Swaminathan We appreciate the comments and have revised the manuscript accordingly. Please see our responses listed under, and our new version of our article. Thank you for your reflections and comments on the health care sytem and the referral mechanism. We agree with you, and will still argue that our findings bear some interest in the difference observed in case fatality rates between those referred from another health centre and those who come straight to the hospital. We have discussed the limitations implied by the lack of severity assessments in the limitations section at the end of the discussion. We have also provided more information on the healthcare systemin Malawi under study setting. Additionally, we have added information on numbers referred from community hospitals to the district hospital with added sentences in the discussion to reflect on how severity of illness may relate to referral status. We are not investigating “type of referral” but rather “referral or not referred”. In this sense “self-referral” might sound confusing. We have therefore renamed the exposure to referred or not-referred. On the matter of chosen hospital in Mchinji we have included the three community hospitals whereof all are CHAM (Christian Health Association of Malawi, the major health provider among NGOs) facilities. These are the hospitals operating within Mchinji district. The study is limited to Mchinji district only. On the matter of representativeness of the sample: We had data collectors present at all facilities ranked as “hospitals” within Mchinji district during the study period. These collected information from all admitted children. The initially planned sample was for one full year of data collection which we expected would give enough numbers to ensure statistically significant results. Unfortunately, data collection was stopped early due to the covid pandemic which made us halt data collection at close to 5000 included children. However, this number turned out to show statistically significant results in terms of mortality difference. Study design: We have changed this and removed the word “retrospective Types of referral and factors associated with mortality: We agree that our findings merit further investigations, and we are currently working on studies to provide more in-depth data to understand the situation better. We are aware that the current study contains several limitations as stated at the end of the discussion. Our primary outcome is hospital mortality, and the duration of admission was not included as part of data collection in this study. We agree with you that there are several additional factors that are highly relevant to understand the reasons for fatal outcomes among admitted children and that the lack of these factors highly impacts the conclusion made from our study. Still, we believe that the finding of a higher case fatality among those referred compared to those who were not referred from another facility provides an interesting information also in that it emphasizes the need to better understand background characteristics and referral practices between different groups. We do by no means think this manuscript can provide a full picture and the various limitations are stated and discussed at the end of the manuscript. We have also added information both in results and discussion on the presumed impact of illness severity on referral decisions and outcomes. Kind regards, on behalf of the research team Annlaug Selstø" } ] } ]	1	https://f1000research.com/articles/12-1053
https://f1000research.com/articles/14-39/v1	07 Jan 25	{ "type": "Research Article", "title": "Assessment of the level of knowledge, attitude, and preference for myopia management among patients and university students in Trinidad", "authors": [ "Kingsley Ekemiri", "Robin Seemongal-Dass", "Destiny Lawrence", "Shaina Oudit", "Chioma Ekemiri", "Virgina Victor", "Magnus C Nsonwu", "John Chigozie Ekenze", "Oforbuike Onyebuchi Ike", "Diane van Staden", "Tiwabwork Tekalign", "Robin Seemongal-Dass", "Destiny Lawrence", "Shaina Oudit", "Chioma Ekemiri", "Virgina Victor", "Magnus C Nsonwu", "John Chigozie Ekenze", "Oforbuike Onyebuchi Ike", "Diane van Staden", "Tiwabwork Tekalign" ], "abstract": "Background Approximately 1.6 billion people worldwide are currently affected by myopia, with estimates suggesting that by 2050, close to half of the global population may experience this condition. Additionally, the prevalence of myopia has been increasing in Trinidad, with rates ranging from 21.5% to 46%. A study has been conducted to determine better patients’ and students’ levels of knowledge, attitudes, and preferences toward the management of myopia in Trinidad.\n\nMethods This cross-sectional study evaluated the knowledge, attitudes, and preferences for myopia management among a sample of 323 participants, including patients and university students in Trinidad and Tobago, aged 18-40. Participants were randomly selected, and data were gathered using a structured questionnaire administered through telephone interviews for patients and emailed to students. Descriptive statistics and inferential analyses, including ANOVA and T-tests, were applied to identify significant associations, with a p-value threshold of less than 0.05 considered statistically significant.\n\nResults A total of 317 participants were examined, resulting in a response rate of 98.1%. The average knowledge score of the participants was 12 out of 25. A slight difference was observed in the knowledge scores of males, with a p-value of 0.052. The results also indicated that the majority of the participants had a good attitude score (21.6 out of 30) toward myopia management. Age and gender had a negligible negative correlation (with a coefficient of -0.022 and p-value of 0.692, respectively) with management preference.\n\nConclusion This study reveals critical gaps in knowledge and diverse attitudes toward myopia management among participants, highlighting the need for targeted educational interventions. While attitudes are generally positive, age and gender influence preferences for myopia correction, with spectacles and contact lenses being the most preferred methods. These insights can guide healthcare professionals in developing tailored approaches for myopia management in Trinidad and Tobago.", "keywords": [ "Myopia", "Eye disease", "Management", "Knowledge", "Trinidad" ], "content": "Introduction\n\nMyopia, also known as near-sightedness, is a common condition that affects a large number of people globally.1 It is a major problem that can cause significant visual loss and other ocular issues.2 The prevalence of myopia is increasing and projections indicate that it will affect almost half of the world’s population by 2050.3,4 Myopia is a prevalent vision disorder impacting people across all age groups and ethnicities. It is linked to several ocular complications, including glaucoma, retinal detachment, and cataracts.5,6\n\nGlobally, around 28.3% of people have mild to moderate myopia, and approximately 4.0% have high myopia.7 Studies indicate that myopia is significantly more prevalent in urban Asian populations compared to Western communities, with rates reaching up to 70% in Singapore, 50% in Taiwan, and 40% in Japan. Both young adults and the elderly appear particularly vulnerable to myopia, with various demographic factors—including socioeconomic status, ethnicity, and occupational demands—contributing to its rising incidence in these groups.8–10\n\nIn Trinidad and Tobago, a Caribbean twin-island country with a diverse population primarily consisting of people of South Asian descent, the prevalence of myopia is also increasing. Among school children, the reported prevalence of myopia is 21.5%, while among university students; it is 46%.11 Given that genes play a crucial role in myopia, there is a critical genetic link between high prevalence of the condition in Asian populations, both in Asia and Trinidad and Tobago.\n\nProper management of myopia is crucial to prevent or delay its progression and minimize the risk of developing associated ocular complications.12\n\nManagement strategies for myopia encompass optical corrections, including glasses and contact lenses, as well as pharmacological interventions and lifestyle modifications.12,13 There exists a notable gap in both knowledge and practices related to myopia management within the general population, encompassing both patients and healthcare professionals. Various factors such as age, gender, educational background, socioeconomic status, and cultural beliefs significantly influence preferences for myopia management.14\n\nWhile numerous studies have been carried out globally to evaluate the knowledge and practices related to myopia management among healthcare professionals and the broader population, significant gaps in understanding remain.15 there are still literary gaps on the knowledge, attitude practices (KAP) relating to myopia management in Trinidad, particularly among patients, healthcare professionals, and the younger generation. Given the increasing cases of myopia and other visual issues, especially among school-going children during the recent COVID-19 pandemic16 and their related consequences17 in Trinidad and Tobago, it is necessary to understand the public health issue and its potential management approaches.\n\n\n\n• To determine patients’ and students’ level of knowledge towards the management of myopia in Trinidad\n\n• To determine patients’ and students’ attitudes towards the management of myopia in Trinidad\n\n• To determine patients’ and students’ preferences towards the management of myopia in Trinidad\n\n\nMethod\n\nThe study utilized a cross-sectional observational study.17 Trinidad, which is one of the twin-islands making the country of Trinidad and Tobago. The country boasts a diverse population of about 1.4 million as of 2019, encompassing various ethnic backgrounds.18–20 This multicultural society includes a variety of ethnic groups, such as Indo-Trinidadians, Afro-Trinidadians, mixed-ethnic individuals, Chinese, and Europeans. This rich tapestry of backgrounds contributes to the unique cultural landscape of the island and plays a significant role in shaping the community’s social dynamics.\n\nInclusion criteria: Participants aged between 18 and 40 years and able and willing to provide valid information, past or present patients of the clinic diagnosed with myopia, and students who were enrolled at the university at the time of the study.\n\nExclusion criteria: Students or practitioners of refractive surgery; non-nationals of Trinidad and Tobago; and, eye care professionals not involved in or without much experience in myopia management.\n\nGood (adequate) knowledge: those participants who scored of 60% or more of a potential 25 points.\n\nSatisfactory knowledge: those participants who scored above 15 out of 25 points.\n\nInsufficient knowledge: those participants who scored scores below 15.21\n\nTo evaluate attitudes toward myopia management, the researchers established criteria where a score of 18 or above, which accounts for 60% or more of the maximum.\n\nGood attitude: those participants who scored score of 30\n\nPoor attitude: those participants who scored scores below 18.21\n\nA non-probability sampling method was employed for this study. Sample size calculations were conducted using Epitools software by Ausvet (available at epitools.ausvet.com.au).21 Utilizing a proportion estimate of 0.3, a precision of 0.05, and a confidence level of 0.95, we determined the required sample size based on a target population of 270,000. The calculated sample size was 323 participants.\n\nA structured questionnaire22,23 comprising four sections was administered to participants in both Group 1 (patients) and Group 2 (students). The questionnaire was specifically designed to collect comprehensive data on demographics, knowledge, attitudes, and preferences related to myopia management.\n\nPatient interviews\n\nFor Group 1 (patients), the questionnaire was administered through telephone interviews. Prior to participation, patients were informed about the study’s purpose and their right to withdraw at any time. Responses were recorded by student researchers (DL, SO) under the supervision of an experienced researcher (KE) to ensure data integrity and adherence to ethical guidelines. A standardized script was employed during the interviews, incorporating prompts to clarify questions and guide participants. This approach minimized variability in question presentation, facilitating clearer and more reliable responses.\n\nUniversity student surveys\n\nGroup 2 (university students) received the same structured questionnaire via email. To enhance participation rates, the email included a brief introduction outlining the study’s objectives and detailed instructions for completing the questionnaire. Students were assured of the anonymity and confidentiality of their responses. Completed questionnaires were submitted through a secure online platform that automatically documented responses, thereby reducing the likelihood of data entry errors.\n\nResponse tracking\n\nTo maximize response rates, a systematic follow-up strategy was implemented. Reminders were sent one week after the initial email and again a few days before the survey closing date to encourage timely completion of the questionnaires.\n\nData analysis was performed using the Statistical Package for Social Science (SPSS) version 29. Descriptive statistics such as frequencies, percentages, and central tendencies were calculated. Inferential tests including ANOVA and T-tests were conducted to determine significant differences between Trinidadian patients and students in these aspects. The assessment utilized a “Total Knowledge” score21,24 as a benchmark for participants’ understanding. Additionally, the significance of this score was determined along with established thresholds for categorizing it, factoring in a weightage of 60% for Knowledge and 40% for Attitude. A p-value of less than 0.05 was considered statistically significant.\n\n\nResults\n\nA sample of 317 participants was examined giving a response rate of 98.1%. The gender distribution was skewed toward females, who made up 64% of the sample. The majority of age (40.4%) falling within the 18-21-year age. Ethnically, East Indians constituted nearly half of the participants at 44.5% ( Table 1).\n\nAccording to this study, the average knowledge score was 12/25. When comparing males and females, a marginal difference in knowledge scores was observed with a p-value of 0.052, implying no significant gender-based difference. However, participants aged 26-30 showed significantly lower scores. An ANOVA test further confirmed disparities in knowledge across age groups, with those aged 26-30 notably trailing their counterparts ( Table 2).\n\nThe average attitude score toward myopia management was 21.6/30. Females exhibited a marginally better attitude than males, with a subtle p-value difference of 0.052. The 26-30 age group registered notably lower scores; however, this age-based difference was not statistically significant (p=0.109). In contrast, a gender-based difference in attitude scores was significant (p=0.005) ( Table 3a).\n\nSubsequent evaluations indicate a distinct disparity in the general attitude between two groups (p=0.007) ( Table 3b). The weighted total score for attitude averaged at 2.68 ± 0.53 ( Table 3c), with no significant gender or age differences (p-values of 0.391 and 0.109, respectively). The total weighted score for attitude was not statistically significant (P=0.730).\n\nAccording to this study result, age and gender have an almost negligible negative correlation (coefficient = -0.022, p=0.692). Age has a weak positive correlation with beliefs about halting myopia progression (coefficient = 0.045). Gender shows a slight negative association (coefficient = -0.036). Preferences for myopia management over traditional optical solutions weakly decline with age (coefficient = -0.042) but show no meaningful connection with gender (coefficient = -0.001). Noteworthy is the current correction method among myopic respondents: it correlates positively with age (coefficient = 0.135) and shows significant ties to beliefs about myopia prevention (coefficient =0.154) and preferences for myopia management (coefficient = 0.144). Gender’s influence remains marginal. The specific preference termed “choice of 9.5” displays only weak connections to both age and gender, each with a coefficient of 0.044 ( Table 4).\n\nThe result of cross-tabulation showed that there is statistically significant association between preference and age with management preference ( Table 5).\n\n\nMyopia management preference\n\nParticipants reported a diverse range of preferred treatments for managing myopia, illustrating the multifaceted approach that individuals and practitioners may adopt in response to this common visual impairment ( Figure 1). Notably, the most popular choices among participants were spectacles and soft contact lenses. This preference aligns with the accessibility and familiarity of these treatments, as spectacles remain the most widely prescribed correction method due to their simplicity, cost-effectiveness, and ease of use ( Figure 1).\n\n\nDiscussion\n\nThis study examines the association between knowledge, attitude, and myopia management preferences with socio-demographic variables. The findings of this study support existing literature16,25 that demonstrates the significant impact of socio-demographic factors such as age, gender, ethnicity, and education level on the management of myopia and other visual impairments. The distribution of age and gender provides valuable insights into how these variables may interact with knowledge, attitudes, and preferences regarding myopia.\n\nThe study found that the average score for “Total Knowledge” was 12 out of 25 possible points, which is considered suboptimal. This aligns with previous literature that has also identified similar knowledge gaps in various demographic settings.26–29 Additionally, the study revealed that the age group of 26-30 showed significantly lower scores, indicating a knowledge disparity within this specific age range. These findings support the idea that targeted educational interventions could be beneficial in managing myopia.30–33 Therefore, any effective myopia management strategy should consider the diverse socio-demographic nature of the population.34\n\nThe overall cohort had a positive attitude towards myopia management. Interestingly, females had a slightly better attitude than males (p=0.052), which is in line with previous research indicating that females are more proactive about healthcare.35–37 The difference in attitude scores between the two groups (p=0.007) suggests that there may be underlying demographic or psychosocial factors that warrant further investigation. These findings are somewhat contrary to existing literature, which often highlights the role of age in shaping attitudes towards healthcare.38–40\n\nMost notably, our findings indicate significant associations between the current correction method for myopic individuals and their age (p=0.010). This is a salient finding because current literature41–44 has been largely inconclusive about the extent of such correlations. Moreover, specific preferences such as the “choice of 9.5” and beliefs about the most effective myopia prevention strategies correlated significantly with age, underscoring the complex relationship between age and healthcare decision-making. However, gender remained a less influential variable throughout our analysis, which is somewhat at odds with studies45–47 that gender plays a significant role in healthcare choices.\n\nPreferences regarding myopia management can be shaped by a multitude of factors, including lifestyle, age, cultural background, and personal beliefs. For instance, while some patients may favor contact lenses over traditional eyeglasses, others might opt for orthokeratology or atropine eye drops. Consequently, understanding these preferences is essential in myopia management, as they significantly impact the treatment options chosen by both patients and healthcare providers.\n\n\nConclusion\n\nThis cross-sectional study highlights the significance of knowledge, attitudes, and practices (KAP) in myopia management within Trinidad. The findings reveal a concerning gap in both knowledge and positive attitudes towards myopia management among patients and students. While female participants exhibited a more favorable attitude, the correlations between age, gender, and myopia management preferences were found to be weak. To enhance patient outcomes and mitigate the impact of myopia on quality of life, it is essential to provide patients and students with accurate and accessible information regarding their treatment options, while also considering their individual preferences and goals. This approach can foster better-informed decision-making and ultimately improve the management of myopia in the population.\n\nThe study findings indicate that patients and students in Trinidad have inadequate knowledge and poor attitudes toward managing myopia. However, female patients and students exhibited a positive attitude towards myopia management, while age and gender did not show strong correlations with myopia preferences. Providing accurate and clear information to patients and students about their treatment options can significantly reduce the impact of myopia on their quality of life.\n\nThis study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. Ethical approval was obtained from the University of The West Indies Ethics Approval Committee, with reference number CREC-SA.1806/10/2022, dated 10th October 2022.\n\nFor patient participants, a willingness request was sent to their addresses. Following their agreement, informed consent was obtained in writing prior to conducting telephonic interviews. For student participants, consent was sought before distributing the questionnaires via email. Written informed consent was also obtained from students prior to the commencement of data collection. All participants were assured of the confidentiality of their responses and their right to withdraw from the study at any time without penalty.\n\nKingsley Ekemiri led the design and article drafting. Dass Robin and Virgina Victor focused on data and methods and refined the methodology. Destiny Lawrence managed the data and analysis. Oudit shaped results and vetting while Chioma Ekemiri and Tiwabwork Tekalign aided in the study design and data analysis. Osaze Okonedo and Diane van Staden contributed to data interpretation and manuscript compilation.", "appendix": "Data availability\n\nOSF: Assessment of the level of Knowledge, Attitude, and Preference for Myopia Management among Patients and University Students in Trinidad Doi: https://doi.org/10.17605/OSF.IO/XNWB248\n\nThis project contains the following underlying data:\n\n• Patients_UWI Students Questionnaire (Responses) (3).xlsx\n\n• Questionnaire (Px & UWI Students) (2).docx\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nSTROBE guideline was used to report the findings of the study.\n\n\nAcknowledgements\n\nThe authors extend their gratitude to the University of the West Indies (UWI), specifically the Optometry Unit within the Department of Clinical Surgical Sciences at the Faculty of Medical Sciences. Their invaluable expertise and supportive environment were instrumental in the realization of this study. We also thank the Couva Multi-Training Facility, the Marketing & Communications Office of UWI, and all the participants for their invaluable contributions and unwavering support throughout the research process.\n\n\nReferences\n\nBaird PN, Saw SM, Lanca C, et al.: Myopia. Nat. Rev. Dis. Prim. 2020; 6(1): 99–119. Publisher Full Text\n\nFlitcroft DI, He M, Jonas JB, et al.: IMI – Defining and Classifying Myopia: A Proposed Set of Standards for Clinical and Epidemiologic Studies. Invest. Ophthalmol. Vis. Sci. 2019; 60(3): M20–M30. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nYılmaz H, Köylü MT, Yeşiltaş YS, et al.: Alterations in the Retinal Nerve Fiber Layer Thickness Color Map in Non- Glaucomatous Eyes with Myopia. Turk. J. Ophthalmol. 2021; 51(1): 26–31. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nNémeth J, Tapasztó B, Aclimandos WA, et al.: Update and Guidance on Management of myopia. European Society of Ophthalmology in Cooperation with International Myopia Institute. Eur. J. Ophthalmol. 2021; 31(3): 853–883. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWilliams K, Hammond C: High Myopia and Its Risks. Community Eye Health. 2019; 32(105): 5–6. Accessed September 15, 2023. PubMed Abstract Reference Source\n\nTheophanous C, Modjtahedi B, Batech M, et al.: Myopia Prevalence and Risk Factors in Children. Clin. Ophthalmol. 2018; 12: 1581–1587. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMcCarty CA, Livingston PM, Taylor HR: Prevalence of Myopia in Adults: Implications for Refractive Surgeons. J. Refract. Surg. 1997; 13(3): 229–234. PubMed Abstract \| Publisher Full Text\n\nHolden BA, Wilson DA, Jong M, et al.: Myopia: A Growing Global Problem with sight-threatening Complications. Community Eye Health. 2015; 28(90): 35. Accessed September 15, 2023. PubMed Abstract Reference Source\n\nSeet B, Wong TY, Tan DT, et al.: Myopia in Singapore: Taking a Public Health Approach. Br. J. Ophthalmol. 2001; 85(5): 521–526. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPan CW, Ramamurthy D, Saw SM: Worldwide Prevalence and Risk Factors for Myopia. Ophthalmic Physiol. Opt. 2011; 32(1): 3–16.\n\nBraithwaite T, Verlander NQ, Peto T, et al.: National Eye Survey of Trinidad and Tobago (NESTT): prevalence, Causes and Risk Factors for Presenting Vision Impairment in Adults over 40 Years. Br. J. Ophthalmol. 2019; 104(1): 74–80. PubMed Abstract \| Publisher Full Text\n\nJain SK, Singh H, Singh H, et al.: Myopia, Its prevalence, Current Therapeutic Strategy and Recent developments: a Review. Indian J. Ophthalmol. 2022; 70(8): 2788–2799.\n\nSaxena R, Dhiman R, Rakheja V, et al.: Current Concepts in the Management of Childhood Myopia. Indian J. Ophthalmol. 2022; 70(8): 2800–2815.\n\nRamsewak S, Verlander NQ, Deomansingh F, et al.: National Eye Survey of Trinidad and Tobago: The Prevalence and Risk Factors for Refractive Error. NESTT Study Group; 2016. Accessed September 15, 2023. Reference Source\n\nRitchey ER: Myopia Management: To Treat or Not to Treat? Reviews of Optometric Business. April 23, 2019. Accessed September 15, 2023. Reference Source\n\nEkemiri K, Ezinne N, Kamalodeen K, et al.: Online e-learning during the COVID-19 Lockdown in Trinidad and Tobago: Prevalence and Associated Factors with Ocular Complaints among Schoolchildren Aged 11–19 Years. PeerJ. 2022; 10: e13334. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nSetia MS: Methodology Series Module 3: Cross-sectional Studies. Indian J. Dermatol. 2016; 61(3): 261–264. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKelly MDA: The Changing Terrain of Racial Inequality in Trinidad and Tobago. Res Soc Stratif Mobil. 2023; 86: 100826. Publisher Full Text\n\nMohammed SR, Sakhamuri T, Sakhamuri S, et al.: Letter from Trinidad and Tobago: No Final Battles in the Weary War On COVID-19? Respirology. 2021; 26(11): 1082–1084. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nGopaul CD, Singh A, Williams A, et al.: Cancer Morbidity and Mortality Trends in Trinidad and Tobago (2008–2018). J. Health Popul. Nutr. 2023; 42(1): 58. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nDebsarma D: Exploring the Strategies for Upgrading the Rural Unqualified Health Practitioners in West Bengal, India: a knowledge, Attitude and Practices assessment-based Approach. Health Policy Open. 2022; 3: 100083. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nRoopa S, Rani M: Questionnaire Designing for a Survey. J. Indian Orthod. Soc. 2012; 46(4): 273–277. Publisher Full Text\n\nHarris L, Brown G: Mixing Interview and Questionnaire methods: Practical Problems in Aligning Data. Pract. Assess. Res. Eval. 2010; 15(1): 1–19.\n\nTrakman GL, Forsyth A, Hoye R, et al.: Developing and Validating a Nutrition Knowledge questionnaire: Key Methods and Considerations. Public Health Nutr. 2017; 20(15): 2670–2679. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nEkemiri KK, Seepersad P, Ezinne NE, et al.: A Pilot Study of Visual Function Parameters and Their Relationship to Road Traffic Accidents among Drivers in Trinidad and Tobago. Global J. Health Sci. 2021; 13(9): 1–24.\n\nMcCrann S, Flitcroft I, Loughman J: Is Optometry Ready for Myopia control? Education and Other Barriers to the Treatment of Myopia. HRB Open Res. 2020; 2: 30. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAldebasi YH: Prevalence of Amblyopia in Primary School Children in Qassim province, Kingdom of Saudi Arabia. Middle East Afr. J. Ophthalmol. 2015; 22(1): 86–91. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAlobaidan OS, Alkhalifah MK, AlSayegh AA, et al.: Knowledge and Practice regarding Contact Lens among Saudi Urban Contact Lens Users. Saudi J. Ophthalmol. 2018; 32(2): 93–96. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCheung SW, Lam C, Cho P: Parents’ Knowledge and Perspective of Optical Methods for Myopia Control in Children. Optom. Vis. Sci. 2014; 91(6): 634–641. PubMed Abstract \| Publisher Full Text\n\nWolffsohn JS, Flitcroft DI, Gifford KL, et al.: IMI – Myopia Control Reports Overview and Introduction. Invest. Ophthalmol. Vis. Sci. 2019; 60(3): M1–M19. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWu LJ, You QS, Duan JL, et al.: Prevalence and Associated Factors of Myopia in High-School Students in Beijing. Khanna RC, ed. PLoS One. 2015; 10(3): e0120764. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWu PC, Chuang MN, Choi J, et al.: Update in Myopia and Treatment Strategy of Atropine Use in Myopia Control. Eye (Lond.). 2018; 33(1): 3–13. PubMed Abstract \| Publisher Full Text\n\nAldael A, Almujalli A, Almatrafi A, et al.: Knowledge, attitude, and Practice about Myopia in School Students in Marat City of Saudi Arabia. J. Family Med. Prim. Care. 2020; 9(7): 3277–3280. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWatts D, Robinson ANR, Brereton BM: Trinidad and Tobago: People, Culture, Map, & Flag. Encyclopædia Britannica; 2023. Accessed September 15, 2023. Reference Source\n\nEngström J, Norin O, de Gosson de Varennes S , et al.: Service Design in healthcare: a segmentation-based Approach. J. Serv. Manag. 2022; 33(6): 50–78. Publisher Full Text\n\nAl Yahyaei A, Hewison A, Efstathiou N, et al.: Nurses’ Intention to Stay in the Work Environment in Acute healthcare: a Systematic Review. J. Res. Nurs. 2022; 27(4): 374–397. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBertakis KD, Azari R, Helms LJ, et al.: Gender Differences in the Utilization of Health Care Services. J. Fam. Pract. 2000; 49(2): 147–152. PubMed Abstract\n\nHolden B, Sankaridurg P, Smith E, et al.: Myopia, an Underrated Global Challenge to vision: Where the Current Data Takes Us on Myopia Control. Eye (Lond.). 2013; 28(2): 142–146. PubMed Abstract \| Publisher Full Text\n\nPress DJ, Eiden SB: Myopia Management in Action. Rev. Optom. April 12, 2019. Accessed September 18, 2023. Reference Source\n\nManoharan MK, Thakur S, Dhakal R, et al.: Myopia Progression Risk Assessment Score (MPRAS): a Promising New Tool for Risk Stratification. Sci. Rep. 2023; 13(1): 8858. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nFotedar R, Rochtchina E, Morgan I, et al.: Necessity of Cycloplegia for Assessing Refractive Error in 12-Year-Old Children: A Population-Based Study. Am. J. Ophthalmol. 2007; 144(2): 307–309. PubMed Abstract \| Publisher Full Text\n\nLee MW, Lee SE, Lim HB, et al.: Longitudinal Changes in Axial Length in High myopia: a 4-year Prospective Study. Br. J. Ophthalmol. 2020; 104(5): 600–603. PubMed Abstract \| Publisher Full Text\n\nZhu H, Huang D, Sun Q, et al.: Normative Visual Acuity in Chinese Preschoolers Aged 36 to. BMJ Open. 2017; 7(7): e014866. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAtowa UC, Hansraj R, Wajuihian SO: Vision problems: a Review of Prevalence Studies on Refractive Errors in school-age Children. Afr. Vis. Eye Health. 2019; 78(1): 7. Accessed September 18, 2023. Publisher Full Text Reference Source\n\nEngström J, Norin O, de Gosson de Varennes S , et al.: Service Design in healthcare: a segmentation-based Approach. J. Serv. Manag. 2022; 33(6): 50–78. Publisher Full Text\n\nAl Yahyaei A, Hewison A, Efstathiou N, et al.: Nurses’ Intention to Stay in the Work Environment in Acute healthcare: a Systematic Review. J. Res. Nurs. 2022; 27(4): 374–397. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBertakis KD, Azari R, Helms LJ, et al.: Gender Differences in the Utilization of Health Care Services. J. Fam. Pract. 2000; 49(2): 147–152. Accessed September 18, 2023. PubMed Abstract\n\nEkemiri KK: Assessment of the level of Knowledge, Attitude, and Preference for Myopia Management among Patients and University Students in Trinidad.2024, October 13. Publisher Full Text" }	[ { "id": "357329", "date": "24 Jan 2025", "name": "Leon Marković", "expertise": [ "Reviewer Expertise myopia", "artificial inteligence", "medical retina", "vitreoretinal surgery" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article provides a comprehensive overview of myopia, its prevalence, complications, and management, with a clear focus on knowledge, attitudes, and preferences in Trinidad. However some issues are:\n1. Operational Definitions Ambiguities:\nDefinitions for \"good,\" \"satisfactory,\" and \"insufficient\" knowledge are provided, but there is no justification for the chosen scoring thresholds (e.g., why is 60% considered adequate knowledge?).\n2. Sample Size Calculation:\nAlthough calculated using Epitools software, the rationale for selecting a proportion estimate of 0.3 and its implications on the results are unclear.\n3. Data Collection Tools and Procedures:\nThe use of telephone interviews for patients and email surveys for students may introduce variability in responses due to differences in communication methods. The standardized script for interviews is mentioned but not provided, leaving its consistency and comprehensiveness open to question.\n4.Statistical Analysis Gaps:\nThe article mentions that gender differences in attitudes are significant (p=0.005) but fails to explore why this might be the case. Despite noting weak correlations between preferences and demographic variables, the discussion does not adequately address their practical significance.\n5. Conclusion Weaknesses:\nThe conclusion reiterates findings but does not offer actionable recommendations for improving knowledge and attitudes toward myopia management. There is little emphasis on public health strategies that could address the gaps identified.\n6. Missing information about the relationship between patients and university students knowledge and their significance\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [] }, { "id": "357325", "date": "28 Jan 2025", "name": "Emmanuel E Okenwa-Vincent", "expertise": [ "Reviewer Expertise Public Health Optometrists with interest in pedriatic and low vision care. I have particular research interest in the impact of myopia management on the behavioral", "cognitive", "and academic performance of children and adolescents" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nGeneral Comment: I appreciate the opportunity to review this article, titled “Assessment of the Level of Knowledge, Attitude, and Preference for Myopia Management Among Patients and University Students in Trinidad.\". This manuscript addresses a highly relevant and timely topic, not only for Trinidad but also as a public health issue of global significance in eye care. The study is well-conducted and demonstrates potential to contribute meaningfully to the existing body of knowledge. However, I believe that with some revisions to the manuscript, it can achieve the level of rigor required for acceptance. Below, I have outlined specific comments and suggestions that, if addressed, could substantially enhance the overall quality and impact of the article.\nArticle summary: The paper sought to understand the knowledge, attitudes, and preferences regarding myopia management within a sample of 317 participants aged 18–40. It highlighted significant gaps in knowledge about myopia and identified spectacles and contact lenses as the most preferred corrective measures. While the study further found that attitudes toward myopia management were generally positive, it emphasized the need for targeted educational interventions to enhance awareness and improve management strategies in Trinidad.\nSpecific comments:\nAbstract:\nIt is worthy of note that while gender and sex are often used interchangeably, they have distinct meanings in social, cultural, and biological contexts: Sex: biological characteristics that define humans as male or female. Gender: social and cultural roles, behaviors, and identities that society associates with being male or female. I think in the context of this work, the authors should stick with the biological description that define humans as males or females… “Sex”.\n\nIntroduction:\nThe section could be rephrased into three coordinated paragraphs and could benefit from an editorial review. For instance, having one single-sentence paragraph (4th paragraph), could imply need for more editorial work. Line 3 of last paragraph of this section: please check relationship between punctuations There seem to be a disagreement between the knowledge gap this study seek to address, and the title of the study. For instance. “…significant gaps in understanding remain.15 there are still literary gaps on the knowledge, attitude practices (KAP) relating to myopia management in Trinidad, particularly among patients, healthcare professionals, and the younger generation.”.. If the topic sought to assess level of KAP about patients and university students, why not keep the knowledge among the study populations of interest to the study? Also what do the authors mean by “Younger generation”? Should the reader need to assume the same to mean “university students”? This needs to be clarified and consistently too. More so, the last paragraph will benefit from better editing if the objectives are summarized in prosed format, as part of the same paragraph.\n\nMethod:\nHow were 323/317 participants consisting of past and recent patients, and also university students selected using a “non-probability method? Also, what specific type of non-probability sampling method was employed, and why? Also, were the two groups of equal samples/sizes? How were the minimum sample sizes separately determined. This doesn’t come out clearly. How was the study questionnaire validated? Also, the emails sent to the student participants, was it an email of a standardized/validated questionnaire, or a link to an online survey? How were the responses transferred to a secured platform? Who has access to this platform? And why was it necessary to do so, since in my opinion, a private email system with restricted access, should have sufficed as a secured means of data retrieval, right? Please change “via” to “through”. The SPSS software is a platform for statistical analyses, using varying/appropriate statistical tools. Data are entered or exported to SPSS software, and appropriate statistical tools, defined apriori, are employed for analyses. What specific central tendency(ies) was/were employed? Although both ANOVA and T-tests can be employed to compare two heterogeneous groups, but it would be good to know if the authors considered conducting a Levene’s test of equal variance?\n\nKey Considerations for Heterogeneous Groups:\nHeterogeneity in Variance: If group variances are unequal, parametric tests (standard t-tests or ANOVA) may not perform well. Hence, using variance-robust versions like Welch’s t-test or Welch’s ANOVA, would have been appropriate. Heterogeneity in Sample Size: Unequal sample sizes can affect test performance, especially when variances are unequal. Welch’s tests handle this better than standard versions. It is important to note that there is nowhere in the paper that the authors indicated the separate sample sizes of either group of participants, not alluding to equality.\n\nThere are way too many subtitles in the method section. The report could benefit significantly both from expert editing review, and improved prosing of the method section, separated by relevant paragraphs. In fact, it would be nice to see three or at most four sub-headings here. For instance; Study design, setting and population; sampling methods; data collection and analysis; ethical considerations (this is missing and aught be presented in the section).\n\nResults:\nAs mentioned previously, “gender” should be changed to “sex” The sociodemographic section should report results separately for the two different groups – patients vs university students No comparison between Trinidadian patients and students shown, yet the subtitles read, Knowledge, attitudes, and preferences of patients and university students. It may appear the focus of each analysis was on intragroup comparisons for sex differences and age variations to responses elicited from participants, but ignored intergroups comparisons of patients vs students. This is an important outcome of the study and has critical implications for the study. Is there a difference between negligible correlation vs weak correlation vs slight association… which is which? What variables in the correlation coefficients were compared? For instance, in the question “Which option do you think would work best for preventing myopia progression?” what options are being referred to… as these were not mentioned anywhere in Table 4? Correlation coefficients nor tests of associations were not mentioned in the method section. It may appear that these were after-thoughts.\nDiscussion:\nThe opening sentence of this section should be rephrased to reflect the study title, rather than connote a different meaning. For instance, “…This study assesses the level of knowledge, attitude, and preference for myopia management among xxxxx…”. In my opinion, it is misrepresentation to infer that the study “…examines the association between knowledge, attitude, and myopia management preferences with socio-demographic variables…”.\nBy the way, why so much focus on gender/sex, and age, comparisons with the outcome variables in the results without any mention nor any data on ethnicity? Thought the authors should consider those as well, and with comparisons between groups of participants. Education level, at least, of the patients-participants should have been an important variable to have been considered for inclusion, else, should be highlighted as an important limitation. This said, it would be nice for the authors to indicate in the method section how the study questionnaire was validated. The first sentence in the second paragraph need to be rephrased, and the result need not be repeated, as it had already been stated in the results section. Indeed, the entire discussion need significant revision for appropriate editing, and also remove all results in discussion section. There should be a line drawn between correlation and association… they can definitely not be used interchangeably as it creates confusion on whether the authors are trying to infer on “causation”? The sentence, “…Preferences regarding myopia management can be shaped by a multitude of factors, including lifestyle, age, cultural background, and personal beliefs…”, may be misleading as the study did not indicate anywhere that lifestyle, cultural background, and personal beliefs were measured in this current study. If it did, then these variables did not come out clearly in the results.\n\nConclusion:\nWhile it is not clear from which results and objectives the conclusions in this study are being drawn from or based upon, it may be especially apparently misleading when “quality of life” is being mentioned as basis for need for bridging knowledge gap among the study participant. Conclusions need to be based on objectives, and results. The limitations to the study need to be embedded and discussed within the discussion section. The limitation to the study discussed in this paper does not appear like a limitation. I encourage the authors to revise the limitations (discuss them within the discussion section). What were the drawbacks to the study, how were they handled/managed, and what is/are the potential implications to the results, including if the reader need to be cautious in interpreting the results. Do they warrant further studies (what type), etc. to address the potential drawbacks. No study is ever perfect!\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [] } ]	1	https://f1000research.com/articles/14-39
https://f1000research.com/articles/13-1266/v1	23 Oct 24	{ "type": "Review", "title": "The science of printing and polishing 3D-printed dentures", "authors": [ "Kavishma Sulaya", "Swapna B V", "Vaishnavi M Nayak", "Kavishma Sulaya", "Swapna B V" ], "abstract": "Objective To analyze the effectiveness of various techniques available for printing, finishing and polishing of 3D printed prosthesis.\n\nMethods The articles were selected from electronic databases including PubMed and Scopus. Recently, lot of advancements have been observed in the field of 3D printing in dentistry.\n\nResults Numerous studies were found explaining the factors affecting the surface roughness such as printing speed, direction, layer thickness, post curing, etc., and the significance in achieving a smooth surface finish of a 3D printed prosthesis. The methods employed to achieve this range, similar to conventional and chairside polishing, are to use advanced coating materials such as light cured glazes to nanoparticles.\n\nConclusion 3D printing is being used in day-to-day practice and the prosthesis must be aesthetic looking to satisfy the patients’ expectations. There is a lack of data supporting any one polishing method for the prosthesis. There is a need for further research on the existing techniques and newer advancements yielding aesthetic prostheses with an optimal surface finish.", "keywords": [ "Additive manufacturing", "3D printed dentures", "Surface roughness", "Chairside polishing", "Glaze materials." ], "content": "Introduction\n\nThree-dimensional (3D) printing has been introduced in the industrial sector since 1980’s.1 Its advent in dentistry has led to the revolutionization of the field. The surface finish and polished surface of the prosthesis plays a vital role as there is an increased demand for esthetic restoration and life-like prostheses. This property is of clinical relevance not only for its esthetic reasons but also as it directly or indirectly aids in the retention of microbial plaque on its surface. Increased surface roughness results in high plaque accumulation, thereby increasing surface fatigue and reducing the biocompatibility of the material leading to oral candidiasis and denture stomatitis. Polishing of the prosthesis is either done by mechanical method (Conventional, chairside) or chemical method to reduce the adherence of the microorganisms. Coating materials can be used as an additional layer for additively manufactured prostheses as an alternative to conventional polishing.\n\nThe Surface roughness is determined using Ra or Rz values. Ra is the average value of the deviation of a measuring profile from a central line along the measuring length.2 Rz is the deviation from the mean line focusing on the highest peak and valley. It is the average of the five individual values in sequence from individual roughness depth. Estimated Ra value can be calculated by dividing Rz value from 4-7 units, but estimated Rz is calculated by multiplying Ra value by 10-15. According to Fernandaz P et al, a surface roughness (Ra) of 0.2 μm was set as the clinically acceptable value.2 The surface roughness is affected by the number of layers added, the speed of printing, the material used, the thickness of the material, the polishing technique, and operator’s skills.3\n\nConventionally, laboratory polishing of the prosthesis is done with pumice slurry and buff followed using aluminum oxide polishing paste. Chairside polishing is done using various chairside kits such as the Shofu kit, JOTA polishing kit, microdont polishing kit, etc., from coarser to fine grit burs at the speed of 5000 rpm. The major disadvantage of these conventional methods is the dimensional change that may occur, increased risk of fracture etc. Chemical polishing includes placement of the denture base in an ultrasonic bath and coating it with another thin layer of resin, laser polishing, etc.4\n\nAdditively manufactured prostheses are fabricated layer by layer which results in a lot of surface irregularities due to its stepwise effect that require adequate polishing.2 A combination of multiple methods is required to finely polish the prosthesis to achieve the required results. There is no standard protocol available to polish a 3D printed prosthesis and the available literature to prove which method of polishing is superior to the other is scarce. Hence this narrative review focuses on understanding the 3D printing process and its effect on polished surface.\n\n\nMethods\n\nThe relevant articles were selected from two databases Pubmed and Scopus after conducting search using the keywords from 1995 to 2024. Recent reviews and original research articles which analysed the data on surface roughness, various polishing and 3d printing techniques were included.\n\n\nDiscussion\n\nAdditive manufacturing (AM) is the method in which materials are combined layer by layer to create objects from 3D model data.5,6 The new successive layers are joined to the preceding layers by either melting, fusing, or polymerization processes. American Society for Testing and Materials classifies AM technology into seven categories based on the printing methods.7,8\n\n1) VAT photopolymerization\n\n2) Fused Deposition Modeling\n\n3) Powder Bed Fusion\n\n4) Material jetting or inkjet printing\n\n5) Binder jetting or three-dimensional printing\n\n6) Direct Energy Deposition\n\n7) Manufacturing of laminated objects.\n\nSome of the methods used for printing complete dentures include\n\nVAT photopolymerization\n\nStereolithography (SLA)\n\nThis was developed in 1963 and was one of the first additive manufacturing method. This technique is based on light polymerization, in which a chain reaction between the resin and the monomer is initiated by an electron beam or UV light. The polymer resin used for printing dentures is supplied in liquid form which includes photopolymers. The building platform is submerged in a liquid polymer tank, which can be moved up, polymerizing the initial layer by laser beam. The building platform is lowered to descend into the tank to create a subsequent layer. This causes polymer liquid to cover the surface of the previously built layer, repeating the polymerization process as the platform moves. This process is repeated until all the layers are built and the 3D model is completed. The completed model is photo cured for increased strength. The models printed using SLA have high resolution and quality but are expensive and time consuming.9 The thickness of each layer is controlled by two factors, i.e. energy of the light source and the amount of exposure.10,11\n\nDigital light processing (DLP)\n\nThe materials used and the process of printing are the same as SLA, but the source of light for polymerization used is different. Laser is used for polymerization in SLA, but a digital projector is used in DLP. DLP method prints at a faster speed compared to SLA, and intensity of the light source can be varied.11–13\n\nFused depositing modeling (FDM)\n\nThe polymer used in this method has thermoplastic properties, the layers can be joined together throughout the printing process and solidify at room temperature once the printing is complete. The most used materials are polylactic acid, acrylonitrile butadiene styrene, and polycarbonates.14,15 The material should have a low melting point, sufficient viscosity to flow out of the nozzle and adequate strength to support the next layers. High speed, easy processing, and low cost are the advantages of FDM. Limitations include low surface quality, layered appearance, and low mechanical strength.16\n\nMaterial jetting\n\nIt is an injection system in which the photopolymer goes through several nozzles to build the 3-dimensional model layer by layer. The material is cured by UV radiation and shares a chemical foundation with vat photopolymerization.17,18\n\nThe accuracy and properties of the final product are affected by various printing and processing parameters and material composition. The printing process parameters include printing direction, layer thickness and post curing which affect the final printing product.10\n\nThe build direction/angle selection is vital, as it influences the amount of support the structures require which impacts the precision of the final product. The printing direction, which establishes the angle between the component layers and the applied force affects the mechanical qualities of the 3D printed denture.19 Thus, selecting the right printing orientation is crucial for optimizing the mechanical properties of the final product. Yan S et al., evaluated the build angle (0°,45°, and 90°) on the surface characteristics of 3D printed complete denture base samples by DLP method and concluded that 0° built specimens exhibited significantly lower mean roughness when compared with 45° and 90°. They exhibited block-like protrusions on the surface which were evenly distributed and surrounded by depression. The highest mean surface roughness was seen in specimen built at 45° followed by 90° group, while the smoothest surface was seen with 0°.20 Ataei et al., evaluated the surface roughness of 3D printed samples at 0° orientation and 100 μm layer thickness and later subjected them to thermocycling. They observed that polishing was an effective way to make layered structure disappear in 3D printed resin. There was no variation in the layered structure in the presence or absence of thermal stress.21 Lee et al., evaluated the surface properties of 3D printed resins with DLP method in three distinct build angles (0,45°, and 90°) and found that the 0° build angle provided a smooth surface, regardless of the thickness. The highest surface roughness was observed at a 45° build angle. However, this study also indicated that decreasing thickness can enhance surface roughness.22 Similarly, Shim et al., also concluded that 45° printing orientation showed the highest value of surface roughness compared with those of the other groups (0° and 90°). The surface obtained from the 0° printing orientation revealed craters of varied sizes, whereas the 45° orientation group displayed recurring oblique ridges. The 90° orientation group displayed asymmetrical surfaces that blended spherical and non-round geometries.23\n\nThe layer thickness (LT) is the measurement of the thickness of each slice of the part that builds upon the layer before it. The layer thickness affects the accuracy and other properties of the final denture.24 Lee et al., evaluated the effect of two different layer thickness (50 and 100 μm) on the surface roughness of 3D printed resins with DLP method. They observed that the surface smoothness achieved with a 100μm layer thickness and 0° built angle was similar to 50 μm layer thickness. These settings could facilitate effective fabrication with favorable surface smoothness, as products with a 100 μm LT could be fabricated faster.22\n\n3D printed resins are photo-polymerized material, and post-curing time affects the performance of the material. The photo initiator initiates the polymerization, using the laser or light projector resulting in partial curing. The unbonded monomers then join to form a polymer, which further develops into a cross-linked macromolecule. The primary surface texture is now developed. The polymerization process is completed by further curing using a light cure unit as a post curing step. The post-curing period as recommended by the manufacturers varies from 20 to 60 minutes to ensure complete polymerization of the material.25,26 Ahmed et al., concluded that 30 minutes is the minimal post-curing time to obtain optimal results since additional curing had no discernible impact on the material’s characteristics.27 Ping li et al., studied the surface topography and roughness of 3D printed resins after various post-curing methods using different devices and observed no significant differences between the post-cured specimens with various devices. Significantly lower Ra values were exhibited by the 3D printed specimens than the conventional poly methyl methacrylate (PMMA).28\n\nIn day-to-day clinical practice, acrylic dentures are subjected to modifications by trimming which would create a rougher surface.4,29,30 To smooth out rough layers, polishing these acrylic dentures is recommended to reduce the free surface energy. The polished surface improves hygiene of denture as it prevents microbial adherence and colonization.4,31 Routinely, in a laboratory setting acrylic dentures are polished with pumice slurry followed by aluminum oxide polishing paste (Al2O3).4,31,32 With the advent of digital dentistry, 3D-printed dentures are being routinely used for fabrication of removable dentures. Inherently, 3D-printed dentures have layers due to their printing nature affecting the surface properties. The increase in the surface roughness of 3D-printed dentures could be attributed to the edge stepwise effects. (Figure 1) Additionally, the chairside corrections done during clinical procedures, adds on to the surface roughness. Although the literature on the effect of conventional laboratory polishing techniques on surface roughness of 3D-printed dentures is limited, the currently available studies have shown clinically acceptable smooth surfaces which prevents sequelae of plaque accumulation.\n\nFernandez et al., compared the surface characteristics of 3D-printed and milled denture base materials with conventional heat-cure resins.2 The study compared resins that were polished or coated to different degrees, such as the intermediate polishing group (pre-polishing with grinding paper 150,180 grit size; brushed along with pumice slurry followed by polishing paste using lathe bristle brush), high gloss polish group (procedure similar to intermediate group, additionally the resin block was polished with polishing paste and soft cloth wheel to attain high gloss), coated resin group (thinly coated with unpolymerized resin for 3D printing procedure and cured with a light curing unit), and coated and polishing (combined procedure of coated and high gloss polished group).2 They concluded that polishing (high gloss), coating and coating along with polishing resins were within the clinically relevant surface roughness threshold.2 The high gloss polished 3D-printed resins provided lower roughness compared to coated specimens with clinically relevant lower Ra values.2 The polishing of 3D-printed dentures showed superior Ra values when compared to milled dentures.\n\nRoutinely chairside manipulation of the denture is required leading to practitioners using chairside polishing kits for polishing. Chairside polishing kit has been used as a substitute method of choice in situations where laboratory polishing cannot be performed.33 With conventionally used heat cured PMMA, the chairside polishing kits have provided clinically acceptable results although inferior to laboratory polishing.33\n\nAl-Dulaijan et al., compared laboratory and chairside polishing on 3D-printed denture resins and concluded that laboratory polishing showed lower Ra values than chairside and unpolished denture base resins.4 Sandpaper of grit size 1000 and 2500 were used for finishing procedures. The specimens for laboratory polishing group were then polished with pumice slurry and brush for 90 seconds at 1500 rpm, followed by universal polishing paste and lathe brush for 15 seconds at 3000 rpm respectively. For chairside polishing three commercially available kits Microdont, Acrypoint and Shofu were used with 3 polishing burs of coarse, medium and fine grain for a minute each. Although conventional polishing showed superior results, the author concluded that chairside polishing kits are an efficient technique when access to laboratory method is limited.4 Quezada et al., investigated the surface roughness of Computer aided designing and Computer aided manufacturing (CAD/CAM) denture resins to conventional PMMA using chairside polishing kit JOTA and found that 3D-printed resin specimen showed lower Ra values to conventional heat cured dentures.3\n\nTo decrease surface roughness, light-cured glazes and coatings have been applied to digitally manufactured dentures.34–36 Additionally, it reduces surface porosity and imperfections, prevents microleakage, and strengthens resin and increases resistance to stains.34–36 Dickinson et al., reported that a low viscosity sealant lowered the surface roughness in acrylic resins (Ra values = 0.2 μm).3,37 Pigmented light cure glaze materials can also be used for the characterization of teeth and gingiva masking the monolithic appearance of the dentures. Silica and titanium nanoparticles are incorporated in dental glaze materials which improve the resin’s surface properties and lower the surface energy, reducing biofilm adhesion.34,38 Choi et al., evaluated the surface of different light polymerized denture glaze materials and concluded that the glaze materials lowered the surface roughness values.34 Ra values varied from 0.26 to 0.15 μm exceeding the threshold limit.34 Along the acceptable polished surface, glaze materials with nanoparticles such as silica dioxide and titanium dioxide also improved the surface hardness and elastic modulus.34,39 This could be attributed to coupling agents such as 3-trimethoxysilylpropyl methacrylate which creates a bond between both the inorganic and organic phases of acrylic resins.34\n\nFernandez et al., evaluated surface roughness of additively fabricated dentures coated with the same unpolymerized material.2 Coated specimens demonstrated Ra values of 0.16 μm well within the clinically relevant threshold of 0.2 μm. Although, solely coated specimens did not yield any superior outcome to solely polished specimens.2 The coated and polished specimens gave superior results.2 However, coating with unpolymerized material to 3D-printed dentures may be regarded as an alternative to conventional polishing.2 Various polishing methods have been summarised in Figure 2.\n\n\nConclusions\n\nSurface roughness of the printed prosthesis depends on the printing orientation, thickness of the layer and the post-curing process. Zero-degree angulation provides a smoother surface. Advised post-curing time is 20 to 60 minutes, following which polishing can be done by conventional laboratory or chairside methods. Light cured glaze coating materials with incorporated nanomaterials provide acceptable surface roughness values along with better surface hardness and modulus of elasticity. However, the current studies conclude that conventional laboratory polishing of 3D-printed dentures is sufficient for achieving a clinically acceptable polish. Still, there is a need for a standardized protocol for finishing and polishing 3D-printed prostheses and the potential for various coating materials to be used as an alternative to the conventional polishing method.", "appendix": "Data availability\n\nNo data are associated with this article.\n\n\nAcknowledgements\n\n-NIL\n\n\nReferences\n\nTian Y, Chen C, Xu X, et al.: A review of 3D printing in dentistry: Technologies, affecting factors, and applications. Scanning. 2021; 2021(1): 1–19. Publisher Full Text\n\nKraemer Fernandez P, Unkovskiy A, Benkendorff V, et al.: Surface characteristics of milled and 3D printed denture base materials following polishing and coating: An in-vitro study. Materials. 2020 Jul 24; 13(15): 3305. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nQuezada MM, Salgado H, Correia A, et al.: Investigation of the effect of the same polishing protocol on the surface roughness of denture base acrylic resins. Biomedicines. 2022 Aug 14; 10(8): 1971. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAl-Dulaijan YA: Evaluation of the effects of different polishing protocols on the surface characterizations of 3D-Printed acrylic denture base resins: An in vitro Study. Polymers. 2023 Jun 30; 15(13): 2913. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nVan Noort R: The future of dental devices is digital. Dent. Mater. 2012 Jan 1; 28(1): 3–12. Publisher Full Text\n\nDovbish VM, Zabednov PV, Zlenko MA: Additive tehnologii. I izdelia iz metala. 57.\n\nISO I: 17296-2 Additive Manufacturing—General Principles—Part2: Overview of Process Categories and Feedstock. Geneva, The Switzerland: ISO; 2016.\n\nAttarilar S, Ebrahimi M, Djavanroodi F, et al.: 3D printing technologies in metallic implants: a thematic review on the techniques and procedures. Int. J. Bioprinting. 2021; 7(1): 306. Publisher Full Text\n\nNgo TD, Kashani A, Imbalzano G, et al.: Additive manufacturing (3D printing): A review of materials, methods, applications and challenges. Compos. Part B. 2018 Jun 143; 143: 172–196. Publisher Full Text\n\nAbedini A: A literature review of 3D printing In dental prosthesis. J. Pharm. Negat. Results. 2022 Dec 31; 13(4): 2039–2050.\n\nMelchels FP, Feijen J, Grijpma DW: A review on stereolithography and its applications in biomedical engineering. Biomaterials. 2010 Aug 1; 31(24): 6121–6130. Publisher Full Text\n\nVinogradov P: 3D printing in medicine: Current challenges and potential applications. 3D Printing Technology in Nanomedicine. Vol. 1. . Missouri: Elsevier Inc.; 2019 Mar 30.\n\nSchweiger J, Edelhoff D, Güth JF: 3D printing in digital prosthetic dentistry: an overview of recent developments in additive manufacturing. J. Clin. Med. 2021 May 7; 10(9): 2010. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMohamed OA, Masood SH, Bhowmik JL: Optimization of fused deposition modeling process parameters: a review of current research and future prospects. Adv. Manuf. 2015 Mar; 3: 42–53. Publisher Full Text\n\nSood AK, Ohdar RK, Mahapatra SS: Parametric appraisal of mechanical property of fused deposition modelling processed parts. Mater. Des. 2010 Jan 1; 31(1): 287–295. Publisher Full Text\n\nChohan JS, Singh R, Boparai KS, et al.: Dimensional accuracy analysis of coupled fused deposition modeling and vapour smoothing operations for biomedical applications. Compos. Part B. 2017 May 15; 117: 138–149. Publisher Full Text\n\nDou R, Wang T, Guo Y, et al.: Ink-jet printing of zirconia: coffee staining and line stability. J. Am. Ceram. Soc. 2011 Nov; 94(11): 3787–3792. Publisher Full Text\n\nSwapna BV: Digital Complete Dentures-An Overview. Cumhuriyet Dent. J. 2024 Feb 16; 27(1): 52–58. Publisher Full Text\n\nLi Y, Teng Z: Effect of printing orientation on mechanical properties of SLA 3D-printed photopolymer. Fatigue Fract. Eng. Mater. Struct. 2024 May; 47(5): 1531–1545. Publisher Full Text\n\nYan S, Zhou JL, Zhang RJ, et al.: Evaluation of the influence of different build angles on the surface characteristics, accuracy, and dimensional stability of the complete denture base printed by digital light processing. Heliyon. 2024 Jan 15; 10(1): e24095. Publisher Full Text\n\nAtaei K, Ghaffari T, Moslehifard E, et al.: Physico-chemical and Mechanical Assessments of a New 3D Printed PMMA-Based Acrylic Denture Base Material. Open Dent. J. 2024 Feb 1; 18(1).\n\nLee WJ, Jo YH, Yilmaz B, et al.: Effect of build angle, resin layer thickness and viscosity on the surface properties and microbial adhesion of denture bases manufactured using digital light processing. J. Dent. 2023 Oct 1; 137: 104608. Publisher Full Text\n\nShim JS, Kim JE, Jeong SH, et al.: Printing accuracy, mechanical properties, surface characteristics, and microbial adhesion of 3D-printed resins with various printing orientations. J. Prosthet. Dent. 2020 Oct 1; 124(4): 468–475. Publisher Full Text\n\nCheng W, Fuh JY, Nee AY, et al.: Multi-objective optimization of part-building orientation in stereolithography. Rapid Prototyp. J. 1995 Dec 1; 1(4): 12–23. Publisher Full Text\n\nFORMLABS: Form Cure time and temperature settings.2021. Reference Source\n\nNext Dent: 3D systems.2022Reference Source\n\nAltarazi A, Haider J, Alhotan A, et al.: Assessing the physical and mechanical properties of 3D printed acrylic material for denture base application. Dent. Mater. 2022 Dec 1; 38(12): 1841–1854. Publisher Full Text\n\nLi P, Lambart AL, Stawarczyk B, et al.: Postpolymerization of a 3D-printed denture base polymer: Impact of post-curing methods on surface characteristics, flexural strength, and cytotoxicity. J. Dent. 2021 Dec 1; 115: 103856. Publisher Full Text\n\nKuhar M, Funduk N: Effects of polishing techniques on the surface roughness of acrylic denture base resins. J. Prosthet. Dent. 2005 Jan 1; 93(1): 76–85. Publisher Full Text\n\nRadford DR, Watson TF, Walter JD, et al.: The effects of surface machining on heat cured acrylic resin and two soft denture base materials: a scanning electron microscope and confocal microscope evaluation. J. Prosthet. Dent. 1997 Aug 1; 78(2): 200–208. Publisher Full Text\n\nGungor H, Gundogdu M, Duymus ZY: Investigation of the effect of different polishing techniques on the surface roughness of denture base and repair materials. J. Prosthet. Dent. 2014 Nov 1; 112(5): 1271–1277. Publisher Full Text\n\nSofou A, Emmanouil J, Peutzfeldt A, et al.: The effect of different polishing techniques on the surface roughness of acrylic resin materials. Eur. J. Prosthodont. Restor. Dent. 2001 Sep 1; 9(3-4): 117–122.\n\nSofou A, Emmanouil J, Peutzfeldt A, et al.: The effect of different polishing techniques on the surface roughness of acrylic resin materials. Eur. J. Prosthodont. Restor. Dent. 2001 Sep 1; 9(3-4): 117–122.\n\nChoi JJ, Uy CE, Ramani RS, et al.: Evaluation of surface roughness, hardness and elastic modulus of nanoparticle containing light-polymerized denture glaze materials. J. Mech. Behav. Biomed. Mater. 2020 Mar 1; 103: 103601. Publisher Full Text\n\nEmmanouil JK, Kavouras P, Kehagias T: The effect of photo-activated glazes on the microhardness of acrylic baseplate resins. J. Dent. 2002 Jan 1; 30(1): 7–10. Publisher Full Text\n\nSahin O, Koroglu A, Dede DÖ, et al.: Effect of surface sealant agents on the surface roughness and color stability of denture base materials. J. Prosthet. Dent. 2016 Oct 1; 116(4): 610–616. Publisher Full Text\n\nDickinson GL, Leinfelder KF: Assessing the long-term effect of a surface penetrating sealant. J. Am. Dent. Assoc. 1939; 124(7): 68–72. 1993 Jul 1. Publisher Full Text\n\nKaizer MR, Almeida JR, Gonçalves AP, et al.: Silica coating of nonsilicate nanoparticles for resin-based composite materials. J. Dent. Res. 2016 Nov; 95(12): 1394–1400. Publisher Full Text\n\nYoshida K, Taira Y, Atsuta M: Properties of opaque resin composite containing coated and silanized titanium dioxide. J. Dent. Res. 2001 Mar; 80(3): 864–868. Publisher Full Text" }	[ { "id": "334672", "date": "28 Oct 2024", "name": "Vidya Shenoy", "expertise": [ "Reviewer Expertise GERIATRIC DENTISTRY" ], "suggestion": "Approved", "report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nArticle is satisfactory and currently, the manuscript presents a well-structured and insightful analysis, contributing meaningfully to the field. Article covers relevant methods of polishing 3D dentures. There is a comprehensive discussion of all the methods including glazing. The facts are adequately supported by the current literature. Overall, it meets approval standards. Recommended for indexing\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes", "responses": [] }, { "id": "342684", "date": "16 Dec 2024", "name": "Shizhu Bai", "expertise": [ "Reviewer Expertise Digital dentistry", "3D printing" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article presents a well-structured review on 3D-printed denture techniques, analyzing printing and polishing methods and their impact on surface roughness, though some details could be further elaborated.\n'Some of the methods used for printing complete dentures include…' Can these technologies, such as FDM and MJ, be used directly to fabricate dentures for clinical use or only for making trial dentures or custom trays? It is recommended that this part be combined with practical clinical applications.\nDLP is the most commonly used printing technology and should be introduced in more detail.\nThe author states that '... which impacts the precision of the final product'. According to ISO 5725-4, accuracy includes both trueness and precision. Does the author mean accuracy?\n\nCurrently, studies on build orientation and layer thicknesses are carried out using standardized specimens made of denture material in the form of discs. When such specimens are placed and sliced horizontally (0°), the stepwise effect is not generated on some of their surfaces, possibly including the surface being tested. However, the morphology of dentures is an irregular geometry, and the authors are advised to specify this, and it cannot be argued that the surface properties of horizontally printed dentures are more advantageous. Similarly, when the specimen is placed horizontally, the effect of the layer thickness on the surface morphology will not be demonstrated on the surface tested but on the sidewalls.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Partly\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes", "responses": [ { "c_id": "13022", "date": "06 Jan 2025", "name": "Vaishnavi M Nayak", "role": "Author Response", "response": "Thank you for your insightful feedback and constructive comments on our manuscript. We appreciate the opportunity to improve our work and have made significant revisions based on your suggestions. In response, we have made the following adjustments: Overall Comment from reviewer : 'Some of the methods used for printing complete dentures include…' Can these technologies, such as FDM and MJ, be used directly to fabricate dentures for clinical use or only for making trial dentures or custom trays? It is recommended that this part be combined with practical clinical applications. DLP is the most commonly used printing technology and should be introduced in more detail. The author states that '... which impacts the precision of the final product'. According to ISO 5725-4, accuracy includes both trueness and precision. Does the author mean accuracy? Currently, studies on build orientation and layer thicknesses are carried out using standardized specimens made of denture material in the form of discs. When such specimens are placed and sliced horizontally (0°), the stepwise effect is not generated on some of their surfaces, possibly including the surface being tested. However, the morphology of dentures is an irregular geometry, and the authors are advised to specify this, and it cannot be argued that the surface properties of horizontally printed dentures are more advantageous. Similarly, when the specimen is placed horizontally, the effect of the layer thickness on the surface morphology will not be demonstrated on the surface tested but on the sidewalls. Response: Thank you for the thorough feedback, the following additions have been made: We have added the clinical applications of different 3D printing techniques. The DLP technique is elaborated in detail. The term is corrected to accuracy. The studies on build orientation and variation in morphology of dentures to that of the sample geometry are specified." } ] } ]	1	https://f1000research.com/articles/13-1266
https://f1000research.com/articles/13-634/v1	14 Jun 24	{ "type": "Research Article", "title": "Association of intradialytic hypertension and antihypertensive medication use in patients undergoing maintenance hemodialysis: a prospective observational study", "authors": [ "Mariam Sherif", "Seeba Zachariah", "Rajaram Jagdale", "Mariam Sherif", "Rajaram Jagdale" ], "abstract": "Background In patients with end-stage kidney disease (ESKD) undergoing maintenance hemodialysis, intradialytic hypertension and intradialytic hypotension are the common complications. The study aimed to collect and assess intradialytic Blood Pressure (BP) complications and their association with different factors, including BP medication.\n\nMethods This was a prospective observational study, conducted at the hemodialysis center in a teaching hospital in the UAE, that provide a specialist’s care for the patients receiving ongoing hemodialysis. Patient demographics, medications used, lab data and the peridialytic BP (pre-, intra-, and post-) dialytic BP were collected for a period of 6 months. SPSS Version 29, Armonk, NY was used for statistical analysis. Pearson Chi-square test and Fischer’s Exact test were used to compare the association between categorical variables to intradialytic hypertension and hypotension.\n\nResults Blood pressure data was collected from 47 hemodialysis patients for a total of 2616 hemodialysis sessions during the 6 months study period. Beta-blockers (68%) and calcium channel blockers (66%) were the commonly used antihypertensive medications in the study population. Intradialytic hypertension events were diagnosed in 49 hemodialysis sessions and intradialytic hypotension was diagnosed in 23 hemodialysis sessions. On comparing the effect of antihypertensive medication to the occurrence of intradialytic BP complications, ARBs and alpha-1 blockers showed no association to intradialytic hypertension, but beta-blockers and calcium channel blockers use were associated with increased number of intradialytic hypertension events (p-value <0.05). On the other hand, antihypertensive medication use showed no association with intradialytic hypotension.\n\nConclusions Patients using ARBs or alpha-1 blockers had higher intradialytic hypertension events. Beta-blocker and calcium channel users had lower intradialytic hypertension events. Antihypertensive use showed no association with intradialytic hypotension events.", "keywords": [ "Hypertension", "comorbidities", "intradialytic hypertension", "intradialytic hypotension", "factors", "dialysis patients" ], "content": "Introduction\n\nAlthough hypertension is prevalent in more than 80% of chronic maintenance hemodialysis patients, there is no consensus about the BP threshold, BP target, and the effect of BP reduction on cardiovascular outcomes. Hypertension in the hemodialysis population is multifactorial and is different from other patient populations.1–5 Patients undergoing hemodialysis may experience several complications in their treatment journey that affect their quality of life. Many patients have varying adherence to therapy and struggle to achieve optimal blood pressure outcomes.6–10\n\nAlthough the drug treatment is effective, the number of patients who achieved adequate BP control is limited. BP obtained in dialysis centers poorly represents the usual level of blood pressure in hemodialysis patients, which makes the management of hypertension particularly challenging. Intradialytic hypertension and hypotension were observed, which might be due to multiple factors. Despite proper estimation of fluid removal during hemodialysis, it has been noted that many patients experience intradialytic BP complications. Factors that affect BP control are a multitude.11–13\n\nAll classes of antihypertensive drugs, including diuretics, were used in the hemodialysis population. The most commonly prescribed was a calcium channel blocker. Antihypertensives of choice varied in patients undergoing hemodialysis compared to patients who were not (stage 1-4 CKD). The choice of antihypertensives varies due to multiple factors, and intradialytic complications associated with antihypertensives need more research in different settings.14,15\n\nThis study was to find details of the influence of intradialytic BP complications due to antihypertensive medicines. The prediction of blood pressure and other outcomes in hemodialysis patients is an important area of research, especially the influence of antihypertensive medications in intradialytic complications. By better understanding the factors that contribute to these complications, clinicians can improve hemodialysis patient care and help them live longer, healthier lives. Thus, the aim of the study was to assess the association of intradialytic hyper or hypotension with the antihypertensive medication use.\n\n\nMethods\n\nThis prospective observational study was conducted in the hemodialysis unit of a 350 bedded tertiary care teaching hospital in the UAE. This unit is considered one of the largest hemodialysis units in the UAE in private sector hospitals. The hemodialysis unit was functioning under the supervision of a nephrologist. Patient information was mostly collected from electronic medical records and the physician’s register of patient’s medications. The data collection process began on November 1, 2022, and continued until the end of April 2023.\n\nAmong the 56 patients undergoing regular hemodialysis, 47 patients were included in the study after excluding those who started maintenance hemodialysis for less than 3 months. The study focused on individuals undergoing hemodialysis due to end-stage renal disease. These patients were closely observed and followed up over a period of six months as part of the study's enrolment and data collection process.\n\nParticipants for the study were selected based on rigorous inclusion and exclusion criteria. Patients who were included in this study were Individuals who underwent maintenance hemodialysis as a component of their daily or weekly management of end-stage kidney disease. Adults aged 18 to 85 years and diagnosed with chronic kidney failure/end-stage kidney disease.\n\nPatient confidentiality was maintained, and consent was obtained from the patients for the study. Ethical approval for the study was granted by the institutional review board of Gulf Medical University. Approval for the study was before starting data collection (IRB approval date: 19 November 2020; Ref No. IRB/COP/STD/07/Nov-2020). The principles of the Declaration of Helsinki were used in this research.\n\nAll data were collected from the electronic medical records and the dialysis register. Recording of blood pressure during the hemodialysis sessions was taken as ambulatory or home BP measurements were not feasible. For every patient, the nurse measured and recorded BP at the start of dialysis (Pre dialysis BP), BP during dialysis (measured every 30 minutes, using an automatic cuff attached to the HD machine, an average of 6-8 BP reading is taken by the researcher (intra dialytic BP) and BP after the dialysis session ends (post dialytic BP). Generally, each hemodialysis session was for 4 hours unless complications led to an early finish. Data collection continued for six months to identify the pattern of blood pressure, intradialytic hypertension, and intradialytic hypotension complications that occurred during each dialysis session.\n\nDescriptive statistics was used to summarize the data. Pearson Chi-square test and Fischer’s Exact test were used to compare the association between categorical variables to intradialytic hypertension and hypotension. SPSS Version 29, Armonk, NY (https://www.ibm.com/support/pages/downloading-ibm-spss-statistics-29011) was used for statistical analysis.\n\n\nResults\n\nAn overview of the sociodemographic and health status characteristics of the 47 study participants is given in Table 1.25\n\nAverage institutional blood pressure recordings before, during, and after dialysis of the study population were provided in Table 2.\n\nCalcium channel blockers and beta blockers were the commonly used antihypertensive medications. Six (13%) patients were not on any antihypertensive medication. A combination of four or more antihypertensives was used by 16 (34%) patients, indicating the presence of resistant hypertension (Figure 1). Systolic BP was elevated during most of the dialysis sessions while the diastolic BP were controlled in most sessions.\n\nX-axis shows percentage of patients on antihypertensives, and Y-axis shows antihypertensive drug class.\n\nA total of 2616 hemodialysis sessions occurred during the 6 months study period. Out of them, 49 (1.9%) sessions had intradialytic hypertension and 23 (0.9%) dialysis sessions had intradialytic hypotension. This include intradialytic hypertension in 16 (34%) patients and Intradialytic hypotension in 11(23%). Both events occurred in 3 (6%) patients. Twenty-three (49%) patients had no interdialytic BP complications.\n\nAssociation between Antihypertensive Medication and Intradialytic hyper or hypotension was provided in Table 3, which is statistically significant for Angiotensin Receptor Blocker (ARB), Beta Blockers, Calcium Channel Blockers, and Alpha-1 Blockers.\n\n* P value <0.05.\n\n# Pearson Chi-Square test or Fischer exact test.\n\nPatients using ARBs or alpha-1 blockers had higher intradialytic hypertension events. Beta-blocker and calcium channel users had lower intradialytic hypertension. Other antihypertensive use did not show any association with intradialytic hypertension. Antihypertensive medication use showed no association with intradialytic hypotension.\n\n\nDiscussion\n\nThe most common intradialytic complication in our study was intradialytic hypertension. Hemodialysis helps in managing hypertension in ESKD patients along with antihypertensive medications. The association of antihypertensive use with intradialytic BP complications was a unique finding in the region. Some of the antihypertensive medications were associated with more intradialytic hypertension than others. Thrice-weekly sessions were the most common approach for maintenance hemodialysis. Frequent dialysis sessions are crucial for effectively removing waste products and excess fluid from the body to maintain proper kidney function. Antihypertensive medications are essential for controlling blood pressure in dialysis patients, as hypertension is a common comorbidity in this population and is associated with increased cardiovascular risks. Effective fluid removal is critical to prevent complications associated with fluid overload, such as congestive heart failure and pulmonary edema in ESKD.16,17\n\nBeta-blockers were the most commonly prescribed cardiovascular medication among dialysis patients. Beta-blockers are well-known for their ability to lower heart rate and blood pressure, making them valuable in managing hypertension and reducing the workload on the heart. Additionally, they have been shown to be beneficial in improving overall cardiovascular outcomes and reducing mortality rates in patients with CKD and ESKD. The use of beta-blockers in this population aligns with current guidelines and represents a proactive approach to cardiovascular risk reduction. Beta-blockers calcium channel blockers (CCBs) were associated with more frequent intradialytic hypertension in our study population. CCBs are also effective in reducing blood pressure and have been shown to improve outcomes in CKD patients, particularly in terms of slowing the progression of kidney disease. CCBs are considered safe and well-tolerated in patients with impaired kidney function, making them a suitable choice for dialysis patients who often have pre-existing cardiovascular complications. Loop diuretics, such as furosemide, are crucial for managing fluid overload and congestive heart failure, common complications in dialysis patients due to impaired kidney function. These medications promote diuresis and help maintain fluid balance and hemodynamic stability in this vulnerable population.14,18,19\n\nThe low utilization of ACE inhibitors in this study may be attributed to individual patient characteristics, contraindications, or specific preferences of healthcare providers. Similarly, thiazide diuretics are often used as add-on therapy to manage hypertension in CKD patients. Thiazide diuretics are effective in promoting diuresis and blood pressure control, but their usage may be limited in patients with advanced kidney disease due to decreased renal excretion and potential electrolyte disturbances. Vasodilators, such as hydralazine and Nifedipine, were also relatively underutilized. Vasodilators act to relax blood vessels, thus reducing blood pressure and improving cardiac function. Their low usage in this study could be attributed to various factors, including the presence of alternative medications or individual patient responses.13,15,18,20\n\nHypertension is a significant concern among dialysis patients due to impaired kidney function and fluid balance. Our study observed that a substantial proportion of patients were prescribed antihypertensive medications. Beta-blockers, such as Bisoprolol, Carvedilol, Metoprolol, Nebivolol, and more. Intradialytic BP complications are reported in many studies, but not their association with antihypertensive medications, making our study unique. Intradialytic hypertension is a concern that needs to be addressed more effectively.21–24\n\n\nConclusion\n\nIntradialytic hypertension was the most common BP complication among our study population (supported by literature), contrary to the common belief that intradialytic hypotension is the most common complication among patients undergoing hemodialysis. Beta-blockers and calcium channel blockers were the most prescribed antihypertensives in the study population. The study population showed more frequently elevated Systolic BP and elevated Diastolic BP were less frequent. Patients using ARBs or alpha-1 blockers had higher intradialytic hypertension events. Beta-blocker and calcium channel users had lower intradialytic hypertension events. On the other hand, antihypertensive medication use showed no association with intradialytic hypotension.\n\nThe study was conducted in one of the biggest private healthcare settings in the United Arab Emirates. Most of the patients were on antihypertensive medications for their hypertension management. This study focused on assessing relationship of antihypertensive medication on intradialytic blood pressure complications and the study being conducted in a single site produces a cohort effect as all patients receive same standard of care during the study period.\n\nThough number of study population was limited, it was enough to find statistically significant association. Medication adherence was not collected in detail in this study. Patients were asked about medication adherence and found they were generally adherent to their antihypertensive medications, as there were clinical pharmacy interventions prior to this study to improve medication adherence. Reinforcement advice was provided to the study participants on the importance of medication adherence.", "appendix": "Data availability\n\nFigshare: BP in Hemodialysis patients.xlsx. https://doi.org/10.6084/m9.figshare.24417031.v2. 25\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nWebster AC, Nagler EV, Morton RL, et al.: Chronic Kidney Disease. Lancet. 2017; 389(10075): 1238–1252. Publisher Full Text\n\nThurlow JS, Joshi M, Yan G, et al.: Global Epidemiology of End-Stage Kidney Disease and Disparities in Kidney Replacement Therapy. Am. J. Nephrol. 2021; 52(2): 98–107. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAl-Shamsi S, Regmi D, Govender RD: Chronic kidney disease in patients at high risk of cardiovascular disease in the United Arab Emirates: A population-based study. PLoS One. 2018; 13(6): e0199920. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nRichards N, Hassan MH, Saleh AK, et al.: Epidemiology and referral patterns of patients with chronic kidney disease in the Emirate of Abu Dhabi. Saudi J. Kidney Dis. Transpl. 2015; 26(5): 1028–1034. PubMed Abstract \| Publisher Full Text\n\nO'Lone E, Viecelli AK, Craig JC, et al.: Cardiovascular Outcomes Reported in Hemodialysis Trials. J. Am. Coll. Cardiol. 2018; 71(24): 2802–2810. Publisher Full Text\n\nAlzahrani AMA, al-Khattabi GH: Factors Influencing Adherence to Hemodialysis Sessions among Patients with End-Stage Renal Disease in Makkah City. Saudi J. Kidney Dis. Transpl. 2021; 32(3): 763–773. PubMed Abstract \| Publisher Full Text\n\nSarafidis PA, Persu A, Agarwal R, et al.: Hypertension in dialysis patients: A consensus document by the European Renal and Cardiovascular Medicine (EURECA-M) working group of the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) and the hypertension and the Kidney Working Group of the European Society of Hypertension (ESH). Nephrol. Dial. Transplant. 2017; 32(4): 620–640. Publisher Full Text\n\nThomas D, Joseph J, Francis B, et al.: Effect of patient counseling on quality of life of hemodialysis patients in India. Pharm. Pract. 2009; 7(3): 181–184. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKelly JT, Su G, Zhang L, et al.: Modifiable lifestyle factors for primary prevention of CKD: a systematic review and meta-analysis. J. Am. Soc. Nephrol. 2021; 32(1): 239–253. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCanaud B, Van der Sande F, Kooman J: Predialysis hyponatremia and positive change of natremia within hemodialysis sessions are strong indicators of poor cardiovascular outcome in hemodialysis patients. Kidney Int. Rep. 2021; 6(2): 248–251. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nAgarwal R: Blood pressure and mortality among hemodialysis patients. Hypertension. 2010 Mar 1; 55(3): 762–768. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBurnier M, Damianaki A: Hypertension as cardiovascular risk factor in chronic kidney disease. Circ. Res. 2023 Apr 14; 132(8): 1050–1063. Publisher Full Text\n\nAhmed A, Jorna T, Bhandari S: Should we STOP angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in advanced kidney disease? Nephron. 2016 Jun 24; 133(3): 147–158. PubMed Abstract \| Publisher Full Text\n\nZhao M, Zhang Z, Pan Z, et al.: N-/T-Type vs. L-Type Calcium Channel Blocker in Treating Chronic Kidney Disease: A Systematic Review and Meta-Analysis. Pharmaceuticals (Basel). 2023 Feb 22; 16(3): 338. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBovée DM, Visser WJ, Middel I, et al.: A Randomized Trial of Distal Diuretics versus Dietary Sodium Restriction for Hypertension in Chronic Kidney Disease. J. Am. Soc. Nephrol. 2020; 31(3): 650–662. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCanaud B, Chazot C, Koomans J, et al.: Fluid and hemodynamic management in hemodialysis patients: challenges and opportunities. J. Bras. Nefrol. 2019 October 24; 41: 550–559. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nFlythe JE, Chang TI, Gallagher MP, et al.: Blood pressure and volume management in dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2020; 97(5): 861–876. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nFu EL, Clase CM, Evans M, et al.: Comparative Effectiveness of Renin-Angiotensin System Inhibitors and Calcium Channel Blockers in Individuals with Advanced CKD: A Nationwide Observational Cohort Study. Am. J. Kidney Dis. 2021; 77(5): 719–729.e1. PubMed Abstract \| Publisher Full Text\n\nMujtaba F, Qureshi R, Dhrolia M, et al.: Frequency of Intradialytic Hypertension Using Kidney Disease: Improving Global Outcomes (KDIGO) Suggested Definition in a Single Hemodialysis Centre in Pakistan. Cureus. 2022 Dec 29; 14(12): e33104. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nHundemer GL, Knoll GA, Petrcich W, et al.: Kidney, Cardiac, and Safety Outcomes Associated with α-Blockers in Patients with CKD: A Population-Based Cohort Study. Am. J. Kidney Dis. 2021; 77(2): 178–189.e1. PubMed Abstract \| Publisher Full Text\n\nInrig JK: Intradialytic hypertension: a less-recognized cardiovascular complication of hemodialysis. Am. J. Kidney Dis. 2010; 55(3): 580–589. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nLocatelli F, Cavalli A, Tucci B: The growing problem of intradialytic hypertension. Nat. Rev. Nephrol. 2010 Jan; 6(1): 41–48. PubMed Abstract \| Publisher Full Text\n\nEftimovska-Otovic N, Grozdanovski R, Taneva B, et al.: Clinical characteristics of patients with intradialytic hypertension. Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2015; 36(2): 187–193. PubMed Abstract \| Publisher Full Text\n\nSantos SF, Peixoto AJ, Perazella MA: How should we manage adverse intradialytic blood pressure changes? Adv. Chronic Kidney Dis. 2012 May; 19(3): 158–165. Publisher Full Text\n\nZachariah S, Jagdale R, Sherief M: BP in Hemodialysis patients.xlsx. [Dataset]. figshare. 2023. Publisher Full Text" }	[ { "id": "302273", "date": "23 Jul 2024", "name": "Carmine Zoccali", "expertise": [ "Reviewer Expertise hemodialysis", "cardiovascular disease" ], "suggestion": "Not Approved", "report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe study aimed to assess intradialytic blood pressure (BP) complications and their association with various factors, including BP medication, in patients with end-stage kidney disease (ESKD) undergoing maintenance hemodialysis. It was a prospective observational study conducted at a hemodialysis center in a teaching hospital, involving 47 patients over a period of 6 months.\nLimitations\nSmall Sample Size: The study involved only 47 patients, which is a relatively small sample size. This limits the generalizability of the findings and increases the risk of type II errors. Confounding Factors: The study is observational and thus inherently susceptible to confounding factors. The association between antihypertensive medications and intradialytic BP complications may be influenced by unmeasured variables such as patient comorbidities, dialysis parameters, and adherence to medication. Contradictory Findings: The study's findings contrast with existing evidence from randomized clinical trials. For instance, small randomized trials have shown that amlodipine is well-tolerated and does not increase the risk of intradialytic hypotension, while beta-blockers are known to worsen hemodynamic tolerance to dialysis (Haddiya I, Valoti S: Current Knowledge of Beta-Blockers in Chronic Hemodialysis Patients. Int J Nephrol Renovasc Dis [Internet] Volume 16: 223–230, 2023). Lack of Randomization: Without randomization, it is difficult to establish causality. The associations observed may not reflect true causal relationships. Short Study Duration: The 6-month duration may not be sufficient to capture long-term trends and outcomes related to intradialytic BP complications.\n\nWhile the study impacts a relevant clinical question, its small sample size and susceptibility to confounding limit the robustness of the conclusions. The findings contrast with existing evidence, particularly regarding the effects of beta-blockers and calcium channel blockers on hemodynamic tolerance during dialysis.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [ { "c_id": "12068", "date": "24 Jul 2024", "name": "Seeba Zachariah", "role": "Author Response", "response": "Philosophical underpinning of this research is real-world observational, but the reviewer comments are from an experimental interventional research viewpoint. The mix up of research paradigms creates confusion. Causal relationship is not a goal of our research, the research is to explore association of certain variables. As the study is a population-based no sampling was performed, no sample size was calculated, all eligible patient data were included. The findings are not for generalizing, but to encourage future research. Patient data for 6 months on BP having a few thousands of measurements provides a robust exploratory assessment, which is statistically valid. Confounding factors were also mentioned ignoring real-world research philosophy. All real-world research accommodates all factors that contribute and do not try to control the variables as in clinical trials. Even pragmatic clinical trials and intention-to-treat analysis are adopting real-world research philosophy elements. It is unfortunate compare all other research to per-protocol analysis type research strategy. Why not this real-world evidence contradicts to a ‘small’ clinical trial. The evidence generated from real-world research and clinical trial are to be interpreted differently or not. Duration of research is fair enough to explore association, may not be enough for finding causal relationship which is not an aim of this research." } ] }, { "id": "302267", "date": "01 Aug 2024", "name": "Peter K Uduagbamen", "expertise": [ "Reviewer Expertise nephrology", "cardiology", "metabolism", "chemical pathology" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAuthors should mention specific timings for BP measurements. How were the necessary precautions in BP measurement effected? What about the dialyzable and the non-dialyzable anti-hypertensive drugs and their effects. Food taken within 30 minutes to an hour prior to dialysis and during dialysis could affect the intradialytic BP pattern, how was this taken care of? A relationship between the hematocrit and the BP variation should also be given as lower values increases the risk of intradialytic hypotension. Intradialytic hypotension commonly occur within the first 2 hours of dialysis while intradialytic hypertension common occur in the later part of dialysis, how was these fathom in the participants' preparation? Again the gradient between pre and intra dialytic solute concentration also determine the intradialytic BP variations. So an assessment of the pre and post dialytic solute concentration would be very important. Thiazides and diuretics particularly the thiazides are better drugs for managing systolic hypertension than other anti-hypertensives. It should have been kept in mind in participants preparation, data collection/analysis and finding a relationship between these drugs and cardiac output, end-diastolic volume and pressure, stroke volume and peripheral resistance. These details are essential to strengthen this study. Increase your references and cite recent studies on this topics. Intra dialytic blood pressure control appear more of a burden in Africa particularly sub-Sahara Africa, perhaps due to several prominent factors. Citing some authors from this region could only strengthen your study the more. Please revise accordingly.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No", "responses": [ { "c_id": "12925", "date": "06 Jan 2025", "name": "Seeba Zachariah", "role": "Author Response", "response": "1. Authors should mention specific timings for BP measurements. How were the necessary precautions in BP measurement effected? Author Response: The dialysis center was functioning from 7 AM to 11 AM and was working in 3 different shifts (morning, noon and evening). Most of the dialysis sessions were for 4 hours. Patients came at their scheduled timing for the dialysis. Pre dialytic BP was measured before the start of dialysis, after 5 min rest period. Intradialytic BP was measured every 30 minutes, using an automatic cuff attached to the hemodialysis machine. All these BP measurements and data entry to the patient medical were done by the well-trained nurses in the center. The researcher calculated the average of 6 BP recording as the intradialytic BP. Precautions were taken to minimize the BP measurement effect by using validated BP monitors, trained nursing staff and by calculating the average of 6 periodic intradialytic BP readings. 2. What about the dialyzable and the non-dialyzable anti-hypertensive drugs and their effects? Author Response: Details about dialyzability of antihypertensives and their effects are added in the introduction and results. 3.Food taken within 30 minutes to an hour prior to dialysis and during dialysis could affect the intradialytic BP pattern, how was this taken care of? Author Response: Food taken with in 1 hour prior to hemodialysis or during dialysis can increase the risk of hypotension by increasing splenic and hepatic blood flow to the abdominal viscera and significantly reduces the venous return. All patients were educated by the dialysis team regarding dialysis procedure and instructions. 4. A relationship between the hematocrit and the BP variation should also be given as lower values increases the risk of intradialytic hypotension. Author Response: This study checked relationship between anemia and BP variation. Hematocrit data was not used. 5. Again the gradient between pre and intra dialytic solute concentration also determine the intradialytic BP variations. So an assessment of the pre and post dialytic solute concentration would be very important. Author Response: Even though using a low-sodium dialysate could reduce intradialytic hypertension events, all patients were given the same standard dialysate at the study site. 6. Thiazides and diuretics particularly the thiazides are better drugs for managing systolic hypertension than other anti-hypertensives. It should have been kept in mind in participants preparation, data collection/analysis and finding a relationship between these drugs and cardiac output, end-diastolic volume and pressure, stroke volume and peripheral resistance. Author Response: These details are essential to strengthen this study. Increase your references and cite recent studies on this topics. Thiazide diuretics were not used among the study population. 7. Intra dialytic blood pressure control appear more of a burden in Africa particularly sub-Sahara Africa, perhaps due to several prominent factors. Citing some authors from this region could only strengthen your study the more. Please revise accordingly. Author Response: 2 citations are replaced with better ones." } ] } ]	1	https://f1000research.com/articles/13-634
https://f1000research.com/articles/14-34/v1	06 Jan 25	{ "type": "Research Article", "title": "Regional Innovation System (RIS) as a means for development: Policies, opportunities and challenges in Ethiopia.", "authors": [ "Kassahun Sube", "Tegegn Belay", "Filimon Hando", "Ashenafi Bayinesagn", "Tegegn Belay", "Filimon Hando", "Ashenafi Bayinesagn" ], "abstract": "Background The successful execution of Science, Technology, and Innovation (STI) policies is crucial for developing a strong Regional Innovation System (RIS) in Ethiopia, which is essential for promoting economic growth and enhancing competitiveness.\n\nMethods This study utilized a document review approach to critically analyze Ethiopia’s current STI policies and legal frameworks within the context of the Regional Innovation System (RIS).\n\nResults The findings indicate potential solutions to strengthen Ethiopia’s regional innovation system, including increasing funding for research and development (R&D), fostering better collaboration between universities and industries, and cultivating an entrepreneurial culture. The analysis reveals that Ethiopia possesses significant opportunities to enhance its STI capabilities due to its strategic location, abundant natural resources, and growing governmental and non-governmental support. However, it also highlights critical implementation gaps in STI policies, such as inadequate infrastructure, poor coordination among stakeholders, weak university-industry partnerships, and limited R&D investment.\n\nConclusion Ethiopia’s STI policies and legal frameworks are essential for driving economic growth, innovation, and competitiveness by fostering an environment that encourages collaboration and technology transfer. Nevertheless, the country faces challenges in effectively implementing these comprehensive policies due to existing barriers like policy gaps and insufficient institutional support. To strengthen its National Innovation System and promote sustainable economic development, Ethiopia must assess current opportunities, address these obstacles, and explore alternative policies that can enhance its STI capabilities.", "keywords": [ "Science Technology and Innovation (STI)", "Regional Innovation system (RIS)", "policies", "competitiveness", "development", "research & development" ], "content": "Introduction\n\nThe promotion of Science, Technology, and Innovation Policies (STIP) is a prerequisite for enhancing competitiveness and sustainable development (Andrade et al., 2022; Asheim et al., 2020; Krammer, 2017). This could be achieved by facilitating the development of policies and legal frameworks, the establishment of institutions, and financing initiatives that promote economic growth, employability, entrepreneurship, and improved efficiency (Ali et al., 2024; Andabayeva et al., 2024). Similarly, a nation’s ability to achieve and maintain sustainable, vibrant economic growth is largely determined by how well its institutions and policies foster the exploration of new knowledge, the progress of technology, and the innovative spirits of its businesses (Khan, 2022; Basheer, et al., 2022). Policies on Science, Technology, and Innovation policies (STIP) are therefore essential to the advancement of a country and are necessary for it to achieve a dynamic, integrated, and self-sufficient economy (Singh et al., 2022; Chauhan et al., 2024).\n\nGlobal, regional, and local policies and legal frameworks have been drafted to bring about economic development and competitiveness among nations (Ali et al., 2024; Muchie & Ezezew, 2022). For instance, the Sustainable Development Goals (SDG), Agenda 2030 stands for collective action on economic, social, and environmental dimensions in a stable and integrated manner. Similarly, the African Union (AU) adopted a long-term Agenda 2063, “The Africa We Want” to foster inclusive growth and sustainable development at local and regional levels. Both the abovementioned policies recognise Science, Technology, and Innovation (STI) is vital role as universal enablers for achieving aspirations and goals. Within the broader framework of AU Agenda 2063, the African Union (AU) launched the Science, Technology, and Innovation Strategy for Africa 2024 (STISA-2024) in 2014 as the regional framework for accelerating the continent’s transition to a knowledge-based, innovation-led economy. Accordingly, pertinent African organizations were created during this process through the implementation of decisions and legal documents into effect, including the Pan-African Intellectual Property Organization (PAIPO), the African Scientific Research and Innovation Council (ASRIC), and the African Observatory for Science, Technology, and Innovation (AOSTI).\n\nTo increase the entire economy’s productivity and competitiveness and facilitate the gradual transition from state to private sector-led growth, the Federal Democratic Republic of Ethiopia (FDRE) Plan and Development Commission developed the Home-Grown Economic Reform (HGER) in 2021. Promoting national innovation, research, and technological capabilities; generating a digital economy and broadening its benefits; enhancing national competitiveness and productivity through the development of technology-based industries; and establishing innovation and technology regulatory systems operating procedures are some of its objectives (Wazza, 2022).\n\nThe Strategic Policy also provides the legal framework for the Ethiopian national innovation system for National Science, Technology, and Mathematics Education, Investment Proclamation, Intellectual Property Law, National Research and Development Strategy, Industrial Parks Development Proclamation, and Technology Incubation and Transfer Policy, Higher Education Proclamation (650/2009) of 2009, the Intellectual Property (IP) Rights System, the National Science, Technology, and Innovation (STI) Policy, and the Professional and Program Mix Policy. Similarly, Higher education institutes are highly required to carry out research, including partnerships with industry, to serve the demands of the development of the nation, and the national legislative and policy frameworks encourage research and innovation that enhances knowledge and technology transfer.\n\nThe 1994 education and training policy has been considered to possess the foundation for the creation and execution of various legislative frameworks, programs, and strategies by the Ethiopian government to regulate the operations in Ethiopian higher education institutions with regard to research and development and university-industry linkages (Kahsay, 2017). The national framework emphasizes technology transfer, university-industry collaboration, and strategies to enhance research and technology transfer in Ethiopian universities, grounded in the Research and Technology Transfer Conceptual and Governance Framework of Ethiopian Higher Education Institutions. The Professional and Program Mix Policy requires a 70:30 undergraduate professional allocation that favors science and technology over the humanities and social sciences (MoE, 2008); this policy contributes to the expansion of training and research collaborations between universities and industry. In addition, the intellectual property rights system was created in 2003 along with the Ethiopian Intellectual Office (MoE, 2008). The absence of institutional IP policies in public research and development institutions, government-owned businesses, and higher education institutions, however, is the most significant problem; additionally, the enterprises overlook the need for IP protection (Kahsay, 2017).\n\n\nMethods\n\nThe study employed a qualitative approach, specifically document review as the primary methodology to conduct a thorough evaluation of the existing Science, Technology, and Innovation (STI) policies and legal frameworks in Ethiopia within the context of the Regional Innovation System (RIS). The main aim was to analyse how these policies correspond with the RIS framework while identifying gaps and opportunities that could inform future policy. The data collection process consisted of a review of relevant documents, which were categorized into four key areas: government publications, including significant policy documents such as the National Science and Technology Policy (2012) and the Investment Proclamation (2020); reports from international organizations like the United Nations and the World Bank; academic literature that examines STI policies in Ethiopia alongside comparative studies in emerging economies; and regional and global initiatives, including frameworks like the Sustainable Development Goals (SDGs).\n\nData analysis involved thematic coding of the collected documents, focusing on several critical themes: institutional frameworks, which entailed identifying institutions responsible for implementing STI policies; policy gaps and challenges, which examined discrepancies between intended policies and actual practices; opportunities for innovation within Ethiopia’s National Innovation System (NIS); and a comparative analysis of Ethiopia’s STI policies against those of Kenya and Rwanda. This thematic analysis was conducted enabling a comprehensive exploration of the relationships between STI policies, regional innovation dynamics, and economic outcomes.\n\nTo enhance the credibility of the findings, a triangulation approach was employed by comparing data from various sources, including government reports, academic literature, and expert opinions. Additionally, feedback from subject-matter experts was sought to validate interpretations derived from the analysed documents. Despite the thorough nature of this document review, certain limitations were acknowledged, such as potential gaps due to reliance on publicly available documents and the evolving nature of policies. The insights generated from this study aim to deepen understanding of how STI policies impact Ethiopia’s regional innovation system and contribute to sustainable development.\n\nScience, Technology, and Innovation Policies (STIP) have gained more attention in the framework of sustainable and inclusive development, even though it is sometimes thought of as a relatively new concept (Khan, 2022). The Science Technology and Innovation Policyies (STIP) are also referred as innovation policies, industrial policies, science policies, research and development policies, and technology policies. It encompasses a variety of strategic initiatives aimed at fostering innovation efforts while also addressing broader goals, including the improvement of quality of life, the promotion of sustainability, and the advancement of social integration (Sagar, 2023). Increased investment in research and development is being made as a result of the national policies’ emphasis on science and technology to promote the quick integration of cutting-edge technologies, strengthen international cooperation, and address grand social issues (Arimoto, 2024).\n\nEmerging economies, including Brazil, India, China, South Korea, and South Africa (BICSS), illustrate that a country’s competitiveness in the global marketplace is contingent upon its proficiency in executing science, technology, and innovation policies. This involves not only the acquisition and adaptation of technical knowledge but also the enhancement of domestic technological capabilities. These countries can close the technological gap with advanced nations and significantly boost productivity (Salami & Soltanzadeh, 2012).\n\nAn examination of the innovation capabilities across eight Asian nations reveals a positive correlation between income levels and both the inputs and outputs of innovation. Countries classified as high- and upper-middle-income predominantly depend on private sector investments in research and development, whereas those in the lower-middle-income bracket, including Indonesia and Bangladesh, are largely supported by public R&D funding. Japan and South Korea stand out with a greater volume of domestic patent filings, in contrast to Malaysia, Thailand, Indonesia, and Bangladesh, which depend significantly on research and development conducted by foreign enterprises. While China has successfully attained substantial innovation outputs through considerable investments in R&D, India has not progressed beyond a lower-middle-income status, primarily due to its limited R&D spending and dependence on government initiatives (Park and Kim, 2021).\n\nThe Lagos Plan of Action, established in 1980, laid the groundwork for the subsequent Lagos Consolidated Plan of Action, which emerged in the early 2000s. This latter plan underscored the significance of Science, Technology, and Innovation (STI) as essential components for fostering socio-economic advancement across African nations (Khan, 2022; Yongabo & Göransson, 2020). Key objectives of these initiatives included enhancing research capabilities and reforming the higher education landscape. A notable commitment was made for African countries to allocate 1% of their Gross Domestic Product (GDP) towards research and development (Khan, 2022). The evolution of innovation and science and technology policies in developing nations is being influenced by the rise of a knowledge-based economy, the forces of globalization, and the involvement of various international organizations, as illustrated by the experiences of the BRIC countries (Gachie and Govender, 2017). However, STI institutionalization in Africa has not kept pace with other regions; many African countries lack sufficient STI management bodies or policies to advance STI successfully. The National Innovation Systems (NIS) in developing nations, particularly those in sub-Saharan Africa, are frequently perceived as “immature” or “catching up” (Skorge, 2024; Yongabo & Göransson, 2020; Seifu et al., 2022).\n\nIn the African context, Science, Technology, and Innovation Policies (STIP) can be reconceptualized as a mechanism for transforming the continent’s rich history, cultural heritage, and artisanal practices into globally recognized creative industries. This would change the way STI is conceptualized and create an ecosystem similar to Silicon Valley, which creates millions of jobs while balancing “grassroots” and “mission-oriented” innovation policies to boost national innovation capacities, encourage inclusive growth, and combat poverty and inequality (Khan, 2022; Mavhunga, 2017). Evidence showcases that while R&D significantly drives innovation, which in turn enhances firm productivity, the engagement in R&D and innovation is largely influenced by access to skilled labour and financial resources, highlighting the importance of developing mechanisms and policies to promote knowledge production and bolster innovation initiatives (Keraga & Araya, 2023).\n\nWith South Africa and Egypt contributing the vast majority of contributions, Africa has the weakest research infrastructure of any continent. It also contributes less than 2% of global research publications, struggles with brain drain, and has a very low innovative profile, with 88% of patent activity concentrated in South Africa. Furthermore, Africa falls short of meeting the GERD target of allocating 1% of GDP for research and development (Khan, 2022; Mavhunga, 2017). In this regard, the latest updates for Ethiopia, Kenya, and Rwanda showed Gross Expenditure on Research and Development (GERD) as follows Kenya (0.8%), Rwanda (0.7%), and Ethiopia (0.3%) (Ogada et al., 2022). In Africa, significant development entities, including universities, research institutions, financial organizations, educational bodies, and intermediary organizations, are present; however, they often exhibit limited competencies. Furthermore, these entities frequently lack the necessary connections and institutional capacity to effectively participate in innovation strategies that are responsive to market demands (Seifu et al., 2022).\n\nThe Global Innovation Index (GII) serves as an annual evaluation that measures the innovation capabilities and achievements of economies across the globe. It includes more than 80 metrics categorized into seven distinct groups: institutions, human capital and research, infrastructure, market sophistication, business sophistication, knowledge and technology outputs, and creative outputs. According to the 2023 Global Innovation Index, each country exhibits distinct characteristics. Ethiopia, categorized as a low-income nation, has a population of 123.4 million, a GDP amounting to 347.8 billion PPP$, and a GDP per capita of 3,434 PPP$, placing it at a rank of 125. In contrast, Kenya, identified as a lower-middle-income country, has a population of 54 million, a GDP of 311.8 billion PPP$, a GDP per capita of 6,122 PPP$, and holds a rank of 100. Similarly, Rwanda, also classified as a lower-income country, has a population of 13.9 million, a GDP of 37.6 billion PPP$, a GDP per capita of 2,836 PPP$, and is ranked 103. This analysis provides a comparative overview of these three nations as reflected in the Global Innovation Index.\n\nThe institutional frameworks of Ethiopia, Kenya, and Rwanda show considerable variations that impact their regional innovation systems. Ethiopia’s institutional score of 32.7 is quite low overall, especially regarding the business environment (30.5) and institutional environment (18.6), which limit Ethiopia’s ability to promote innovation. On the other hand, Kenya scored 45.0, indicating some progress toward innovation but still requiring improvements. This is due to a more favourable regulatory environment (49.0) and a moderately supportive corporate climate (30.5). Rwanda is a leader in regional innovation, with a noteworthy overall score of 65.4, driven by a strong business climate (79.1) and a solid regulatory framework (63.2). These differences suggest that Ethiopia and Kenya should learn from Rwanda’s successful policies to strengthen their institutional frameworks and improve their business environments to increase their capacity for innovation. A thorough grasp of the institutional environment is essential for policymakers hoping to boost local innovation systems and stimulate economic growth. In terms of the institutional framework, Singapore, Switzerland, and Finland are the top-ranking countries globally, with scores of 98.4, 87.3, and 85.4, respectively.\n\nRwanda leads both nations in terms of human capital and research, scoring 22.6, thanks to significant investments in education (37.7) and higher education (26.6), as well as an emphasis on R&D (3.5). Ethiopia may need to strengthen its tertiary education and research initiatives to maximize its innovation potential and competitiveness within the region. This analysis highlights the decisive role that education and research play in nurturing innovation. Kenya and Rwanda are making progress in developing their human capital and R&D frameworks. The disparities in these nations’ approaches to R&D and education show how different investment and emphasis levels can influence their entire innovation ecosystems, underscoring the need for deliberate improvements in human capital development to spur regional advancement. Sweden, Singapore, and South Korea have the highest human capital scores in the world, at 66.9, 63.2, and 62.7, respectively.\n\nThe analysis of the infrastructural landscapes in Ethiopia, Kenya, and Rwanda reveals notable differences that have important implications for their different regional innovation systems. Ethiopia has a 12.1% total infrastructure score, indicating that there is room for growth, especially in the Information and Communication Technologies (ICT) category, where Ethiopia scored 17.4. Kenya, on the other hand, has a more solid infrastructure foundation, obtaining a respectable 25.3 and a remarkable 56.4 in ICTs, highlighting the country’s sophisticated digital ecosystem and the government’s dedication to online services and e-participation. With an infrastructure score of 27.9, which emphasizes its effective use of ICTs at 53.7, and a general infrastructure score of 18.3, which reflects its strategic investments in technology and development, Rwanda leads the pack in this comparative assessment. The implications for regional innovation systems are significant: Kenya and Rwanda, with their stronger infrastructure, are better positioned to lead in regional innovation, allowing for increased connectivity, sustainable ecological practices, and greater entrepreneurial activity, while Ethiopia, with its relatively underdeveloped infrastructure, may find it difficult to foster innovation. On the global stage, Finland, Sweden, and Denmark are the leading three states in terms of infrastructure, with scores of 69.2, 67.6, and 65.6, respectively.\n\nWhen comparing the market sophistication of Rwanda, Kenya, and Ethiopia, certain interesting differences surface that have important ramifications for their respective regional innovation systems. Ethiopia has a 19.8 market sophistication score, compared to Rwanda’s 18.6 and Kenya’s higher 22.1 scores. To be more precise, Kenya scores 21.5, which indicates that it has a strong investment performance and offers a conducive atmosphere for funding innovation. Ethiopia’s investment score, however, lower at 0.4, emphasizes difficulties in bringing in both foreign and domestic funding, which may impede the development of creative businesses. Kenya is probably positioned to maximize its potential for regional competitiveness, although differences in investment and general market sophistication could result in diverse innovation paths. On a global scale, the leading countries in market sophistication are the USA, Hong Kong, and the United Kingdom, with scores of 82.9, 71.8, and 69.3, respectively.\n\nEthiopia’s business sophistication score of 14.7 indicates difficulties in creating a strong innovation environment. Nonetheless, with a score of 24.2, Kenya tops the list, demonstrating a higher ability to integrate knowledge workers and create innovative connections—two factors that are essential for promoting innovation and technological growth. Rwanda’s business sophistication score of 20.0 indicates a well-rounded strategy, bolstered by its focus on knowledge absorption (26.7) and innovation connections (24.9). Kenya appears to have a more dynamic environment for promoting innovation, which can propel economic development more successfully than Ethiopia’s existing situation, based on its better ratings for knowledge workers (22.7) and innovation links (23.2). On a global scale, Sweden, the USA, and Singapore lead in business sophistication, with impressive scores of 78.5, 69.9, and 65.6, respectively.\n\nThe comparative analysis of the knowledge and technology outputs among Ethiopia, Kenya, and Rwanda reveals distinct. Ethiopia’s knowledge and technology outputs stand at 17.9, with a particularly strong emphasis on knowledge creation (19.2) and knowledge impact (24.1). In contrast, Kenya demonstrates slightly higher overall outputs at 18.4, with significantly higher levels of knowledge diffusion (20.4) compared to Ethiopia and Rwanda. Rwanda, with the lowest overall score of 13.6, exhibits strengths in knowledge impact (27.7) but struggles in knowledge creation (8.2) and diffusion (5.1). These differences indicate that while Kenya and Ethiopia are focusing on leveraging knowledge creation and impact to drive innovation, Rwanda’s approach seems to centre on maximizing the impact of existing knowledge. The varied performance in these metrics suggests that fostering regional collaboration and targeted investments in knowledge diffusion and creation could enhance the innovation ecosystems of all three nations, ultimately leading to a more integrated and competitive regional economy. In terms of knowledge and technology outputs, Switzerland, the USA, and Sweden rank as the top three, with scores of 65.3, 63.9, and 63.4, respectively.\n\nA comparative examination of the creative outputs and innovation capabilities in Ethiopia, Kenya, and Rwanda reveals notable differences that have significant implications for their regional innovation systems. As the data indicates, Ethiopia exhibits a creative output score of 4.5, driven predominantly by intangible assets (2.1) and a nascent sector for online creativity (13.6). In contrast, Kenya’s creative outputs are markedly higher at 14.1, buoyed by substantial intangible assets (18.9) and a thriving online creativity score of 17.2. While lower in overall creative output at 6.9, Rwanda shows strengths in intangible assets (7.0) and online creativity (12.2) that reflect its commitment to fostering a digital economy. These disparities highlight Kenya’s more advanced creative economy, emphasizing the need for Ethiopia and Rwanda to enhance their intangible assets and digital creativity initiatives to foster innovation. The implications for the regional innovation system are profound; enhanced collaboration among these nations could facilitate knowledge sharing and resource allocation, ultimately driving a more robust and integrated creative economy across the East African region. Switzerland, the United Kingdom, and Hong Kong lead the global GII in terms of creative outputs and innovative capabilities, with scores of 68.5, 60.0, and 59.2, respectively.\n\nEthiopia, Kenya, and Rwanda have established legal institutions to coordinate STI activities, with the Ministry of Science and Technology in Ethiopia, the National Council of Science and Technology in Kenya and Rwanda, and the Kenya National Innovation Agency in Kenya. The human resource capacity varies across countries, with Ethiopia and Kenya having a majority of personnel in agriculture and veterinary sciences, while Rwanda has a majority in natural sciences. The majority of personnel are from government institutions in Ethiopia (70.1%) and Rwanda (56.1%), while in Kenya, they are from higher education institutions (56.7%). Rwanda has made progress in STEM education, with 22.4% student enrollment, but female students make up less than a third of this total. The countries have made progress in establishing centres of excellence under the Africa Centre of Excellence program and industrial parks, with Ethiopia leading the region with five industrial parks. There is a pressing necessity to strengthen collaborations between countries, enhance infrastructure, encourage investments from the private sector, and cultivate human resources, particularly emphasizing STEM fields and the participation of women, in order to improve the execution of science, technology, and innovation (STI) initiatives.\n\nThe National Science and Technology Policy, established in 2012, serves as a foundational framework aimed at promoting research, development, and innovation within the nation. It promotes a conducive ecosystem that will support innovation, research, and technology as engines of economic growth and sustainable development. It emphasises public-private partnerships in technology development and commercialisation, strengthens the capacity and efficiency of the research and innovation ecosystem, and creates an environment that is conducive to technology transfer and intellectual property protection. According to the STI Policy, research is an essential part of a strategic plan to effectively adopt foreign technologies, modify them for the local context, employ them successfully, and share knowledge through connections between academia and industry (Mamo, 2015). The results of research endeavours are anticipated to impact the nation’s progress.\n\nThe Ethiopian Ministry of Education introduced a STEM Education program in 2016 to improve the national academic framework. STEM aims to upgrade the standard of instruction in these areas and provide students with the tools they need to succeed in the modern workforce. The initiative serves a crucial function in fostering innovation and advancing technological development within the country. The program seeks to educate students in STEM subjects to produce a workforce capable of fostering innovation and advancing the growth of a knowledge-based economy.\n\nThe Ethiopian Investment Commission (EIC) enacted the Investment Proclamation (1180/2020), which offers incentives, guarantees, and protection to investors to encourage their investment in various sectors of the Ethiopian economy. The commission serves as a liaison between government agencies and business sectors, offering guidance, support, and encouragement all through the investment process. Concerning the regional innovation system, the Investment Proclamation functions as a tool for promoting innovation and technology transfer by offering incentives for investments in critical areas like technology, R&D, and innovation. Additionally, the proclamation promotes the creation of creative companies and the uptake of novel technologies.\n\nEthiopia’s Intellectual Property Law (320/2003) gives researchers, inventors, and business owners the legal means to safeguard their intellectual property to promote innovation and technological development. The proclamation guarantees that entrepreneurs and innovators have the sole right to their projects, including inventions, designs, and works, and it provides the processes for registering and upholding intellectual property rights in Ethiopia. Enforcing intellectual property rights guarantees that innovators can profit from their works and stimulates additional creativity and investment in the nation, all of which contribute to the formation of a conducive environment for innovation.\n\nEthiopia passed a National Research and Development Strategy in 2021 to advance technological development, innovation, and research in several fields. The strategy describes the top priorities for R&D, which include improving the standard of education, encouraging industry-academia partnerships, and developing the research infrastructure. By concentrating on these areas, the ministry hopes to promote national competitiveness, foster sustainable economic growth, and use research and innovation to address societal issues.\n\nThe National Research and Development Strategy offers a road map for orchestrating R&D activities with national priorities, encouraging stakeholder partnerships, and optimising resources to foster economic growth and innovation. The strategy promotes for the development of a supportive environment that fosters research and development initiatives, encourages the generation and dissemination of knowledge, and aids in the commercialization of research outcomes by clearly outlining specific objectives and actionable plans. Employing these initiatives, the ministry strives to strengthen Ethiopia’s innovation ecosystem, cultivate a research and innovation culture, and propel sustainable growth within the nation.\n\nEthiopia enacted the Industrial Parks Development Proclamation (886/2015) to inspire the foundation of industrial parks throughout the nation to foster industrialisation and economic growth. The proclamation lays forth guidelines for designing, building, and operating industrial parks to bring in foreign and domestic capital, encouraging local businesses to integrate into global value chains and create employment opportunities. Beyond and above, the proclamation aspires to promote manufacturing operations, boost exports, and advance Ethiopia’s socio-economic development by offering incentives and infrastructure support to companies working within industrial parks.\n\nCreating a digital strategy for Ethiopia (2021) is crucial to leveraging the capacity of technology to boost the national economy, enhance social services, and generate employment. Developing a digital strategy for Ethiopia involves incorporating the National Innovation System into account and creating a cooperative ecosystem capable of leveraging the advantages enjoyed by the government, industry, universities, and civil society. Ethiopia has the potential to build a dynamic innovation ecosystem that accelerates digital transformation and quickens economic progress through promoting collaborations and knowledge exchange. This strategy entails funding R&D, enabling tech startups, and encouraging an innovative culture that honours entrepreneurship and inventiveness. By aligning digital strategies with national priorities and leveraging existing resources, Ethiopia can position itself as a leader in the digital economy and drive inclusive and sustainable development for all its citizens.\n\nAddis Ababa University established an innovation and incubation policy in 2022 aimed at fostering the development and success of start-ups and small businesses within the technology sector. According to the policy, the incubators offer emerging businesses access to resources like workspace, funding, networking opportunities, and mentorship in a nourishing environment. On the other hand, innovation policies provide structures and principles for advancing entrepreneurship, technology transfer, and research and development. A conducive setting for innovation, economic growth, and improved global competitiveness is possible to establish by countries through the combination of technology incubation and robust innovation policies. Technology incubation and innovation policies are critical in supporting local talent development, university-industry linkage, and technology transfer.\n\nProfessional and Program Mix Policy (MoE, 2008) offers a comprehensive overview of the professional program mix, annual intake, and enrollment growth in Ethiopian public higher education institutions. It outlines thoroughly the 70:30 undergraduate professional balance favouring technology and science over the arts and social sciences. This approach has ramifications for training and research cooperation between universities and industry. This policy’s potential impact on Ethiopia’s national innovation system makes it relevant.\n\nThe Higher Education Proclamation (650/2009) serves as the fundamental legislative framework governing the education system at the national level. This legislation outlines the establishment, functioning, and regulatory compliance of higher education institutions within the country. It sets forth standards for curriculum development, accreditation processes, academic autonomy, and the administration of higher education. The primary goals of the Higher Education Proclamation include ensuring the delivery of high-quality education, fostering innovation and research, and cultivating a skilled workforce capable of contributing to the socioeconomic development of the nation. The proclamation mandates universities to identify their main research areas and themes during conversations with key stakeholders, taking into account the nation’s top priorities and the institution’s competitive advantages; university partnership on research schemes with other domestic and foreign institutes, research centres, and businesses is authorised under the proclamation; the proclamation makes it apparent that collaborations with business are important for research and technology transfer.\n\nThe implementation of directives concerning research, technology transfer, university-industry collaboration, and community services for higher education institutions in Ethiopia, as outlined in Directive No: Research 01/2019, aims to strengthen the research and innovation capacities of these institutions. It is clearly stated under the preamble as:\n\n“It is mandatory to put in a place and coordinate a well-developed system or research, technology transfer, university-industry linkage, and community services to contribute in ensuring sustainable and holistic development across the nation.” p1\n\nThe objective of the directive is to cultivate an environment of innovation and cooperation among higher education institutions, which will ultimately result in the creation of new technologies, products, and services that serve the broader interests of society. By promoting collaboration between researchers and industry partners, as well as encouraging engagement with the community, these initiatives aim to stimulate economic development and improve the region’s competitive edge. Most importantly, the directive encourages universities to allocate grants and seed money to commercialise inventions in their laboratories and academic units.\n\nEthiopian National Innovation System (NIS) has the untapped potential to significantly enhance social development, economic growth, and global competitiveness through science, technology, and innovation. Ethiopia can establish itself as a centre for innovation excellence and propel the innovation landscape of the African continent by capitalising on its advantages, tackling its current problems, and encouraging cooperation either inside or outside the country. Ethiopia is poised to assume a pivotal role in shaping the trajectory of science, technology, and innovation within the region by making strategic investments, forming partnerships, and enacting legislation that fosters entrepreneurship and innovation. Ethiopia has made great progress toward establishing a conducive ecosystem that is favorable to innovation employing policies, initiatives, and partnerships that support research, technology transfer, and knowledge exchange. Establishing research institutes, incubation centres, and innovation hubs that act as catalysts for entrepreneurship and innovation has resulted in the development of a solid foundation in science and technology.\n\nEthiopia’s national development is driven by several key factors. Primarily, the country possesses a wealth of natural resources and is strategically situated in the Horn of Africa, which provides proximity to the Middle East and its lucrative markets. The remarkable economic growth observed over the past two decades underscores Ethiopia’s potential to cultivate a strong economy, with aspirations to achieve lower-middle-income status by 2025. The government has actively pursued the establishment of a regional Innovation System by developing various policies and legal frameworks related to Science, Technology, and Innovation (STI). This commitment is reflected in increased funding for research and development, the strengthening of institutional capacities, the enhancement of academia-industry collaboration, and the implementation of effective STI policies aimed at diversifying and strengthening the economy.\n\nIn alignment with its ambition to attain middle-income status by 2025, Ethiopia has prioritized structural transformation, industrialization, and urbanization. This focus has facilitated significant advancements in the country’s energy, transportation, and telecommunications infrastructure. Central to this economic strategy is substantial public investment in infrastructure, which aims to rectify existing deficits and create a conducive environment for subsequent private sector development. Most significantly, the Ethiopian government has been actively building industrial parks to increase the country’s overall economic growth through the transfer of technology, knowledge, and skills, the creation of productive jobs for the populace, and the export of manufactured goods that earn foreign exchange (Jote, 2020).\n\nInitiatives are also underway to establish linkages between industrial parks and universities across the nation. Most industrial parks have been located adjacent to universities to accommodate large-scale industrialisation projects. For instance, the Hawassa Industrial Park, which was constructed near Hawassa University, is dedicated to significant domestic and foreign apparel and textile firms with an export revenue target of over US$1 billion and 60,000 employees. The industrial parks of Bole Lemi-I and II, along with the Kilinto Industrial Park situated in the suburbs of Addis Ababa, demonstrate the broader network of industrial zones across Ethiopia, which includes locations in Dire Dawa, Mekelle, Adama, Kombocha, Jimma, Bahir Dar, Debre Birhan, and Aysha Dewalle (Salmi et al., 2017). In summary, these industrial parks have played a crucial role in advancing Ethiopia’s industrial landscape by generating employment opportunities, enhancing government revenue and export levels, diversifying the range of industrial products, and attracting both Foreign Direct Investment and foreign exchange (Jote, 2020).\n\nMeaningful STI policymaking cannot be developed, carried out, monitored, or modified without an in-depth understanding of the nation’s context, strengths and weaknesses of the nation’s Science, Technology, and Innovation (STI) agents, their interactions, and incentives as well as barriers that they encounter, all of which are extremely country-specific (Adenle et al., 2023). Despite the progress made in science, technology, and innovation, Ethiopia still faces challenges in scaling up its innovation ecosystem to meet the demands of a rapidly evolving global market (Liche & Střelcová, 2023; Gashahun, 2020). One of the most critical challenges is failing to effectively translate the policy into practice. Most policies that come from the top down to the bottom have implementation issues. As Agu et al. (2021) the ‘Top-Down’ approach to policy formulation coupled with limited public awareness of the significance of STI has curtailed efforts in effectively implementing the policy; also, the absence of programs that translate STI policy objectives into action contributes to the inefficiencies in the implementation processes.\n\nMeaningful policymaking in Science, Technology, and Innovation (STI) necessitates a comprehensive understanding of the specific context of a nation, including the strengths and weaknesses of its STI stakeholders, their interactions, incentives, and the barriers they face, all of which are uniquely determined by the country’s circumstances (Adenle et al., 2023). In Ethiopia, despite advancements in science, technology, and innovation, significant obstacles remain in enhancing its innovation ecosystem to align with the demands of a swiftly changing global market. Ineffective translation of policy into actionable practice is a significant challenge, often due to a top-down approach and lack of public awareness, exacerbated by the absence of tangible action initiatives (Agu & Ndinda, 2021).\n\nFurthermore, there is a huge gap in coordination and collaboration among various stakeholders in the science, technology, and innovation ecosystem by National Innovation actors. Despite the effective partnerships between government agencies, research institutions, academia, and industry are essential to fostering innovation, knowledge exchange, and technology transfer, the Ethiopian Innovation ecosystem is not conducive and well-orchestrated (Tekle, 2024; Kebebe, 2019). The STI policy aims to facilitate linkages among stakeholders, but in practice, there is immature coordination and collaboration, resulting in a disconnect rather than synergy, despite its commitment (Agu & Ndinda, 2021).\n\nRobust advancement in research and development is thought to promote science, technology, and innovation while also boosting competitiveness and economic growth. Research leadership and administration (motivation, teamwork, salary, external influence, political burden, lack of clear vision), communication and outsourcing of research (lack of funds, lack of communication, lack of industrial linkage, lack of partnership, lack of trained journalists), and lack of national strategy & policy (lack of information centre, lack of funds, lack of teamwork, lack of national research centre) are some of the concerns regarding research outputs (Tesfa, 2015). Furthermore, Gelata et al. (2022) examined e-commerce in Ethiopia and noted that the country’s business had considerable hurdles, including a lack of infrastructure, a lack of trust, security risks, and a lack of a regulatory framework. The Ethiopian industry’s barriers include information technology, inadequate personnel training and expertise, a deficiency in IT infrastructure, customer awareness, and behaviour. The absence of well-structured data warehouses, coupled with inadequately designed websites that provide minimal or no information regarding stakeholders, significantly hinders the understanding of advancements within the sector (Agu & Ndinda, 2021). Outdated laboratory facilities, insufficient equipment, and above all the poor telecommunication networks in Ethiopia contribute to the poor performance.\n\nThe lack of financial resources is the most significant barrier to STI development in developing countries, and Ethiopia is no exception. The critical challenges associated with funding have been categorized into two primary issues. First, there is a significant dependence on state funding coupled with inadequate involvement from the private sector, which has severely hindered science, technology, and innovation (STI) initiatives (Gobena et al., 2021). Second, the lack of various nationally established guidelines and research evaluation frameworks for the distribution of limited financial resources constitutes an additional obstacle, contributing to inefficiencies and the misallocation of resources (Agu & Ndinda, 2021).\n\nConcerning the University-industry linkage (Partnership), several efforts exist to create a conducive learning environment for actors to engage in partnerships. Partnerships among National Innovation actors, the status of collective learning among actors is very low in Ethiopia is very low, particularly the roles of R&D institute, TVET College, and University Industries Linkage are very low in collaboration (Gobena et al., 2021; Ayenew & Teklay, 2017; Ayenew, 2015). In spite of the government’s efforts to enhance and maintain a productive linkage between university and industry, the relation remains in its early developmental stage, with a significant number of outstanding tasks yet to be addressed (Degaga and Senapathy, 2021).\n\nThe role that Science, Technology, and Innovation (STI) policies and legal frameworks play in strengthening Regional Innovation Systems (RIS) and enhancing regional competitiveness has become realised progressively in recent years. Science, Technology, and Innovation (STI) policies significantly determine global, regional, and national social and economic development. The latter part of the 20th century marked a significant formal acknowledgment of this role, largely attributable to the growing dependence on knowledge-based innovation. During this period, the connections among diverse participants within the ecosystem—such as governmental bodies, academic institutions, research and development entities, and industrial sectors—have emerged as essential components (Galvao et al., 2019). Most importantly, establishing a strong and adaptable STI ecosystem is a dynamic process that calls for ongoing partnerships, fine-tuning, and adaptability. Policymakers must therefore be adaptable, eager to absorb knowledge from ecosystem players, and prepared to change course when new insight becomes available, or circumstances warrant it. Agile policy development is essential to fostering a vibrant innovation ecosystem in which companies, academics, and investors may work together productively to advance novel concepts and technology (Ratanawaraha et al., 2024).\n\nThe Ethiopian government acknowledges the significant importance of Science, Technology, and Innovation (STI). It has therefore enacted various STI policies over the years and established institutions, strategies, and programmes across the key priority sectors to provide opportunities to encourage economic growth. Ethiopia spends about 0.51% of its gross domestic product (GDP) on STIs, which is below the African Union’s (AU) recommended target of 1%. Several stakeholders participate in the STI ecosystem in Ethiopia, with the nature of participation ranging from policy development, regulation, and implementation of STI programs, initiatives, plans, and projects. The different stakeholders have different mandates and exert different levels of power and influence across the STI landscape.\n\nEmerging economies depend on a combination of technological advancement and homegrown innovation to enhance their national innovation systems and policy frameworks, thereby maximizing the advantages of global knowledge transfer for science, technology, and innovation collaboration. This is because many of these nations want to achieve economic growth and competitiveness. Industry, academic institutions, and research centres must change to build mutually beneficial partnerships and complement each other’s strengths to achieve the goals of STI cooperation. Collaborations ought to be established in critical domains such as institutional policy and governance frameworks, higher education in science and technology, entrepreneurship, research infrastructure, legal systems, and technology transfer (Adenle et al., 2023). The adoption of incremental innovations, prioritizing innovation in sectors with significant economic impacts, concentrating on demand-oriented innovation, implementing spatial innovation, and creating a governmental coordination platform for development priorities and collaboration among ecosystem factors are the five main directions proposed by Shkabatur et al. (2022) for innovation and entrepreneurship policy. These strategies aim to enhance economic growth, improve productivity, and generate jobs.\n\nThe key to maximising the effectiveness of the national innovation system is to strengthen research by creating substantial and long-term funding sources, safeguarding the research council already in place, endorsing the professional association, and figuring out how to leverage the tremendous amount of knowledge and expertise held by professionals from Ethiopia’s diaspora (Tesfa, 2015). To promote economic growth and optimise Ethiopia’s economy’s competitiveness, the national innovation actors ought to be motivated to engage in R&D and learning initiatives, whether by creating new ones or modifying existing ones (Gobena & Kant, 2022)\n\nPolicymakers in Ethiopia ought to focus on increasing the number of citable journals, encouraging patent registrations, and promoting technology exports within the context of research and development (R&D) innovation to stimulate economic growth (Agezew, 2024). Merely increasing research funding may prove insufficient for economic advancement unless it is paired with targeted R&D initiatives that have a direct economic impact. This underscores the necessity for policies that facilitate collaboration among government entities, academic institutions, and the private sector to enhance innovation and technology transfer. A supportive policy framework, the expansion of industries, the enactment of intellectual property rights protection laws, a burgeoning economy, the establishment of science and technology universities, the development of industrial parks, and improvements in infrastructure represent significant opportunities (Degaga & Senapathy, 2021). A coordinated effort among government bodies, universities, industries, and other relevant stakeholders is essential to address the aforementioned challenges and revitalize university-industry linkages (UIL). Furthermore, it is imperative to leverage the emerging opportunities identified and to strengthen the enabling environment for UIL to thrive with increased vigor.\n\nThe effective optimization of Science, Technology, and Innovation (STI) policies within the nation represents a vital component in fostering economic development and enhancing competitiveness. This can be accomplished through the augmentation of productivity, the minimization of costs, and the enhancement of operational efficiency. The implementation of STI policies holds the promise of generating substantial benefits for the economy as a whole. Therefore, and this is very important, Ethiopia needs to make an effort to maximise STI’s potential to accelerate both its economic growth and social well-being. Despite the previously mentioned initiatives to formulate all-encompassing policies on Science, Technology, and Innovation (STI) and to institute a Regional Innovation System (RIS), the current situation suggests a discrepancy in the efficient execution of the policies.\n\n\nConclusion\n\nThe policies and legal frameworks governing Science, Technology, and Innovation (STI) are crucial for Ethiopia’s pursuit of economic development, innovation, and enhanced competitiveness. These frameworks foster an environment conducive to collaborative learning, entrepreneurship, research, and the transfer of technology. The effective operation of the Ethiopian National Innovation System relies on a robust policy and legal foundation, which is established by existing policies such as the National Science and Technology Policy, the Strategic Policy for National Science, Technology, and Mathematics Education, the Investment Proclamation, the Intellectual Property Law, the National Research and Development Strategy, the Industrial Parks Development Proclamation, the Digital Strategy for Ethiopia, the Technology Incubation and Transfer Policy, the Professional and Program Mix Policy, and the Higher Education Proclamation. By evaluating current opportunities, addressing existing challenges, and suggesting alternative policies, Ethiopia can enhance its STI policies to bolster a Regional Innovation System that promotes economic growth, technological progress, and sustainable development.\n\nThe study investigated existing barriers in the ecosystem; Ethiopia faces challenges in creating comprehensive STI policies and successfully implementing them into practice. It emphasises how important it is to harness the outcomes of innovations within a strong policy framework and how STI capacity-building is necessary for sustainable development. Among the issues that must be resolved are policy gaps and the requirement for more robust institutional assistance. The policies and legal frameworks governing Science, Technology, and Innovation (STI) are crucial for Ethiopia’s pursuit of economic development, innovation, and enhanced competitiveness. These frameworks foster an environment conducive to collaborative learning, entrepreneurship, research, and the transfer of technology. The effective operation of the Ethiopian National Innovation System relies on a robust policy and legal structure, which is established by existing policies such as the National Science and Technology Policy, the Strategic Policy for National Science, Technology, and Mathematics Education, the Investment Proclamation, the Intellectual Property Law, the National Research and Development Strategy, the Industrial Parks Development Proclamation, the Digital Strategy for Ethiopia, the Technology Incubation and Transfer Policy, the Professional and Program Mix Policy, and the Higher Education Proclamation. By evaluating current opportunities, addressing existing challenges, and suggesting alternative policies, Ethiopia can enhance its STI policies to bolster a Regional Innovation System that promotes economic growth, technological progress, and sustainable development.\n\nEthical approval and consent were not required.", "appendix": "Data availability\n\nNo data associated with this article.\n\nThe article does not contain any associated data because it primarily focuses on the evaluation of existing Science, Technology, and Innovation (STI) policies and legal frameworks in Ethiopia rather than presenting original empirical research findings. It serves as a methodological discussion and analysis of the current state of STI in the context of the Regional Innovation System (RIS), emphasizing policy gaps and recommendations for improvement without generating new data. Therefore, no datasets are available for publication as the content centers on policy analysis and strategic insights rather than quantitative or qualitative research outputs.\n\nNo extended data associated with this article.\n\n\nReferences\n\nAdenle AA, De Steur H, Mwongera C, et al.: Global UN 2030 agenda: How can Science, Technology and Innovation accelerate the achievement of Sustainable Development Goals for All? PLOS Sustainability and Transformation. 2023; 2(10): e0000085–e0000085. Publisher Full Text\n\nAgezew BH: The Effect of Research and Development on Economic Growth in Ethiopia: The Untapped Potential for Prosperity. Education Research International. 2024; 2024: 1–7. Publisher Full Text\n\nAgu AG, Kalu OO, Esi-Ubani CO, et al.: Drivers of sustainable entrepreneurial intentions among university students: an integrated model from a developing world context. International Journal of Sustainability in Higher Education. 2021; 22(3): 659–680. Publisher Full Text\n\nAgu A, Ndinda C: Strengthening gender and inclusivity in the national system of Science, Technology, and Innovation (STI): literature review: Ethiopia.2021. Reference SourceReference Source\n\nAli MA, Kamraju M, Sonaji DB: Economic policies for sustainable development: Balancing growth, social equity, and environmental protection. ASEAN Journal of Economic and Economic Education. 2024; 3(1): 23–28.\n\nAndabayeva G, Movchun V, Dubovik M, et al.: Labor market dynamics in developing countries: analysis of employment transformation at the macro-level. Journal of Innovation and Entrepreneurship. 2024; 13(1): 65. Publisher Full Text\n\nAndrade R, Pinheiro P, Carvalho L, et al.: Building a Bridge: Knowledge Sharing Flows into Entrepreneurial Ecosystems. Journal of Open Innovation: Technology, Market, and Complexity. 2022; 8(3): 144. Publisher Full Text\n\nArimoto T: The transformation of science, technology and innovation (STI) policy in Japan. Asia Pacific Business Review. 2024; 30(3): 485–498. Publisher Full Text\n\nAsheim BT, Isaksen A, Trippl M: The role of the Regional Innovation System approach in contemporary regional policy: is it still relevant in a globalised world? Regions and Innovation Policies in Europe. 2020; 12–29. Publisher Full Text\n\nAyenew Y: Assessment of the status of linkage between universities and industries in Ethiopia (A study on four selected universities). Adigrat University; 2015.\n\nAyenew Y, Teklay A: University-industry linkage in Ethiopia, a study on two selected Universities. Indo–Asian Journal of Multidisciplinary Research (IAJMR). 2017; 3(1): 992–998.\n\nBasheer M, Nechifor V, Calzadilla A, et al.: Balancing national economic policy outcomes for sustainable development. Nature Communications. 2022; 13(1): 5041. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nChauhan A, Trikha R, Singh K: Reinvigorating Science, Technology, and Innovation in the Country by Factoring Components of the Innovation System.2024; 57–105. Publisher Full Text\n\nDegaga A, Senapathy M: Challenges and Opportunities of University and Industry Nexus in Ethiopia: A Systematic Review. Shanlax International Journal of Management. 2021; 9(2): 97–111. Publisher Full Text\n\nGachie W, Govender DW: Commercialization of higher education institutions’ research within the National System of Innovation. African Journal of Science, Technology, Innovation and Development. 2017; 9(4): 387–397. Publisher Full Text\n\nGalvao A, Mascarenhas C, Marques C, et al.: Triple helix and its evolution: a systematic literature review. Journal of Science and Technology Policy Management. 2019; 10(3): 812–833. Publisher Full Text\n\nGashahun AD: University-industry linkage practice in Ethiopia: a study on Debre Markos institute of technology, Debre Markos University. International Journal of Scientific and Engineering Research. 2020; 11: 1913–1920. Reference Source\n\nGelata FT, Gemada SC, Jiqin H: Review of the E-commerce business models in Ethiopia. European Journal of Applied Sciences. 2022; 10(5). Publisher Full Text\n\nGobena AE, Kant S: Assessing the effect of endogenous culture, local resources, eco-friendly environment and modern strategy development on entrepreneurial development. Journal of Entrepreneurship, Management, and Innovation. 2022; 4(1): 118–135. Publisher Full Text\n\nGobena ST, Gopal M, Abeya TG: Status of Technology Transfer and Innovation in Ethiopia. Educational Research (IJMCER). 2021; 3(4): 122–130.\n\nJote A: The Economic Contribution of Industrial Parks in Ethiopia. St. Mary’s University; 2020. (Doctoral dissertation). Reference Source\n\nKahsay M: The Links between Academic Research and Economic Development in Ethiopia: the Case of Addis Ababa University. European Journal of STEM Education. 2017; 2(2): 1–10. Publisher Full Text\n\nKebebe E: Bridging technology adoption gaps in livestock sector in Ethiopia: A innovation system perspective. Technology in Society. 2019; 57: 30–37. Publisher Full Text\n\nKeraga MN, Araya M: R&D, innovations, and firms’ productivity in Ethiopia. African Journal of Science, Technology, Innovation and Development. 2023; 15(3): 311–324. Publisher Full Text\n\nKhan MS: Absorptive capacities approaches for investigating national innovation systems in low and middle income countries. International Journal of Innovation Studies. 2022; 6(3): 183–195. Publisher Full Text\n\nKrammer SMS: Science, technology, and innovation for economic competitiveness: The role of smart specialization in less-developed countries. Technological Forecasting and Social Change. 2017; 123: 95–107. Publisher Full Text\n\nLiche MB, Střelcová AB: The Pathway towards Triple Helix: Technology Development Evaluation in Ethiopian Science & Technology Universities. Triple Helix. 2023; 10(1): 12–39. Publisher Full Text\n\nMamo FP: Revenue generation strategies in Sub-Saharan African universities.2015. Reference Source\n\nMavhunga C: What do science, technology, and innovation mean from Africa? The MIT Press; 2017. Publisher Full Text\n\nMinistry of Education (MoE): Annual Intake and Enrolment Growth and Professional and Program Mix of Ethiopian Public Higher Education: Strategy and Conversion Plan, 2008/09-2011/12. Unpublished. Addis Ababa: Federal Democratic Republic of Ethiopia; 2008. Reference Source\n\nMuchie M, Ezezew W: Analysis of the Relationship between Innovation and Ethiopian Economic Growth.2022. Publisher Full Text\n\nOgada TP, Partey S, Ramasamy J, et al.: Overview of the science, technology and innovation landscape of Eastern Africa.2022.\n\nPark T, Kim JY: An exploratory study on innovation policy in eight Asian countries. Journal of Science and Technology Policy Management. 2021; 13: 273–303. Publisher Full Text\n\nRatanawaraha A, et al.: Policies to promote private sector engagement in Science, Technology and Innovation: Workbook.2024. Reference Source\n\nSagar S: Innovation and Sustainability in Business: Navigating the Future Landscape. IOSR Journal of Business and Management (IOSR-JBM). 2023; 25(12): 51–60. Publisher Full Text\n\nSalami R, Soltanzadeh J: Comparative analysis for science, technology and innovation policy; Lessons learned from some selected countries (Brazil, India, China, South Korea and South Africa) for other LdCs like Iran.2012. Publisher Full Text\n\nSalmi J, Sursock A, Olefir A: Improving the Performance of Ethiopian Universities in Science and Technology. World Bank, Washington, DC eBooks; 2017. Publisher Full Text\n\nSeifu M, et al.: A state-initiated multi-stakeholder platform as an instrument to build agricultural innovation system capacity: a case study from Ethiopia.2022. Publisher Full Text\n\nShkabatur J, Bar-El R, Schwartz D: Innovation and entrepreneurship for sustainable development: Lessons from Ethiopia. Progress in Planning. 2022; 160: 100599. Publisher Full Text\n\nSingh RB, Paroda RS, Dadlani M: Science, technology and innovation. Indian agriculture towards 2030. 2022; 51. 821.\n\nSkorge O: Bottlenecks and Innovation Performance.2024.\n\nTekle K: Role of Knowledge Management Practices in Enhancing Innovation and Competitiveness in the Ethiopian Leather Industry. African Journal of Information and Knowledge Management. 2024; 3(1): 26–39. Publisher Full Text\n\nTesfa B: Challenges of Ethiopian Researchers and Potential Mitigation with Ethiopian Science, Technology and Innovation Policy.2015.\n\nWazza M: Ten Years Development Plan of Ethiopia (2021-2030): A Critical Review.2022.\n\nYongabo P, Göransson B: Constructing the national innovation system in Rwanda: efforts and challenges. Innovation and Development. 2020; 12: 155–176. Publisher Full Text" }	[ { "id": "358945", "date": "04 Feb 2025", "name": "Shem Sikombe", "expertise": [ "Reviewer Expertise Supply Chain Management", "Research and Inovation", "Knowledge Management", "Operations Management and General Management." ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nTitle: Regional Innovation Systems as a Means for Development: Policies, Opportunities, and Challenges in Ethiopia\nIntroduction Thank you for the opportunity to review and provide insights into this research. The study is highly relevant, given the increasing emphasis on Science, Technology, and Innovation (STI) as a driver of economic development.\nThe article highlights the role of STI in fostering economic growth at both global and regional levels. Additionally, it provides a comprehensive review of policies supporting STI, thereby offering a well-defined contextual framework for the study.\nTo enhance clarity, the research objectives should be explicitly stated. Based on the title and scope of the study, the following research objectives are suggested:\nTo review the policies supporting Regional Innovation Systems (RIS) in Ethiopia. To explore the opportunities for leveraging RIS for economic development. To identify the main challenges hindering RIS from contributing to economic development.\nLiterature Review The section titled \"Science, Technology, and Innovation Policies (STIP) in Emerging Economies,\" which currently appears after the methods section, would be more appropriately positioned within the literature review. Integrating this section into the literature review will enhance the logical flow and coherence of the study.\nMethods The methodology section needs further elaboration to ensure enhanced credibility. Specifically, the process of identifying and selecting documents for analysis needs clarification. The following aspects should be explicitly addressed:\nWhat were the inclusion and exclusion criteria for document selection? What specific topics or themes did these documents address? Who authored these documents, and what credibility do they hold in the field?\nThe coding process and theme generation should be clearly explained. Furthermore, the approach to data saturation remains ambiguous. The study should clarify the following:\nHow was data saturation determined? Were the themes inductively generated from the data, or were they deductively derived based on predefined categories?\nFindings The findings section would benefit from a more structured thematic organisation. Grouping findings under specific themes such as challenges, opportunities, and policy implications would enhance clarity and readability. A possible thematic structure could be:\nChallenges in Promoting RIS: A synthesis of the main challenges identified in the reviewed documents. Opportunities for RIS: Potential avenues for leveraging RIS to drive economic growth. Policy Implications: Key policy recommendations emerging from the study.\nOverall, this research provides valuable insights into how RIS can support economic development in Ethiopia.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [] } ]	1	https://f1000research.com/articles/14-34
https://f1000research.com/articles/13-837/v1	26 Jul 24	{ "type": "Research Article", "title": "Analysis of the dynamics of transition from non-colonization to colonization and Staphylococcus aureus bacteremia in hemodialysis patients using Markov models.", "authors": [ "Daniela Montoya-Urrego", "Johanna M Vanegas", "J Natalia Jiménez", "Difariney González-Gómez", "Daniela Montoya-Urrego", "Johanna M Vanegas", "J Natalia Jiménez" ], "abstract": "Background Hemodialysis patients are frequently colonized by Staphylococcus aureus, leading to severe infections with high mortality rates. However, little is known about transition from non-colonization to colonization or bacteremia over time. The aim was to analyze the behavior of S. aureus colonization, identifying the probability of transition from non-colonized to colonized state or bacteremia, and the influence of some covariates.\n\nMethods The study was conducted in a dialysis unit associated with a high complexity hospital in Medellín between October 2017 and October 2019. An initial measurement was taken to evaluate S. aureus colonization, and follow-up measurements were performed 2 and 6 months later. Bacteremia evolution was monitored for 12 months. A two-state recurrent continuous-time Markov model was constructed to model transition dynamics from non-colonization to S. aureus colonization in hemodialysis patients. Subsequently, the model was applied to a third state of bacteremia.\n\nResults Of 178 patients on hemodialysis, 30.3% were colonized by S. aureus. Transition intensity from non-colonization to colonization was three times higher (0.21; CI: 0.14-0.29) than from colonization to non-colonization (0.07; CI: 0.05-0.11). The colonization risk increased in patients with previous infections (HR: 2.28; CI: 0.78-6.68), hospitalization (HR: 1.29; CI: 0.56-2.99) and antibiotics consumption (HR: 1.17; CI: 0.53-2.58). Mean non-colonized state duration was 10.9 months, while in the colonized state was 5.2 months. In the 3-state model, it was found that patients colonized were more likely to develop S. aureus infection (13.9%).\n\nConclusion A more likely transition from non-colonization to colonization was found, which increases with factors such as previous infection. In addition, the development of bacteremia was more likely in colonized than in non-colonized patients. These results underline the importance of surveillance and proper management of S. aureus colonization to prevent serious complications, such as bacteremia, and improve prognosis in this vulnerable population.", "keywords": [ "Markov models", "Multistate models", "Staphylococcus aureus", "Hemodialysis", "Colonization", "Bacteremia." ], "content": "Introduction\n\nStaphylococcus aureus is one of the microorganisms that most frequently colonizes and causes invasive infection, such as bacteremia in hemodialysis patients.1 In addition to increasing the risk of endogenous infection by up to 77.8% in this group of patients, colonization by S. aureus favors the dissemination of this bacterium at hospital and community level, due to the fact that colonized patients constantly circulate among these environments and act as asymptomatic reservoirs and carriers of the microorganism for long periods of time.2,3 The situation become more worrying when isolates are methicillin-resistant (MRSA), because treatment options are reduced, the prognosis for the patient worsens and morbidity, mortality and the cost of care increase significantly.1\n\nColonization by S. aureus in hemodialysis patients can be persistent, which refers to the permanent presence of the microorganism over time; or intermittent, in which the microorganism can be present or absent at different times.3,4 There is little information on the probability of switching between the non-colonized state and the colonized state and vice versa, as well as the period of permanence of patients in each state and the implications for infection. This is important because, if patients remain colonized for a longer period of time, this favors the risk of invasive infections such as bacteremia, since the colonizing bacteria can contaminate catheters or other devices and reach the bloodstream.5\n\nIn this sense, Markov models emerge as a useful statistical tool to study the behavior of colonization over time, allowing to estimate the transition between states, in this case from a state of non-colonization to one of colonization or infection.6,7 This type of statistical model allows modelling systems that change randomly, and assumes that future states depend only on the current state, not on the events that occurred before it. Therefore, they allow finding the probability that a system is in a particular state and its permanence time in that state, thus predicting the behavior of the states over time.6\n\nIn this study, we proposed to analyze the behavior of colonization by S. aureus, identifying the probabilities of change from non-colonized to colonized states and bacteremia, and the influence of some covariables in these transitions. This will allow designing and directing strategies to avoid progression to states that compromise the patient’s prognosis, such as colonization and infection.\n\n\nMethods\n\nA cohort of 210 hemodialysis patients was taken from a previous study that was carried out in a dialysis unit in Medellín, Colombia, in which colonization by S. aureus was evaluated at three moments in time: at the beginning of the study, at two and at 6 months; and the development of bacteremia during a 12-month follow-up.4 This study included patients from a dialysis unit associated to a high complexity hospital in Medellín, over 18 years of age, with chronic kidney disease and central venous catheter on hemodialysis. Patients who had only the baseline measurement were excluded from the present study. Informed consent was signed by each patient.\n\nColonization was assessed in nostrils and skin around the insertion of the hemodialysis catheter at the beginning of the study, at 2 and 6 months later. Infection was defined as the diagnosis of bacteremia according to the criteria given by the Center for Disease Control and Prevention (CDC), as the presence of fever, chills or hypotension with bacteria identified in the blood and not related to an infection at any other site.8\n\nAdditionally, demographic and clinical variables were evaluated, such as age, sex, smoking, history of hospitalization, previous infection, antibiotic use, comorbidities, and catheter or fistula use. To apply the Markov model, two possible recurrent states were initially considered: 1: Non-colonized and 2: Colonized. Subsequently, at a second stage, 3 states were considered: 1: Non-colonized, 2: Colonized and 3: Bacteremia. Consequently, individuals can independently transit between states where the probability of transition is not time-dependent.9 Transitions are defined as changes from one state to another, and this process can be specified in terms of transition intensities. For each patient a transition history was established based on a maximum of three observations during the follow-up period, in which the state of colonization, non-colonization or infection was determined.\n\nThe clinical and epidemiological information was obtained by a questionnaire designed for this purpose, which was applied to all the hemodialysis patients in the company of a researcher by interview. Similarly, the clinical histories provided by the dialysis center were taken into account to know the clinical history of patients.\n\nTo detect S. aureus colonization, samples were obtained from nostrils and skin around the catheter insertion, using a sterilized cotton swab with sterile 0.9% saline solution. Each swab was transported in AMIES medium (transport medium with activated carbon) and then enriched for 18 to 24 hours at 37°C in trypticase soy broth (TSB- OXOIDTM, CM0129), prepared according to manufacturer’s instructions, adding 30 g to 1 liter of water. Subsequently, it was plated on mannitol salt agar for the selection of fermenting colonies indicative of S. aureus. Preliminary identification was performed by phenotypic methods based on colony morphology in sheep blood agar and positive catalase and coagulase tests. Identification of isolates and antibiotic susceptibility was determined using the Vitek®-2 automated system (bioMérieux) according to Clinical and Laboratory Standards Institute (CLSI) cut-off points.10\n\nCategorical variables were described as absolute and relative frequencies. Quantitative variables were expressed as mean and standard deviation or median and interquartile range, according to the assumption of normality. Subsequently, Markov models were applied, in which the probability of an event occurring depends only on the immediately preceding event.6 The modeling was carried out with the inter-occurrence times, whose construction was made by transforming the moment of the first measurement as time zero, the other measurements being taken as time 1 (Measurement 1) and time 2 (Measurement 2). The Markov model allows estimating the transition intensity functions between states, identifying all the transitions that occurred between observations, estimating the maximum probability of transition from one state to another and estimating the maximum probabilities when covariables are present.6,11\n\nIn relation to the above, two transition matrices were calculated: the transition count matrix Q and the transition probability matrix P. The transition matrix Q represents the count of individuals that changed from state r to state s during a time interval, qrs. From matrix Q, the probability matrix P is obtained by dividing each of the elements of matrix Q by the row total. The prs elements of the matrix P present the probability of change from one state to another in that time interval.12\n\nIn the transition count matrix Q and the probability matrix P, the rows designate the states from which a transition may occur, e.g., the first row corresponds to state 1, the second row to state 2, and so on; while the columns represent the states to which a transition may occur. The sum of the probabilities of a row of the transition matrix is equal to 1. The transition probabilities are presented with the 95% confidence interval. For the case of patients with S. aureus all possible transitions between states are allowed, in all states there is a positive probability of reaching it.\n\n\nResults\n\nOf 210 hemodialysis patients, 32 were excluded from the present study because only had the initial observation, leaving a total of 178 patients included. The majority of patients were female (51.7%, n=92), and the mean age was 62 years (SD 15.9). Clinical data revealed that 68.5% (n=122) of patients had been hospitalized in the last year, while 57.3% (n=102) consumed antibiotics in the previous 6 months. The most common comorbidities were diabetes mellitus (44.4%, n=79), heart failure (24.7%, n=44), and coronary artery disease (20.2%, n=36). At baseline, 30.3% (n=54) of patients had S. aureus colonization.\n\nThe recurrent two-state model (Non-Colonized - Colonized) is shown in Figure 1. During the follow-up period, and considering all three measurements, the transition intensity was 3 times higher for going from a non-colonized to colonized state (0.21; CI: 0.14-0.29) compared to the transition from colonized to non-colonized state (0.07; CI: 0.05-0.11). The probabilities of remaining in the same state decreased over time, contrary to the transition between the two states, which presented higher likelihoods over time (Table 1).\n\nThe arrows indicate the allowed transitions between states. Patients can remain in one state in consecutive cycles.\n\nIn the presence of most of the covariates analyzed, such as smoking, previous hospitalization, antibiotic use and comorbidities, the transition intensities from the colonized to the non-colonized state doubled with respect to the transition intensities from the non-colonized to the colonized state, with the exception of previous infection, which presented similar intensities in both transitions (Table 2).\n\nOn the other hand, no evidence was found of the influence of the covariates studied on transition risk. However, significant tendencies to exceed the risk threshold for transition from the non-colonized state to the colonized state were observed in the presence of previous infection (HR: 2.28; CI: 0.78-6.68), previous hospitalization (HR: 1.29; CI 0.56-2.99), antibiotic consumption (HR: 1.17; CI 0.53-2.58) and heart failure (HR: 2.00; CI 0.84-4.78). On the other hand, the factors that showed a tendency to increase the transition risk from colonized to non-colonized state were history of hospitalization (HR: 1.62, CI 0.76-3.46) and smoking (HR:1.62; CI: 0.78-3.33). However, these risk indices were not significant (Table 2).\n\nRegarding the average time spent (in months) in one of the two states analyzed, it was found that there was longer duration of colonization in presence of hypertension (5.33; CI: 3.72-7.63) and in patients with previous antibiotic use (4.98; CI: 2.86-8.65).\n\nIn a second stage of the analysis, a third condition was incorporated: S. aureus bacteremia. Regarding this, 35.2% (n=64) of the patients were found to be in the colonized state, 64.8% (n=118) in the Non-colonized state and 4.39% (n=23) in the infected state.\n\nIn the three-state model, the results were similar to those presented in the two-state model. There was a 16.7% probability of moving from the non-colonized state to the colonized state. The probability of moving from the colonized state to the non-Colonized state was 32.7%. Staying in the non-Colonized state had a probability of 80.3%, while in the colonized state had a probability of 53.2%. On the other hand, the probability of a non-colonized person becoming infected was 2.8%, and among the colonized patients, 13.9%. There was also a longer stay in the Non-Colonized state (9.3 months) compared to the Colonized state (25 days) and the Infected state (4 days) (Figure 2).\n\nThe arrows indicate the allowed transitions between states. Patients can remain in one state in consecutive cycles.\n\nRelated with the probability of moving from the Non-Colonized to Colonized state, it increased from the baseline measurement to the 12-month measurement (from 0.11 to 0.27), as did the probability of moving from Non-Colonized to Infected (from 0.03 to 0.06). In contrast, the probability of moving from colonized to infected status decreased over time, from 0.11 at baseline to 0.06 at 12 months (Table 3).\n\n\nDiscussion\n\nIn this study, Markov models were used to analyze the behavior of S. aureus in hemodialysis patients, and to predict its change between the states of non-colonization, colonization and bacteremia over time. Transition models have positioned as a powerful tool for studying transitions from one state to another, allowing to shed light on behaviors and outcomes of interest in some diseases and infections, such as smoking, diabetes and cancer.13–15 Unlike other estimation models, such as Generalized Estimating Equations (GEE), with Markov models it is possible to simultaneously study transitions in both directions, such as from non-colonized to colonized and from colonized to non-colonized. In addition, make it possible to identify factors that may behave differently from one direction to the other.16 Particularly in the case of the use of Markovian models to evaluate S. aureus colonization, several studies have been reported.17–19 However, the application of Markov models to evaluate the transition of states in hemodialysis patients presents limited evidence.\n\nConsidering the above, the results of this study show that, for patients who started in a non-colonized state, the probability of changing to a colonized state was 14.7%, lower than the probability of changing from the colonized to the non-colonized state (Figure 1). However, the transition intensity was found to be 3 times higher in the switch from the non-colonized to colonized state (Table 1). This may be due to the fact that this type of patient has specific baseline conditions and clinical characteristics that favor colonization, such as high antibiotic consumption, presence of different comorbidities, constant transit between the community and medical centers, frequent hospitalizations and regular contact with medical personnel and other patients.20,21 Similarly, in the few studies that have used Markovian models to understand the behavior of S. aureus in other populations, they reach the same conclusion, demonstrating that previous antibiotic use is related to the acquisition of Methicillin-Resistant S. aureus (MRSA) strains in nursing homes.19,22 This similarity may be due to the fact that, in this type of population, as well as in hemodialysis patients, there is an environment with conditions that favor colonization by this type of bacteria.\n\nOn the other hand, trends were found that the risk of passing from the non-colonized state to the colonized state increased when the patient had a previous infection, previous hospitalization, and antibiotics consumption; also, that the time spent in the colonized state increased when the patient had arterial hypertension and previously used antibiotics. This is in agreement with what has been reported by other authors, who have found an association between previous hospitalization and the risk of S. aureus colonization, and reinforce the importance of the previous conditions of hemodialysis patients in colonization.23,24 Likewise, it has been described that most invasive S. aureus infections are of endogenous origin in these patients,25 therefore, remaining in a colonized state for a longer period of time increases the risk of developing an infection by this bacterium, such as bacteremia.4 Carrier status increases the spread of the microorganism at the hospital and community level, since patients constantly circulate between these two environments, and have a care link, not only with health personnel but also with their home contacts and general community.20,25,26\n\nRegarding the 3-state model, in which infection was considered, it was found that there is a greater probability that a colonized person will develop an infection compared to a non-colonized person. This is in agreement with what has been described in previous studies, which show that colonized persons have a higher risk of infection, especially bacteremia5; it has even been reported that 77.85% of hemodialysis patients who developed bacteremia due to S. aureus were previously colonized.2 In addition, the need to prevent colonization that can lead to infection is emphasized, due to the great implications in morbidity, mortality and worse prognosis of patients.27,28 On the other hand, it was found that the time spent in the non-colonization state is longer than the time spent in colonization or infection, this may be due to the fact that patients go from colonization to infection or that they receive antibiotic treatment. This may also explain why the probability of remaining in the same state decreases over time.\n\nFinally, high frequencies of colonization and infection in hemodialysis patients demonstrate the importance of maintaining active epidemiological surveillance in order to take actions to prevent infection. One way is to evaluate the possibility of establishing decolonization protocols that reduce the incidence of infections.29 In a study that also used Markov models to model the decolonization of S. aureus, it was shown that the use of mupirocin as a therapy to decolonize patients’ nostrils was effective and reduced autoinoculation and infection.18 In the same sense, infections by this bacterium generate a high cost in the health system, especially in hemodialysis patients, so being able to predict the behavior of S. aureus from colonization to infection can reduce the economic burden, both for the health system and for the patient and their family.30,31\n\n\nConclusion\n\nThe Markov model are a tool that can be used to determine the behavior between states of non-colonization, colonization, and S. aureus bacteremia in hemodialysis patients. The evidence of a more likely transition from non-colonization to colonization, especially favored by factors such as previous infections and antibiotic use, highlights the need to adequately manage S. aureus colonization and to have strategies to prevent it. Likewise, this study showed a higher probability of developing bacteremia in colonized patients, which draws attention to the importance of early intervention of colonization in order to avoid its progression. Finally, the use of modeling tools to address this type of problem allows the continuation and improvement of active epidemiological surveillance, making it possible to identify, design and implement evidence-based strategies aimed at preventing colonization and infection in these patients.\n\n\nEthics and consent\n\nThis research project conforms to the international ethical standards set forth in the Nuremberg Code, the Declaration of Helsinki, the Belmont Report and the World Health Organization’s Good Clinical Practice recommendations. The research was approved by the Ethics Committee for Human Investigations of the University of Antioquia (CBEIH-SIU) with the approval act No 17-65-689 dated May 3, 2017. Informed consent was signed by each patient.", "appendix": "Data availability statement\n\nEthical and security consideration\n\nThe study data have sensitive and private information about the patients who participated. If the reviewers or the reader need access to the data, they can request it by e-mail to the corresponding author (difariney.gonzalez@udea.edu.co). The data can be sent as long as it does not conflict with the consent signed by the patients.\n\nFigshare: Clinical and epidemiological information collection form. https://doi.org/10.6084/m9.figshare.26170027. 32\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nSchamroth Pravda M, Maor Y, Brodsky K, et al.: Blood stream Infections in chronic hemodialysis patients - characteristics and outcomes. BMC Nephrol. 2024 Jan; 25(1): 3. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nVanegas JM, Salazar-Ospina L, Roncancio GE, et al.: Staphylococcus aureus colonization increases the risk of bacteremia in hemodialysis patients: a molecular epidemiology approach with time-dependent analysis. Am. J. Infect. Control. 2021; 49(2): 215–223. PubMed Abstract \| Publisher Full Text\n\nPatel G, Jenkins SG, Mediavilla JR, et al.: Clinical and Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus among Patients in an Ambulatory Hemodialysis Center. Infect. Control Hosp. Epidemiol. 2011; 32(9): 881–888. PubMed Abstract \| Publisher Full Text\n\nVanegas JM, Salazar-Ospina L, Gallego MA, et al.: A longitudinal study shows intermittent colonization by Staphylococcus aureus with a high genetic diversity in hemodialysis patients. Int. J. Med. Microbiol. 2021; 311(1): 151471. PubMed Abstract \| Publisher Full Text\n\nPrice AM, Sarween N, Gupta I, et al.: Risk factors and short-term outcomes for methicillin-resistant Staphylococcus aureus and methicillin-sensitive Staphylococcus aureus colonization among hemodialysis patients. Saudi J. Kidney Dis. Transplant an Off. Publ. Saudi Cent Organ Transplantation, Saudi Arab. 2019; 30(6): 1351–1363. Publisher Full Text\n\nPutter H, Fiocco M, Geskus RB: Tutorial in biostatistics: competing risks and multi-state models. Stat. Med. 2007 May; 26(11): 2389–2430. PubMed Abstract \| Publisher Full Text\n\nPowell GA, Verma A, Luo Y, et al.: Modeling Chronic Obstructive Pulmonary Disease Progression Using Continuous-Time Hidden Markov Models. Stud. Health Technol. Inform. 2019 Aug; 264: 920–924. PubMed Abstract \| Publisher Full Text\n\nEvent CDCBI: Central Line-Associated Bloodstream Infection and Non-Central Line Associated Bloodstream Infection. Device-associated Modul. 2018.\n\nSaint-Pierre P, Combescure C, Daurès JP, et al.: The analysis of asthma control under a Markov assumption with use of covariates. Stat. Med. 2003 Dec; 22(24): 3755–3770. PubMed Abstract \| Publisher Full Text\n\nClinical and Laboratory Standards Institute: M100 Performance Standards for Antimicrobial Susceptibility Testing, 29th.2019; 224.\n\nNúñez E, Steyerberg EW, Núñez J: Regression Modeling Strategies. Rev. Esp. Cardiol. 2011; 64(6): 501–507. PubMed Abstract \| Publisher Full Text\n\nUrban DL, Wallin DO: Introduction to Markov Models BT - Learning Landscape Ecology: A Practical Guide to Concepts and Techniques. Gergel SE, Turner MG, editors. New York, NY: Springer New York; 2002; pp. 35–48.\n\nYeh H-W, Ellerbeck EF, Mahnken JD: Simultaneous evaluation of abstinence and relapse using a Markov chain model in smokers enrolled in a two-year randomized trial. BMC Med. Res. Methodol. 2012; 12(1): 95. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWang Y, Shtylla B, Chou T: Order-of-Mutation Effects on Cancer Progression: Models for Myeloproliferative Neoplasm. Bull. Math. Biol. 2024 Feb; 86(3): 32. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBauvin P, Delacôte C, Wandji LCN, et al.: Early prediction of the impact of public health policies on obesity and lifetime risk of type 2 diabetes: A modelling approach. PLoS One. 2024 Mar 28; 19(3): e0301463. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBible J, Albert PS, Simons-Morton BG, et al.: Practical issues in using generalized estimating equations for inference on transitions in longitudinal data: What is being estimated?. Stat. Med. 2019 Mar; 38(6): 903–916. PubMed Abstract \| Publisher Full Text\n\nCai Y, Philips EC, Arora S, et al.: Cost-effectiveness of a real-time spatiotemporal mapping surveillance system for meticillin-resistant Staphylococcus aureus prevention. J. Hosp. Infect. 2024 Jan; 143: 178–185. PubMed Abstract \| Publisher Full Text\n\nPoyraz O, Sater MRA, Miller LG, et al.: Modelling methicillin-resistant Staphylococcus aureus decolonization: interactions between body sites and the impact of site-specific clearance. J. R. Soc. Interface. 2022 Jun; 19(191): 20210916. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBatina NG, Crnich CJ, Döpfer D: Acquisition and persistence of strain-specific methicillin-resistant Staphylococcus aureus and their determinants in community nursing homes. BMC Infect. Dis. 2017 Dec; 17(1): 752. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nScheuch M, Freiin von Rheinbaben S, Kabisch A, et al.: Staphylococcus aureus colonization in hemodialysis patients: a prospective 25 months observational study. BMC Nephrol. 2019; 20(1): 153. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMontoya Urrego D, Vanegas JM, Jiménez JN: The remarkable genetic relationship between Staphylococcus aureus isolates from hemodialysis patients and their household contacts: Homes as an important source of colonization and dissemination. PLoS One. 2022; 17(4): e0267276. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nBatina NG, Crnich CJ, Anderson DF, et al.: Models to predict prevalence and transition dynamics of methicillin-resistant Staphylococcus aureus in community nursing homes. Am. J. Infect. Control. 2016 May; 44(5): 507–514. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nKaranika S, Zervou FN, Zacharioudakis IM, et al.: Risk factors for meticillin-resistant Staphylococcus aureus colonization in dialysis patients: a meta-analysis. J. Hosp. Infect. 2015; 91(3): 257–263. PubMed Abstract \| Publisher Full Text\n\nMehraj J, Witte W, Akmatov MK, et al.: Epidemiology of Staphylococcus aureus Nasal Carriage Patterns in the Community. Curr. Top. Microbiol. Inmunol. 2016; 398(July): 435. Publisher Full Text\n\nvon Eiff C , Becker K, Machka K, et al.: Nasal Carriage as a Source of Staphylococcus aureus Bacteremia. N. Engl. J. Med. 2001 Jan 4; 344(1): 11–16. PubMed Abstract \| Publisher Full Text\n\nDavis MF, Iverson SA, Baron P, et al.: Household transmission of meticillin-resistant Staphylococcus aureus and other staphylococci. Lancet Infect. Dis. 2012; 12(9): 703–716. PubMed Abstract \| Publisher Full Text\n\nChristine J-M, Mandler K, Alosh MH, et al.: Risk Factor Analysis for 30-day Mortality After Surgery for Infective Endocarditis. Thorac. Cardiovasc. Surg. 2024. (EFirst). Publisher Full Text\n\nBravo Thompson HA, Campos Herrera FA, Macías Ibiricu DA, et al.: Factors Related to the Development of Infective Endocarditis in Hemodialysis Patients in a Third-Level Hospital in Panama. Cureus. 2024 Jan; 16(1): e52385. PubMed Abstract \| Publisher Full Text\n\nPrice A, Sarween N, Gupta I, et al.: Meticillin-resistant Staphylococcus aureus and meticillin-susceptible Staphylococcus aureus screening in a cohort of haemodialysis patients: carriage, demographics and outcomes. J. Hosp. Infect. 2015 May 1; 90(1): 22–27. PubMed Abstract \| Publisher Full Text\n\nHirabayashi A, Yahara K, Oka K, et al.: Comparison of disease and economic burden between MRSA infection and MRSA colonization in a university hospital: a retrospective data integration study. Antimicrob. Resist. Infect. Control. 2024 Feb; 13(1): 27. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nGidengil CA, Gay C, Huang SS, et al.: Cost-effectiveness of strategies to prevent methicillin-resistant Staphylococcus aureus transmission and infection in an intensive care unit. Infect. Control Hosp. Epidemiol. 2015 Jan; 36(1): 17–27. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nMontoya D: Clinical and epidemiological information collection form.2024. Publisher Full Text Reference Source" }	[ { "id": "313718", "date": "05 Sep 2024", "name": "Thanaa Rasheed Abdulrahman", "expertise": [ "Reviewer Expertise Microbiology", "medical", "clinical and diagnostic bacteriology", "moleculer microbiology", "immunology", "parasitology" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear Editor The answer below for both questions. Are sufficient details of methods and analysis provided to allow replication by others? Are all the source data underlying the results available to ensure full reproducibility? The author followed the Markov model in conducting the research in terms of the transition between colonization, non-colonization, and infection, but he did not explain the details of the test, how the period was calculated, and how long each transition was. The details of the work must be added to make it a reliable reference research. Also, the author could have followed up on the period or generation time of bacteria between the transition from non-colonized to colonized or bacteremia, and whether it can contribute to stopping the transition or introducing a treatment to stop colonization.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "12721", "date": "04 Nov 2024", "name": "Daniela Montoya Urrego", "role": "Author Response", "response": "Dear reviewer, Thank you for guidance reviewing our submission. The manuscript has been revised and your comments have been directly addressed. We believe that these revisions lead to a significantly improved manuscript and we hope it is now acceptable for publication. Comment 1: The author followed the Markov model in conducting the research in terms of the transition between colonization, non-colonization, and infection, but he did not explain the details of the test, how the period was calculated, and how long each transition was. The details of the work must be added to make it a reliable reference research. Response: The colonization screening process are detailed in the Methods section, likewise the screening periods established in the methodology were based on a previous study conducted by our research group, also considering that colonization can behave intermittently over time, appearing or disappearing at different moments. Several studies have shown that hemodialysis patients can transition between non-colonization and colonization in short periods of time, ranging from 2 weeks to 2 months after starting dialysis therapy, especially in those with catheters. References: Scheuch M, Freiin von Rheinbaben S, Kabisch A, et al.: Staphylococcus aureus colonization in hemodialysis patients: a prospective 25 months observational study. BMC Nephrol. 2019;20(1):153. 31060511 10.1186/s12882-019-1332-z PMC6503363 Grothe C, Taminato M, Belasco A, Sesso R, Barbosa D. Screening and treatment for Staphylococcus aureus in patients undergoing hemodialysis: a systematic review and meta-analysis. BMC Nephrol. 2014;15(1):202 Agrawal V, Valson AT, Bakthavatchalam YD, Kakde S, Mohapatra A, David VG, et al. Skin Colonizers and Catheter Associated Blood Stream Infections in Incident Indian Dialysis Patients. Indian J Nephrol. 2022;32(1):34–41 For this reason, repeated measurements were taken over time to capture these changes in patient status. While we acknowledge that conducting more frequent measurements would have been ideal, it was not possible in this study, because the budget available for the research was only sufficient for three observations over time. However, we appreciate the comment and will take it into account for future research. Regarding the duration of each transition, this was calculated using the transition matrix Q, in which temporal homogeneity is assumed in the transitions between states. In this study, we used a continuous-time Markov model to analyze transitions between non-colonization, colonization, and infection states. Markov models are particularly well-suited for this type of research because they allow us to model the dynamics of transitions over time based solely on the patient’s current state without considering previous states, this is a Markovian property of homogeneity. This approach assumes that once the patient enters a given state, the probability of moving to a new state depends only on that current state and not on any prior states. This allows us to calculate the probabilities of changing from one state to another based on the patient's current state, maintaining the constancy of the transition probabilities over time. The methods section was enhanced in the manuscript to better explain this part. Comment 2: Also, the author could have followed up on the period or generation time of bacteria between the transition from non-colonized to colonized or bacteremia, and whether it can contribute to stopping the transition or introducing a treatment to stop colonization. Response: Given the intermittent nature of colonization, measurements were taken at short intervals to capture and identify all potential transitions, including the onset of bacterial colonization. For example, we observed cases where patients initially showed a non-colonization status at baseline but transitioned to colonization at subsequent measurements. Importantly, all patients started follow-up without bacteremia, and follow-up continued until the first episode of bacteremia, so the occurrence of bacteremia did not influence data on transitions between non-colonization and colonization. Furthermore, it is worth mentioning that the renal unit did not have a decolonization protocol in place, meaning that patients were not treated to control colonization. Treatment was only started when an infection was present. However, antibiotic consumption was included in the state-to-state transition analysis in order to assess the influence of this covariate on transition risk (Table 2)." } ] }, { "id": "316810", "date": "19 Sep 2024", "name": "Stephan Harbarth", "expertise": [ "Reviewer Expertise Healthcare epidemiology", "infection control", "MSSA/MRSA" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for the opportunity to review the interesting study by Montoya-Urrego et. al. The study addresses a relevant research question on the dynamics of Staphylococcus aureus colonization and bloodstream infection among hemodialysis patients in a Colombian healthcare setting. The investigators used transition intensities to quantify the rate at which patients move between non-colonization, colonization and infection states. They derive transition probability matrices and intensities from patient observations, which is the mainstay of multi-state modelling. The study has important findings for clinicians taking care of hemodialysis patients: first, there is a higher probability for transition from a non-colonized to a colonized state, which highlights the challenge in S. aureus prevention. Second, it identifies previous infections, hospitalization, and antibiotic use as significant risk factors for transition to a colonized state, in accordance with existing literature. Last, it highlights the importance of active S. aureus surveillance in hemodialysis patients. All these findings have implications on infection prevention and control practice and can inform future interventions targeting this patient group, beyond conventional decolonization strategies. After reading the manuscript we found that while the study rationale and objectives are clearly described, there are a few important issues that need to be better addressed in the sections about methodology, results, and discussion. Furthermore, a separate Limitations section should be added to the manuscript.\nMajor comments\nApplying Markov models to study the dynamics of colonization and infection by S. aureus is an interesting approach, yet there is an important limitation to this approach that should be acknowledged. For the case of S. aureus colonization among hemodialysis patients, the probability of colonization depends also on the number of patients colonized in the same unit, namely ‘colonization pressure’, as well as on other factors such as hospital environment and thus, it is not at all random. This cannot be accounted in such a model for and should be discussed as an important limitation of the chosen modelling approach. The model’s assumption of constant transition rates over time is problematic from a clinical perspective. Acquisition probability might change according to various factors, such as hospitalization, administration of antibiotics, use of invasive instrumentation etc. As such, the clinical relevance of these findings is questionable. This is another limitation that should be discussed in the manuscript. The methods section lacks important information that is critical for interpreting the study findings. The authors cite their previous publication (Vanegas et al 2021) that served as a basis for this secondary data analysis; however, essential information should be described in the current manuscript as well, for example the complete lack of decolonization measures for patients undergoing chronic hemodialysis in the studied hemodialysis clinic. Selection bias might be introduced by exclusion of patients with baseline measurement only (15% of all patients). The missing measurements could be not missing at random, as hemodialysis patients have increased mortality rates and can have renal transplantation, and the follow-up is not expected to be complete. These two events are competing events that should be accounted for in the model if such data exists, otherwise they should be further discussed in the limitations section. In line with the previous comment, specific information on the status of colonization and infection for the patients at the different time points assessed should be presented in a supplement. This information is crucial to assess the internal validity of the model and should be disclosed to the reader. The authors should consider providing an anonymized dataset (or a synthetic data set) and their analysis code for transparency, reproducibility, and educational purposes. The definition used for bacteremia state may be problematic, as it includes only a subgroup of patients with primary bloodstream infection, excluding central-line associated bloodstream infections (CLABSI). The latter constitute a substantial part of S. aureus bloodstream infections in this patient population. This should be addressed, and better clarified in case CLABSIs were indeed included. The sampling strategy for S. aureus colonization is not comprehensive, as it includes only nostrils and catheter insertion site. The colonization prevalence might have been different if additional sites were screened, see also: McKinnell JA et al, Infect Control Hosp Epidemiol. 2013. As such, the sensitivity of the screening approach in the primary study should be also discussed as possible source of bias. There is no mention of the distinction between MRSA and MSSA in this analysis (presented in the index publication in 2021). Analysis by MRSA/MSSA might have not been possible due to a limited number of patients with MRSA included in the original dataset, yet this should be discussed in the current study as well.\nMinor comments:\nThe external validity of findings is limited, since this study relies on a small patient sample in a single centre hemodialysis unit of patients receiving hemodialysis through a venous catheter, with three S.aureus sampling events. This should be discussed as a limitation. As patients are included at an arbitrary timepoint during the hemodialysis treatment, it is unclear how these transition intensities behave during the time course of hemodialysis. This also should be discussed and possible implications on the study findings should be addressed. The statistical methods could benefit from more detailed explanation including the theoretical relations between P,Q, qrs, with formula and which software was used, and what packages with their respective versions. The abstract needs to be revised some phrases such as ‘some variables’ and ‘high complexity hospital’ can be substituted with more precise terms and data.\nOptional suggestion to extend the current analysis: The authors could consider an option of adding a complementary simulation analysis to enrich the current study. For example, a sensitivity analysis of the Markov model and/or a scenario-based analysis reflecting on specific infection prevention interventions. Possible suggestions:\nSimulation with Non-Fixed Time Intervals: a time-varying/non-homogeneous Markov model can be used to simulate a scenario where transition rates can vary over time. This would better capture periods when the risk of infection or colonization is higher (e.g., hospitalization or administration of antibiotic treatments). The results obtained can be then compared to the homogeneous model to analyze the impact of varying transition rates on the duration of colonization or infection periods. Simulation of the effect of preventive intervention strategies on colonization. This simulation can be used to evaluate different preventive strategies, such as improved hygiene measures or changes in care protocols (e.g., systematic disinfection of catheters/ decolonization of S. aureus carriers). This analysis could test the impact of such interventions on reducing transitions from non-colonization to colonization accounting for different levels of adherence to these measures and observe their effect on reducing transitions.\n\nStructured feedback:\nIs the work clearly and accurately presented and does it cite the current literature? Partially, the literature review is adequate, yet additional information is needed in the methods, results and a limitations section in the discussion to improve the readability and interpretability of this manuscript. Is the study design appropriate and is the work technically sound?\nYes, the data is sparse, with few measurement points for small sample, but overall, this manuscript has a nice implementation of this modelling approach.\nAre sufficient details of methods and analysis provided to allow replication by others?\nNo, additional information is needed, and the analysis code should be shared in supplement or through an adequate repository (GitHub ,Zenodo, etc) please see specific comments above.\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes.\nAre all the source data underlying the results available to ensure full reproducibility?\nYes, However, we still recommend that the number of patients with available data in each of the 3 measurement points to be reported in an aggregate manner in the manuscript. Are the conclusions drawn adequately supported by the results? Yes.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes", "responses": [ { "c_id": "12722", "date": "04 Nov 2024", "name": "Daniela Montoya Urrego", "role": "Author Response", "response": "Dear reviewers, Thank you for your valuable feedback on our submission. We have carefully revised the manuscript and addressed all of your comments. We believe these changes have substantially strengthened the paper, and we hope it now meets the criteria for publication. Major comments: Comment 1: Applying Markov models to study the dynamics of colonization and infection by S. aureus is an interesting approach, yet there is an important limitation to this approach that should be acknowledged. For the case of S. aureus colonization among hemodialysis patients, the probability of colonization depends also on the number of patients colonized in the same unit, namely ‘colonization pressure’, as well as on other factors such as hospital environment and thus, it is not at all random. This cannot be accounted in such a model for and should be discussed as an important limitation of the chosen modelling approach. Response: We fully agree with your observation, so it was added to the discussion within the limitations of our study. We appreciate that you have raised this very relevant point. Comment 2: The model’s assumption of constant transition rates over time is problematic from a clinical perspective. Acquisition probability might change according to various factors, such as hospitalization, administration of antibiotics, use of invasive instrumentation etc. As such, the clinical relevance of these findings is questionable. This is another limitation that should be discussed in the manuscript. Response: Thank you for your valuable comment. Although Table 2 analyses the influence of different covariates on transition risks, for example antibiotic use, previous hospitalizations, history of infections and presence of comorbidities, we recognize that assuming constant transition rates over time may overlook important clinical factors. We have addressed this limitation in the discussion section of the manuscript. Comment 3: The methods section lacks important information that is critical for interpreting the study findings. The authors cite their previous publication (Vanegas et al 2021) that served as a basis for this secondary data analysis; however, essential information should be described in the current manuscript as well, for example the complete lack of decolonization measures for patients undergoing chronic hemodialysis in the studied hemodialysis clinic. Response: We agree with the observation, thank you for your comment. Our previous publication (Vanegas et al., 2021) is cited because, as the reviewers point out, it forms the foundation for the analysis in this study. However, as suggested, we complete the methods section in more detail with essential information such as the absence of decolonization protocols. Comment 4: Selection bias might be introduced by exclusion of patients with baseline measurement only (15% of all patients). The missing measurements could be not missing at random, as hemodialysis patients have increased mortality rates and can have renal transplantation, and the follow-up is not expected to be complete. These two events are competing events that should be accounted for in the model if such data exists, otherwise they should be further discussed in the limitations section. Response: Thank you for your observation. We have added the reasons for patients having only one measurement in the results section. Additionally, we have included these events as a limitation in the discussion section, acknowledging that mortality and renal transplantation are competing events. In future studies, we will consider performing different types of risk analysis to account for such competing events. Thank you again for your value comment. Comment 5 and 6: In line with the previous comment, specific information on the status of colonization and infection for the patients at the different time points assessed should be presented in a supplement. This information is crucial to assess the internal validity of the model and should be disclosed to the reader. The authors should consider providing an anonymized dataset (or a synthetic data set) and their analysis code for transparency, reproducibility, and educational purposes. Response: A synthetic data set was added with the information requested by the reviewers (Extended Data). Comment 7: The definition used for bacteremia state may be problematic, as it includes only a subgroup of patients with primary bloodstream infection, excluding central-line associated bloodstream infections (CLABSI). The latter constitute a substantial part of S. aureus bloodstream infections in this patient population. This should be addressed, and better clarified in case CLABSIs were indeed included. Response: Thank you for your observation. We confirm that central-line associated bloodstream infections (CLABSI) were indeed included in our analysis. This has now been clarified in the methodology section to ensure that the definition of bacteremia is more precise. Comment 8: The sampling strategy for S. aureus colonization is not comprehensive, as it includes only nostrils and catheter insertion site. The colonization prevalence might have been different if additional sites were screened, see also: McKinnell JA et al, Infect Control Hosp Epidemiol. 2013. As such, the sensitivity of the screening approach in the primary study should be also discussed as possible source of bias. Response: We recognize that S. aureus colonization can occur in multiple body sites, but the nasal region is the most common and is considered a strong indicator of overall colonization. Studies show that nasal colonization correlates highly with colonization at other body sites, so focusing on the nostrils offers high sensitivity for detecting S. aureus colonization. However, we will take your valuable suggestion into account in future studies to improve the accuracy of detection, and we included this limitation in the discussion section. Thank you for your observation. References: Sakr A, Brégeon F, Mège J-L, Rolain J-M, Blin O. Staphylococcus aureus Nasal Colonization: An Update on Mechanisms, Epidemiology, Risk Factors, and Subsequent Infections. Front Microbiol. 2018;9:2419 A. ML, M. CJ, Pauline C, Gail M, Dan M. Methicillin-Resistant Staphylococcus aureus Colonization at Different Body Sites: a Prospective, Quantitative Analysis . J Clin Microbiol. 2011 Mar 1;49(3):1119–21 Comment 9: There is no mention of the distinction between MRSA and MSSA in this analysis (presented in the index publication in 2021). Analysis by MRSA/MSSA might have not been possible due to a limited number of patients with MRSA included in the original dataset, yet this should be discussed in the current study as well. Response: As noted by the reviewers, a separate analysis of the behavior of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible Staphylococcus aureus (MSSA) was not possible due to the limited number of MRSA-colonized patients in the dataset. This point was added to the discussion section as a limitation. Minor comments: Comment 1: The external validity of findings is limited, since this study relies on a small patient sample in a single center hemodialysis unit of patients receiving hemodialysis through a venous catheter, with three S. aureus sampling events. This should be discussed as a limitation. Response: Thanks for the comment, it has been discussed as a limitation in the manuscript. However, the institution where the research was conducted is one of the largest in the city and serves a diverse population from various areas, which increases external validity. Comment 2: As patients are included at an arbitrary timepoint during the hemodialysis treatment, it is unclear how these transition intensities behave during the time course of hemodialysis. This also should be discussed and possible implications on the study findings should be addressed. Response: The hemodialysis time of each patient was not taken into account in this study, so it is discussed within the limitations. Thank you for the observation. Comment 3: The statistical methods could benefit from more detailed explanation including the theoretical relations between P,Q, qrs, with formula and which software was used, and what packages with their respective versions. Response: The explanation of the statistical analysis has been improved in the methods section, including information on the software used. Thank you for your feedback. Comment 4: The abstract needs to be revised some phrases such as ‘some variables’ and ‘high complexity hospital’ can be substituted with more precise terms and data. Response: The Abstract was adjusted according to your recommendations. Optional suggestion to extend the current analysis: The authors could consider an option of adding a complementary simulation analysis to enrich the current study. For example, a sensitivity analysis of the Markov model and/or a scenario-based analysis reflecting on specific infection prevention interventions. Possible suggestions: Simulation with Non-Fixed Time Intervals: a time-varying/non-homogeneous Markov model can be used to simulate a scenario where transition rates can vary over time. This would better capture periods when the risk of infection or colonization is higher (e.g., hospitalization or administration of antibiotic treatments). The results obtained can be then compared to the homogeneous model to analyze the impact of varying transition rates on the duration of colonization or infection periods. Simulation of the effect of preventive intervention strategies on colonization. This simulation can be used to evaluate different preventive strategies, such as improved hygiene measures or changes in care protocols (e.g., systematic disinfection of catheters/ decolonization of S. aureus carriers). This analysis could test the impact of such interventions on reducing transitions from non-colonization to colonization accounting for different levels of adherence to these measures and observe their effect on reducing transitions. Response: Thank you for your valuable suggestions on possible complementary analyses. We agree that incorporating additional simulations would provide a clearer understanding of the dynamics of the model. In particular, it would be interesting to explore time-varying transition rates and assess the impact of infection prevention interventions. We assure you that these insights will be taken into account for future extensions of this research. For the current study, we aimed to focus on providing an initial exploration of the transitions between non-colonization, colonization, and infection using a simpler Markov model. Your recommendations will certainly guide us in refining and enriching our analysis in subsequent studies." } ] } ]	1	https://f1000research.com/articles/13-837
https://f1000research.com/articles/13-1232/v1	15 Oct 24	{ "type": "Case Report", "title": "Case Report: Invasive candidiasis of the head and neck in a five-month-old infant: A case study", "authors": [ "Sameh Mezri", "Eya Laabidi", "Chaima Zitouni", "Wadii Thabet", "Sameh Mezri", "Eya Laabidi", "Wadii Thabet" ], "abstract": "Invasive sino-orbital fungal infection is an uncommon, yet severe condition that predominantly affects individuals with compromised immune systems. In this study, we report the case of a 5-month-old immunocompetent infant who exhibited persistent dacryocystitis despite receiving broad-spectrum antibiotics. Subsequently, the patient developed ethmoiditis, orbital subperiosteal abscess, and ulceration of the hard palate. Mycological and histological samples were indicative of Candida infections. The patient underwent sinus surgery and surgical debridement, along with antifungal therapy. The treatment was successful, and the follow-up was uneventful for up to 6 months. To our knowledge, this is the first reported case of invasive sino-orbital candidiasis in an immunocompetent infant with dacryocystitis as the entry point. This study explores the clinical features, management approaches, and outcomes of this potentially fatal disease.", "keywords": [ "Candidiasis", "invasive", "pediatric", "sinusitis", "dacryocystitis" ], "content": "Introduction\n\nInvasive sino-orbital fungal infection (ISOFI) is a severe and potentially life-threatening condition in which fungi invade the sinus and orbital regions. Diagnosis can be challenging and often delayed because of the nonspecific nature of the signs and symptoms.\n\nHerein, we report a case of ISOFI originating from dacryocystitis. The patient was a 5-month-old, immunocompetent infant.\n\nTo the best of our knowledge, ISOFI has only been reported in immunocompromised patients, and no study has reported it in an immunocompetent pediatric population. This case is unusual because the entry point for the infection was dacryocystitis.\n\nThis study investigated the clinical features, management approaches, and outcomes of this potentially fatal disease.\n\n\nCase report\n\nA 5-month-old female with no previous medical history was admitted to our pediatric department with fever, medial canthal purulent discharge, tenderness, and swelling of the left eye (Figure 1). Blood tests showed an elevated white blood cell count and high C-reactive protein (CRP) levels. Initial CT revealed the presence of dacryocystitis. The patient was treated with amoxicillin–clavulanate.\n\nThe condition progressed with ongoing fever and, after five days, the emergence of a necrotic ulceration on the palate (Figure 2). A repeat CT scan revealed ethmoiditis and an orbital subperiosteal abscess measuring 16 × 7 mm, with no evidence of bone lysis (Figure 3).\n\n(A) At the time of diagosis. (B) After 3 weeks. (C) After 6 weeks.\n\n(A) Axial CT scan image demonstrating left ethmoidal sinus opacification. (B) Axial CT scan image showing subperiostal abscess in the medial wall of the left orbit.\n\nA swab of the nasal cavity, palate, and eye discharge was obtained, followed by bacteriological and mycological examinations. Biopsies of the nasal and palatine mucosae were also performed. A biopsy of the palate identified yeast with angioinvasion. Mycological examination of the biopsy samples and eye discharge revealed Candida Tropicalis, which was found to be sensitive to Amphotericin B, Voriconazole, Caspofungin, and Fluconazole. Bacterial analysis of eye discharge revealed Pseudomonas aeruginosa, which was susceptible to high doses of ceftazidime.\n\nIn response to these findings, fluconazole was promptly initiated and amoxicillin-clavulanate was replaced with high-dose ceftazidime. The patient underwent urgent surgery, which included drainage of the subperiosteal abscess through external orbitotomy, left ethmoidectomy, and surgical debridement of the ulceronecrotic palatine lesion.\n\nImmunological tests, including complete blood count, HIV serology, nitroblue tetrazolium test, HLA-DR typing, quantitative immunoglobulins (IgG, IgA, IgM), total complement activity, and lymphocyte phenotyping (CD3, CD4, CD45, CD8, B cells, and natural killer cells CD16/CD56) were normal, indicating no underlying immunosuppression.\n\nThe patient responded well to the treatment. Fever and inflammatory marker levels resolved within 5 days. The canthal discharge was cleared, and the palatine tissue defect healed after six weeks. A follow-up CT scan three weeks after completing the treatment showed complete resolution of the infection.\n\nSix months after treatment, the patient remained symptom-free.\n\n\nDiscussion\n\nOnly 1.2% of all dacryocystitis cases are caused by fungal agents.1 Aspergillus Niger and Trichosporon, and other fungi have been reported.2,3 However, Candida rarely affects the lacrimal drainage system.2 Most cases occur in immunocompromised patients.4 Cases have also been reported in patients with nasolacrimal stents,1 dacryoliths, and ophthalmic surgery.2 To our knowledge, only two cases of fungal dacryocystitis in the pediatric population have been reported in the literature, both of which are associated with infections caused by Aspergillus Fumigatus and Aspergillus Niger.5 Our case appears to be the first instance of fungal dacryocystitis related to Candida infection in a child. In our case, dacryocystitis was the initial site of invasive fungal infection. Davies et al.5 reported two cases of ISOFI occurring after dacryocystitis. In both cases, the patients were children aged 9–11 years with a history of leukemia under chemotherapy.5 In contrast, our patient was significantly younger (5 months), and investigations did not reveal any immunodeficiencies.\n\nAlthough rare, ISOFI is most frequently observed in immunocompromised patients.6 However, it is important to consider this diagnosis, especially if there is no improvement with antibiotic treatment even in immunocompetent patients. The diagnosis of ISOFI presents significant challenges because there are no specific clinical or imaging signs. Common symptoms include fever, nasal congestion, crusting, rhinorrhea, and lateral or retro-orbital pain.7,8\n\nComputed tomography (CT) and Magnetic Resonance Imaging (MRI) are crucial for assessing the full extent of the infection and for surgical planning, with some data suggesting that MRI may be more sensitive than CT for diagnosis. CT can reveal bony erosion, sinus opacification, calcifications, mucosal thickening, and orbital cellulitis. MRI outlines the spread of infection through soft tissues, detects abscesses and necrosis, and assesses the impact on surrounding structures while also identifying complications.7,9\n\nTraditional microbiological techniques, light microscopy, and culture methods are generally effective for identifying Candida spp. In some cases, combining different techniques and additional specific tests, such as antigen detection and PCR, can be useful. Sometimes, the simultaneous presence of bacteria in clinical samples might be misleading,8 as in our case, in which we noted the presence of Pseudomonas in the ocular samples. Therefore, biopsies should be repeated as needed to increase the chances of isolating fungi.7,10\n\nA treatment protocol for invasive candidiasis was established by the Infectious Diseases Society of America (IDSA) in 201611 and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in 2012,12 involving initial echinocandin administration followed by a transition to azoles.8,10\n\nThe duration of treatment varies across different studies and typically depends on the severity of the disease and presence of underlying comorbidities. In ISOFI, even with timely surgical debridement and adjunct systemic antifungal therapy, the mortality rate remains high, ranging from 50% to 80% (19). Rapid diagnosis, treatment, and better control of the predisposing factors for immunosuppression are essential to improve the mortality rate.10,13\n\n\nConclusion\n\nIn conclusion, invasive sino-orbital fungal infection is a rare and poorly documented condition, especially in children. There are no specific signs of this pathology, making it essential to consider a fungal origin in severe cases, particularly if there is no improvement with antibiotic treatment. This consideration should also be applied to immunocompetent patients, even though the condition can occur in those with normal immune status. In addition, this case highlights that dacryocystitis can serve as an entry point for this infection.\n\nEarly and prolonged treatment, along with surgical intervention, is necessary. Currently, there are no specific treatment guidelines, especially when the fungal agent is Candida, as the available data primarily consists of case reports. Despite treatment, the mortality rate remains high, mainly because of underlying medical comorbidities and delayed diagnosis.\n\n\nConsent statement\n\nThe authors declare that signed consent to publish was obtained from the legal guardian (parent) of the patient regarding the publication of data and findings related to this study.", "appendix": "Data availability\n\nNo data associated with this article.\n\n\nReferences\n\nToledano Fernández N, García Sáenz S, Arteaga Sánchez Á, et al.: Dacriocistitis micótica asociada a prótesis naso-lagrimal. Caso clínico. Arch. Soc. Esp. Oftalmol. 2002; 77(7): 389–392. PubMed Abstract\n\nPurgason PA, Hornblass A, Loeffler M: Atypical Presentation of Fungal Dacryocystitis. Ophthalmology. 1992; 99(9): 1430–1432. PubMed Abstract \| Publisher Full Text\n\nCodère F, Anderson RL: Bilateral Candida albicans dacryocystitis with facial cellulitis. Can. J. Ophthalmol. J. Can. Ophtalmol. 1982; 17(4): 176–177.\n\nObi E, Roy A, Bates V, et al.: Bilateral chronic fungal dacryocystitis caused by Candida dubliniensis in a neutropenic patient: Figure 1. J. Clin. Pathol. 2006; 59(11): 1194–1195. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nDavies BW, Gonzalez MO, Vaughn RC, et al.: Dacryocystitis As the Initial Presentation of Invasive Fungal Sinusitis in Immunocompromised Children. Ophthalmic Plast. Reconstr. Surg. 2016; 32(4): e79–e81. PubMed Abstract \| Publisher Full Text\n\nAdulkar NG, Radhakrishnan S, Vidhya N, et al.: Invasive sino-orbital fungal infections in immunocompetent patients: a clinico-pathological study. Eye. 2019; 33(6): 988–994. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nVinh D, Yim M, Dutta A, et al.: Pediatric invasive fungal rhinosinusitis: An investigation of 17 patients. Int. J. Pediatr. Otorhinolaryngol. 2017; 99: 111–116. PubMed Abstract \| Publisher Full Text\n\nPappas PG, Lionakis MS, Arendrup MC, et al.: Invasive candidiasis. Nat. Rev. Dis. Primer. 2018; 4(1): 18026. Publisher Full Text\n\nGroppo ER: Computed Tomography and Magnetic Resonance Imaging Characteristics of Acute Invasive Fungal Sinusitis. Arch. Otolaryngol. Neck Surg. 2011; 137(10): 1005–1010. PubMed Abstract \| Publisher Full Text\n\nBhandari S, Agarwal S, Bhargava S, et al.: Post Covid-19 Sinonasal Candidiasis: A Crisis Within the Pandemic. Indian J. Otolaryngol. Head Neck Surg. 2023; 75(2): 523–528. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nPappas PG, Kauffman CA, Andes DR, et al.: Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin. Infect. Dis. 2016; 62(4): e1–e50. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nCornely OA, Bassetti M, Calandra T, et al.: ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin. Microbiol. Infect. 2012 Dec 18; 18: 19–37. Publisher Full Text\n\nValera FCP, Lago TD, Tamashiro E, et al.: Prognosis of acute invasive fungal rhinosinusitis related to underlying disease. Int. J. Infect. Dis. 2011; 15(12): e841–e844. PubMed Abstract \| Publisher Full Text" }	[ { "id": "342998", "date": "02 Dec 2024", "name": "László Galgóczy", "expertise": [ "Reviewer Expertise mycologist", "molecular identification of human pathogenic fungi", "antifungal susceptibility testing" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe present manuscript provide important information about a case and successful treatment of an invasive sino-orbital fungal infection caused by Candida tropicalis in immunocompetent infant. Considering that it is a unique case and the treatment was successful, the manuscript has potential high interest among clinical mycologists. I suggest to accept the manuscript for indexing after improvement. My comments are detailed below.\nAbstract „Invasive sino-orbital fungal infection”- In fact, it is rare among immunocompetent patients. Please clarify. “Mycological and histological samples were indicative of Candida infections.- Please, discuss in details in the main text, how was the infectious agent identified. What kind of method was used? It was identified based on micromorphology or molecular markers/techniques were involved in the correct identification at species level?\nIntroduction “Invasive sino-orbital fungal infection (ISOFI) is a severe and potentially life-threatening condition”, “the best of our knowledge, ISOFI has only been reported in immunocompromised patients” – Please provide a literature for these statements. “…and outcomes of this potentially fatal disease” – Please, discuss why it should be fatal and provide literature for this statement.\nCase report “Mycological examination of the biopsy samples and eye discharge revealed Candida Tropicalis, which was found to be sensitive to Amphotericin B, Voriconazole, Caspofungin, and Fluconazole. Bacterial analysis of eye discharge revealed Pseudomonas aeruginosa, which was susceptible to high doses of ceftazidime.” – As I noted for the abstract, please provide the detailed method what was used for the identification of the infectious agents. Was it only a microscopic examination or some kind of diagnostic technique was applied to identify them at species level. Were they identified based on some kind of molecular marker? Which method was used to reveal the antifungal/antibiotic susceptibility of the infectious agents? Was it a clinically approved method, such as CLSI or EUCAST? „fluconazole was promptly initiated and amoxicillin-clavulanate” – What was the applied dosage? Candida Tropicalis – Candida tropicalis (in Italic) amphotericin B, Voriconazole, Caspofungin, and Fluconazole - amphotericin B, voriconazole, caspofungin, and fluconazole\nDiscussion Aspergillus Niger – Aspergillus niger (in Italic) Trichosporon – Trichosporon spp. (in Italic) Candida – Candida spp. (in italic) Aspergillus Fumigatus and Aspergillus Niger - Aspergillus fumigatus and Aspergillus niger (species names in Italic) Pseudomonas – Pseudomonas (in Italic)\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes", "responses": [ { "c_id": "12958", "date": "06 Jan 2025", "name": "Chaima zitouni", "role": "Author Response", "response": "Response to Reviewer Report by László Galgóczy, University of Szeged, Szeged, Hungary We sincerely thank Dr. László Galgóczy for the thoughtful review and valuable comments, and here are our detailed responses to the comments provided: Abstract „Invasive sino-orbital fungal infection”- In fact, it is rare among immunocompetent patients. Please clarify. “Mycological and histological samples were indicative of Candida infections.- Please, discuss in details in the main text, how was the infectious agent identified. What kind of method was used? It was identified based on micromorphology or molecular markers/techniques were involved in the correct identification at species level? Introduction “Invasive sino-orbital fungal infection (ISOFI) is a severe and potentially life-threatening condition”, “the best of our knowledge, ISOFI has only been reported in immunocompromised patients” – Please provide a literature for these statements. “…and outcomes of this potentially fatal disease” – Please, discuss why it should be fatal and provide literature for this statement. Case report “Mycological examination of the biopsy samples and eye discharge revealed Candida Tropicalis, which was found to be sensitive to Amphotericin B, Voriconazole, Caspofungin, and Fluconazole. Bacterial analysis of eye discharge revealed Pseudomonas aeruginosa, which was susceptible to high doses of ceftazidime.” – As I noted for the abstract, please provide the detailed method what was used for the identification of the infectious agents. Was it only a microscopic examination or some kind of diagnostic technique was applied to identify them at species level. Were they identified based on some kind of molecular marker? Which method was used to reveal the antifungal/antibiotic susceptibility of the infectious agents? Was it a clinically approved method, such as CLSI or EUCAST? „fluconazole was promptly initiated and amoxicillin-clavulanate” – What was the applied dosage? Candida Tropicalis – Candida tropicalis (in Italic) amphotericin B, Voriconazole, Caspofungin, and Fluconazole - amphotericin B, voriconazole, caspofungin, and fluconazole Discussion Aspergillus Niger – Aspergillus niger (in Italic) Trichosporon – Trichosporon spp. (in Italic) Candida – Candida spp. (in italic) Aspergillus Fumigatus and Aspergillus Niger - Aspergillus fumigatus and Aspergillus niger (species names in Italic) Pseudomonas – Pseudomonas (in Italic) Author Response: We have made the requested modifications to the manuscript. Specifically, we clarified the rarity of ISOFI in immunocompetent patients and provided further details on the methods used to identify the infectious agents, including microscopy and molecular techniques for species-level identification. We also added the appropriate references to support the statements about the severity and potential fatality of ISOFI. In the case report, we included the details of the diagnostic techniques used for fungal and bacterial identification, as well as the susceptibility testing methods, ensuring that clinically approved methods were specified. The dosage of fluconazole has been included, and we corrected the formatting for species names as requested throughout the manuscript." } ] } ]	1	https://f1000research.com/articles/13-1232
https://f1000research.com/articles/14-31/v1	06 Jan 25	{ "type": "Brief Report", "title": "Expression status transition of NOTCH1 accompanies chromatin remodeling in human early retinal progenitor cells", "authors": [ "Yoshitoku Watabe", "Sakurako Kobayashi", "Takahiro Nakayama", "Satoru Takahashi", "Masaharu Yoshihara", "Yoshitoku Watabe", "Sakurako Kobayashi", "Takahiro Nakayama", "Satoru Takahashi" ], "abstract": "Background The regulation of receptor expression is crucial for fine-tuned signal transduction. Notch signaling is a key signaling pathway involved in retinal development. Although the involvement of this signaling pathway in the differentiation of retinal ganglion cells has been documented, less is known about its involvement in earlier stages of retinal progenitor cell differentiation. We aimed to clarify the timing of Notch receptor expression in undifferentiated retinal progenitor cells and elucidate the possible involvement of chromatin remodeling in the regulation of Notch receptor expressions.\n\nMethods We re-analyzed publicly available human fetal retina single-cell RNA-seq and ATAC-seq data (GSE183684) using Seurat/Signac pipelines.\n\nResults On days 59, 74, and 78, we observed NOTCH1 mRNA expression in early retinal progenitor cells, which diminished at later stages of differentiation. Integration of single-cell RNA-seq and ATAC-seq revealed that chromatin remodeling in part of the NOTCH1 locus was accompanied by transitions in its mRNA expression. Importantly, chromatin accessibility in the region upstream of NOTCH1 depended on the differentiated cell types.\n\nConclusions These results suggest that chromatin remodeling may be involved in the differential expression of NOTCH1, although another type of Notch mRNA expression regulation may exist.", "keywords": [ "differentiation", "epigenetics", "eye development", "single-cell ATAC-seq", "single-cell RNA-seq" ], "content": "Introduction\n\nSignal transduction depends on the expression of receptors regulated at multiple levels. These regulations include chromatin remodeling and DNA-binding proteins, such as transcription factors and transcriptional repressors. Because fine-tuned signal transduction is necessary for development, it is important to clarify the regulatory mechanisms of receptor expression.\n\nNotch signaling in mammals is dependent on the binding of five canonical DSL ligands and four Notch receptors.1 It has been suggested that Notch loci are subject to chromatin remodeling under both normal2–7 and pathological8–16 conditions. In terms of developmental biology, the retina is a good model for investigating cellular differentiation involving Notch signaling.17 The developed retina is composed of multiple cell types, including retinal ganglion cells, bipolar cells, photoreceptors, amacrine cells, horizontal cells, and Müllar glial cells, all of which originate from the retinal progenitor cells (RPCs). RPC is characterized by the expression of Lhx2, Pax6, Rax, and Vsx2 while there are some additional marker genes for developing horizontal cells/retinal ganglion cells (Onecut1/2),18 developing amacrine cells (Elavl2/4),19 developing photoreceptors/amacrine cells/Müllar glial cells (Eef1a1),20 developing retinal ganglion cells (Meis2),21 developing horizontal cells (Lhx1, Ptf1a),22 and glial cells (Pax2).23 Of the four Notch receptors in mammals, Notch1, has been suggested to be involved in the maintenance of RPCs and differentiation into retinal ganglion cells.24 However, it is unclear when and how Notch receptor expression is switched on and off in RPCs during early differentiation. Here, we re-analyzed a public multi-omics dataset of single-cell RNA-seq and single-cell ATAC-seq from three human fetal retinas25 to clarify the timing of Notch receptor expression and examine the involvement of chromatin remodeling in this receptor expression switch.\n\n\nMethods\n\nA single-cell multi-omics dataset (GSE183684)25 was downloaded from the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/); data from days 59, 74, and 78 in the dataset were selectively used because they contained many undifferentiated retinal progenitor cells. The data were processed in Seurat version 5.1.026 and Signac version 1.14.027 pipelines in R version 4.4.1 on the Ubuntu 22.04.4 LTS environment. Pseudotime analysis and integration of the single-cell RNA-seq data and the single-cell ATAC-seq data was conducted by using the “FindTransferAnchors” function of Signac and Monocle3 version 1.3.7,28 respectively. The conditions used in the analysis are provided in the GitHub repository.\n\n\nResults\n\nFirst, early gestational stage samples were characterized (day 59). Uniform manifold approximation and projection (UMAP) analysis of single-cell RNA-seq identified 13 clusters ( Figure 1A), which were further characterized by marker gene expression ( Figure 1B). This sample primarily contained RPCs with various differentiation statuses except for PAX2-expressing glial cells. Early RPCs (RPC1-3 and MKI67-expressing Proliferating RPC) were characterized by LHX2, PAX6, RAX, and VSX2. In addition, pseudotime analysis suggested that these RPCs differentiated into either ONECUT1/2-expressing, ELAVL2/4-expressing, or EEF1A1-expressing RPCs ( Figure 1C). Next, we examined Notch mRNA expression and found that NOTCH1-3 were expressed primarily in early RPCs, with NOTCH1 and NOTCH3 being the most prominent genes ( Figure 1D). Then, we re-analyzed single-cell ATAC-seq data for this day 59 sample, which was mathematically integrated with its single-cell RNA-seq data by using the “FindTransferAnchors” function of Signac ( Figure 1E). In the early RPCs (RPC1/2 and MKI67-expressing Proliferating RPC), we observed peaks between Chr9 136510000-136520000 of the NOTCH1 gene, which diminished in the other RPC clusters. These results imply that Notch expression transition during RPC differentiation might be associated with the chromatin remodeling of NOTCH1 ( Figure 1F). However, we noted that chromatin accessibility of the upstream region of the NOTCH1 locus remained high in ONECUT1/2-expressing RPCs. In contrast to these populations, chromatin accessibility of the NOTCH1 locus in ELAVL2/4-expressing RPCs was very low, which was consistent with the low mRNA expression in these RPC populations. In addition, the chromatin accessibility of the NOTCH3 locus remained unchanged during RPC differentiation, although its mRNA expression diminished ( Figure 1G). Since NOTCH2 and NOTCH4 were less prominent, the feature plots of the marker genes and the dot plots of the Notch genes from single-cell RNA-seq along with coverage plots of NOTCH2 and NOTCH4 from single-cell ATAC-seq are available in “Additional_file_1” in our GitHub repository.\n\n(A) UMAP analysis of the single-cell RNA-seq data identified 13 clusters. (B) Dot plot of marker genes. Note that early RPC clusters expressed LHX2, PAX6, RAX, and VSX2. (C) Monocle3 pseudotime analysis for clarifying the differentiation status. (D) Feature plot of NOTCH1-4. Note that NOTCH1 and NOTCH3 expression was prominent in the early RPC clusters. (E) UMAP analysis of the single-cell ATAC-seq data, which was integrated with the single-cell RNA-seq data. (F) The coverage plot of the NOTCH1 locus showing the chromatin accessibility. Note that the upstream of the gene is on the right. (G) The coverage plot of the NOTCH3 locus. Note that the upstream of the gene is on the right.\n\nTo examine whether the changes in Notch mRNA expression and chromatin accessibility of the Notch loci in the day 59 sample were representative, we investigated another early gestational stage sample (day 74). UMAP analysis identified 15 clusters ( Figure 2A) that were further characterized by marker gene expression ( Figure 2B). This sample primarily contained RPCs with various differentiation statuses. Early RPCs (RPC1-6) were characterized by LHX2, PAX6, RAX, and VSX2. In addition, pseudotime analysis suggested that these RPCs differentiated into either ELAVL2/4-expressing, ONECUT1/MEIS2-expressing, or ONECUT2-expressing RPCs ( Figure 2C). ONECUT1/MEIS2-expressing RPCs differentiated into RPCs that markedly expressed VSX2. Next, we examined Notch mRNA expression and found that NOTCH1-3 were expressed primarily in early RPCs, with NOTCH1 and NOTCH3 being the most prominent genes, similar to the day 59 sample ( Figure 2D). We then re-analyzed the single-cell ATAC-seq data for this sample, which were integrated with the single-cell RNA-seq data ( Figure 2E). In the early RPCs (RPC1-3), we observed peaks between Chr9 136510000-136520000 of the NOTCH1 gene, which diminished in the other RPC clusters. These results confirmed that Notch expression transition during RPC differentiation might be associated with the chromatin remodeling of NOTCH1 ( Figure 2F). However, we noted that the chromatin accessibility of the upstream region of the NOTCH1 locus remained high in ONECUT-expressing RPCs. In contrast to these populations, the chromatin accessibility of the NOTCH1 locus in ELAVL2/4-expressing RPCs was very low, which was consistent with the low mRNA expression in these RPC populations. In addition, the chromatin accessibility of the NOTCH3 locus remained unchanged during RPC differentiation ( Figure 2G). In summary, similar to the day 59 sample, in the day 74 sample, a concomitant mRNA decrease and chromatin remodeling in NOTCH1 were observed, while chromatin accessibility in the upstream region of the NOTCH1 locus remained high in ONECUT-expressing RPCs. The feature plots of the marker genes and dot plots of the Notch genes from single-cell RNA-seq along with coverage plots of NOTCH2 and NOTCH4 from single-cell ATAC-seq are available in “Additional_file_2” in our GitHub repository.\n\n(A) UMAP analysis of the single-cell RNA-seq data identified 15 clusters. (B) Dot plot of marker genes. Note that early RPC clusters expressed LHX2, PAX6, RAX, and VSX2. (C) Monocle3 pseudotime analysis. (D) Feature plot of NOTCH1-4. Note that NOTCH1 and NOTCH3 expression were prominent in the early RPC clusters. (E) UMAP analysis of the single-cell ATAC-seq data which was integrated with the single-cell RNA-seq data. (F) The coverage plot of the NOTCH1 locus. (G) The coverage plot of the NOTCH3 locus.\n\nTo further confirm the developmental changes in Notch mRNA expression and chromatin accessibility at the Notch loci, we investigated an additional early gestational stage sample (day 78). UMAP analysis identified 17 clusters ( Figure 3A) that were further characterized by marker gene expression ( Figure 3B). The sample primarily contained RPCs with various differentiation statuses. Early RPCs (RPC1-3 and MKI67-expressing Proliferating RPC1-2 cells) were characterized by LHX2, PAX6, RAX, and VSX2. In addition, pseudotime analysis suggested that these RPCs differentiated into ONECUT1/2-expressing RPCs, which later differentiated into PTF1A and LHX1-expressing RPCs, MEIS2-expressing RPCs, or ELAVL2/4-expressing RPCs ( Figure 3C). Next, we examined Notch mRNA expression and found that NOTCH1-3 were expressed primarily in early RPCs, with NOTCH1 and NOTCH3 being the most prominent genes ( Figure 3D). We then re-analyzed the single-cell ATAC-seq data for the day 78 sample, which was integrated with the single-cell RNA-seq data ( Figure 3E). In the early RPCs (RPC1-3), we observed peaks between Chr9 136510000-136520000 of the NOTCH1 gene, which diminished in the other RPC clusters ( Figure 3F). However, we noted that the chromatin accessibility of the upstream region of the NOTCH1 locus remained high in ONECUT-expressing RPCs. In contrast to these populations, the chromatin accessibility of the NOTCH1 locus in ELAVL2/4-expressing RPCs was very low, which was consistent with the low mRNA expression in these RPC populations. In addition, the chromatin accessibility of the NOTCH3 locus remained unchanged during RPC differentiation ( Figure 3G). In summary, examination of all three independent samples suggested that NOTCH1 mRNA expression decreased, which was concomitant with chromatin remodeling in Chr9 136510000-136520000 of the NOTCH1 locus. The feature plots of the marker genes and the dot plots of the NOTCH genes from single-cell RNA-seq along with coverage plots of NOTCH2 and NOTCH4 from single-cell ATAC-seq are available in “Additional_file_3” in our GitHub repository.\n\n(A) UMAP analysis of the single-cell RNA-seq data identified 17 clusters. (B) Dot plot of marker genes. Note that early RPC clusters expressed LHX2, PAX6, RAX, and VSX2. (C) Monocle3 pseudotime analysis. (D) Feature plot of NOTCH1-4. Note that NOTCH1 and NOTCH3 expression were prominent in early RPC clusters. (E) UMAP analysis of the single-cell ATAC-seq data which was integrated with the single-cell RNA-seq data. (F) The coverage plot of the NOTCH1 locus. (G) The coverage plot of the NOTCH3 locus.\n\n\nDiscussion\n\nThe involvement of Notch signaling in cell fate choices is well documented, including in Drosophila neurogenesis29 and mammalian biliary development.30 Although the regulation of Notch receptor expression is necessary for these processes, to the best of our knowledge, few studies have used genome-wide investigations of the underlying molecular mechanisms. To examine chromatin remodeling in such regulatory mechanisms, we re-analyzed a single-cell RNA-seq and ATAC-seq dataset from developing retinas in which differentiation trajectories were well characterized. By re-analyzing three independent samples, we observed chromatin remodeling in part of the NOTCH1 locus, concomitant with changes in its mRNA expression during RPC differentiation.\n\nTranscriptional regulation occurs at many levels, including DNA-binding proteins and miRNAs, as well as chromatin remodeling. Importantly, the chromatin accessibility of the upstream regions of the NOTCH1 locus was unaffected in ONECUT-expressing RPCs. Therefore, the observed mRNA changes might be driven by pathways other than chromatin remodeling. Indeed, NOTCH3 mRNA expression also diminished during differentiation, although we observed no chromatin remodeling in the NOTCH3 locus. Because chromatin accessibility in ELAVL2/4-expressing RPCs was very low, this ensured low mRNA expression of NOTCH1.\n\nAn ophthalmological study revealed that the epigenetic landscape of cell type-specific enhancers shifted during differentiation of RPCs.31 For example, in the single-cell ATAC-seq data from embryonic day 14.5 mouse retina, motif enrichment for Lhx2, Rax and Pax6 in the early RPCs were observed, and footprinting analysis validated binding of those transcription factors to their motifs. These high chromatin accessibilities decreased as they differentiated into retinal ganglion cells and non-retinal ganglion cells. Although that study is excellent in providing comprehensive and in-depth insights, ours is unique in focusing on the Notch loci for clarifying the regulatory mechanisms in view of Notch signaling biology.\n\nFinally, we note that further investigations, such as a large deletion of these regions, will be needed to evaluate the contribution of the identified chromatin remodeling to the differential expression of Notch receptors in RPC subsets.\n\nThis study does not generate new data from human. Therefore, we consider that there are no special requirements on recruitment and publication. In addition, this study does not involve analysis of animals and plants.\n\nNot applicable.\n\n\nAuthors’ contributions\n\nY. W.: Data Curation, Formal Analysis, Software, Visualization, Writing – Original Draft Preparation\n\nS.K.: Writing – Original Draft Preparation\n\nT.N.: Writing – Original Draft Preparation\n\nS.T.: Supervision, Writing – Review & Editing\n\nM.Y.: Conceptualization, Formal Analysis, Funding Acquisition, Methodology, Project Administration, Software, Writing – Original Draft Preparation", "appendix": "Data availability\n\nA single-cell multiomics dataset (GSE183684)18 was downloaded from the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE183684).\n\nThe original data in the present study including additional data available from: https://github.com/Yoshitokky/Notch1_retina_multiomics_data/tree/main.32\n\nArchived software available from: https://doi.org/10.5281/zenodo.14507019.32\n\nLicense: OSI approved open license software is under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nThe project contains the following underlying data:\n\n• Additional_file_1.jpg (Extended data for d59 data).\n\n• Additional_file_2.jpg (Extended data for d74 data).\n\n• Additional_file_3.jpg (Extended data for d78 data).\n\n• Figure 1A. png\n\n• Figure 1B. png\n\n• Figure 1C. png\n\n• Figure 1D_NOTCH1.png\n\n• Figure 1D_NOTCH2.png\n\n• Figure 1D_NOTCH3.png\n\n• Figure 1D_NOTCH4.png\n\n• Figure 1E. png\n\n• Figure 1F. png\n\n• Figure 1G. png\n\n• Figure 2A. png\n\n• Figure 2B. png\n\n• Figure 2C. png\n\n• Figure 2D_NOTCH1.png\n\n• Figure 2D_NOTCH2.png\n\n• Figure 2D_NOTCH3.png\n\n• Figure 2D_NOTCH4.png\n\n• Figure 2E. png\n\n• Figure 2F. png\n\n• Figure 2G. png\n\n• Figure 3A. png\n\n• Figure 3B. png\n\n• Figure 3C. png\n\n• Figure 3D_NOTCH1.png\n\n• Figure 3D_NOTCH2.png\n\n• Figure 3D_NOTCH3.png\n\n• Figure 3D_NOTCH4.png\n\n• Figure 3E. png\n\n• Figure 3F. png\n\n• Figure 3G. png\n\n• Additional_file_1_A.png\n\n• Additional_file_1_B.png\n\n• Additional_file_1_C.png\n\n• Additional_file_1_D.png\n\n• Additional_file_2_A.png\n\n• Additional_file_2_B.png\n\n• Additional_file_2_C.png\n\n• Additional_file_2_D.png\n\n• Additional_file_3_A.png\n\n• Additional_file_3_B.png\n\n• Additional_file_3_C.png\n\n• Additional_file_3_D.png\n\n\nAcknowledgements\n\nThe authors thank Editage (https://www.editage.jp) for their support with English language editing.\n\n\nReferences\n\nKopan R, Ilagan MX: The canonical Notch signaling pathway: unfolding the activation mechanism. 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PubMed Abstract \| Publisher Full Text\n\nTanimizu N, Miyajima A: Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors. J. Cell Sci. 2004; 117: 3165–3174. PubMed Abstract \| Publisher Full Text\n\nGe Y, Chen X, Nan N, et al.: Key transcription factors influence the epigenetic landscape to regulate retinal cell differentiation. Nucleic Acids Res. 2023; 51: 2151–2176. PubMed Abstract \| Publisher Full Text \| Free Full Text\n\nWatabe Y, Yoshihara M: Notch1_retina_multiomics_data. GitHub.2024-12-9. [Computer software]. Reference Source\n\nWatabe Y, Yoshihara M: Notch1_retina_multiomics_software. GitHub.2024-12-9. [Computer software]. Reference Source" }	[ { "id": "359501", "date": "05 Feb 2025", "name": "Mariko Kashiwagi", "expertise": [ "Reviewer Expertise Skin biology", "Immunology", "Gene regulation" ], "suggestion": "Approved With Reservations", "report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nRemarks to the Author:\nIn this manuscript, the authors investigated whether NOTCH family genes (NOTCH1–4) were expressed in retinal progenitor cells (RPCs) and whether changes in chromatin accessibility at promoter regions contributed to their transcriptional activation. To address these questions, they reanalyzed publicly available single-nucleus RNA sequencing (snRNA-seq) and snATAC-seq datasets of the human fetal retina across three developmental stages (GSE183684). Overall, the analytical pipelines are valid and appropriately implemented. However, several concerns regarding the experimental design and the interpretation of the results require further consideration.\nMajor Concerns and Comments: 1. Chromatin Accessibility Analysis: During development, enhancer regions play a crucial role in dynamic, lineage-specific gene regulation by modulating chromatin structure and recruiting transcription factors. In contrast, promoter regions generally maintain a more stable configuration following cellular differentiation into a specific lineage. With this in mind, I recommend that the authors expand their chromatin accessibility analysis beyond the promoter and gene body to include the 5' upstream and 3' downstream regions. This broader approach may provide a more comprehensive understanding of how various regulatory elements, including enhancers, contribute to the transcriptional regulation of NOTCH genes.\n2. Interpretation of the Results: The authors stated in the text that \"NOTCH1-3 were expressed primarily in early RPCs, with NOTCH1 and NOTCH3 being the most prominent genes.\" However, this claim is not fully supported by the data (Fig. 1D, Additional File 1B; Fig. 2D, Additional File 2B; Fig. 3D, Additional File 3B). A comprehensive interpretation of the three developmental stages suggests that NOTCH1 was the predominant isoform expressed in early RPC clusters, although expression levels varied across clusters and stages. At day 59, the expression hierarchy was NOTCH2 > NOTCH3, whereas at days 74 and 78, NOTCH2 and NOTCH3 exhibited similar expression levels. The authors are advised to interpret these data more carefully.\nAdditionally, although NOTCH2 expression was consistently observed across all three stages (days 59, 74, and 78), the corresponding ATAC peaks were either absent or very low. The manuscript did not provide any discussion of this discrepancy. The authors should address this issue to clarify the relationship between chromatin accessibility and NOTCH2 expression, while also discussing whether this discrepancy may stem from technical limitations or reflect underlying biological factors.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly", "responses": [] } ]	1	https://f1000research.com/articles/14-31

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